Reduction in parvalbumin expression not loss of the parvalbumin-expressing GABA interneuron subpopulation in genetic parvalbumin and shank mouse models of autism
Open accessAbstract
BACKGROUND: A reduction of the number of parvalbumin (PV)-immunoreactive (PV(+)) GABAergic interneurons or a decrease in PV immunoreactivity was reported in several mouse models of autism spectrum disorders (ASD). This includes Shank mutant mice, with SHANK being one of the most important gene families mutated in human ASD. Similar findings were obtained in heterozygous (PV+/-) mice for the Pvalb gene, which display a robust ASD-like phenotype. Here, we addressed the question whether the observed reduction in PV immunoreactivity was the result of a decrease in PV expression levels and/or loss of the PV-expressing GABA interneuron subpopulation hereafter called "Pvalb neurons". The two alternatives have important implications as they likely result in opposing effects on the excitation/inhibition balance, with decreased PV expression resulting in enhanced inhibition, but loss of the Pvalb neuron subpopulation in reduced inhibition. METHODS: Stereology was used to determine the number of Pvalb neurons in ASD-associated brain regions including the medial prefrontal cortex, somatosensory cortex and striatum of PV-/-, PV+/-, Shank1-/- and Shank3B-/- mice. As a second marker for the identification of Pvalb neurons, we used Vicia Villosa Agglutinin (VVA), a lectin recognizing the specific extracellular matrix enwrapping Pvalb neurons. PV protein and Pvalb mRNA levels were determined quantitatively by Western blot analyses and qRT-PCR, respectively. RESULTS: Our analyses of total cell numbers in different brain regions indicated that the observed "reduction of PV(+) neurons" was in all cases, i.e., in PV+/-, Shank1-/- and Shank3B-/- mice, due to a reduction in Pvalb mRNA and PV protein, without any indication of neuronal cell decrease/loss of Pvalb neurons evidenced by the unaltered numbers of VVA(+) neurons. CONCLUSIONS: Our findings suggest that the PV system might represent a convergent downstream endpoint for some forms of ASD, with the excitation/inhibition balance shifted towards enhanced inhibition due to the down-regulation of PV being a promising target for future pharmacological interventions. Testing whether approaches aimed at restoring normal PV protein expression levels and/or Pvalb neuron function might reverse ASD-relevant phenotypes in mice appears therefore warranted and may pave the way for novel therapeutic treatment strategies.
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Written from the paper’s full text.
TL;DR
In genetic mouse models of autism (PV+/-, PV-/-, Shank1-/-, Shank3B-/-), reduced PV immunoreactivity reflected lower Pvalb mRNA/PV protein rather than loss of Pvalb neurons, since VVA+ neuron numbers were unchanged. The authors conclude PV down-regulation may be a convergent ASD endpoint shifting excitation/inhibition balance toward enhanced inhibition.
Key findings
- In PV+/- mice, PV+ cells were reduced to ~60% of WT across mPFC, SSC, and striatum, while VVA+ cell numbers were unchanged (average 98% of WT); PV-/- mice had essentially no PV+ cells but VVA+ numbers averaged 99% of WT.
- In Shank1-/- SSC, PV+ cells were reduced to 62% of WT with unchanged VVA+ cells; in Shank3B-/- striatum, PV+ cells were reduced to ~58% of WT with unchanged VVA+ cells.
- PV protein and Pvalb mRNA were reduced by ~50% in PV+/- mice; in Shank3B-/- striatum, mRNA was 53 ± 8% and protein 50 ± 9% of WT, with similar transcriptional down-regulation in Shank1-/-.
- Co-localization showed ~70% double-labeled PV+/VVA+ cells in WT vs ~55% in PV+/-; ~75% of PV+ cells were VVA-surrounded in all regions with no WT vs PV+/- difference, while VVA+ cells expressing PV fell from ~68% in WT to ~45% in PV+/-.
Methods
- Stereology using the optical fractionator was used to estimate PV+ and VVA+ cell numbers in mPFC, SSC, and striatum of postnatal day 25 male PV+/+, PV+/-, PV-/-, Shank1-/-, and Shank3B-/- mice; an EGFP-Pvalb reporter line was also used.
- PV protein levels were measured by Western blot with calbindin D-28k, GAPDH, or Ponceau Red normalization; Pvalb mRNA was measured by qRT-PCR normalized to 18S rRNA.
- Five animals per genotype from heterozygous breedings were analyzed, including littermate controls; statistics used Student’s t-test for mRNA/protein and one-way ANOVA with Tukey’s post hoc test for stereology.
Limitations
- No dedicated limitations section is included; the authors note that VVA/PNN staining is developmentally and layer-dependent, activity-regulated, and altered under pathological conditions, and that PNN overlap with PV+ neurons is not absolute.
- Evident from the text: only male mice were used, all analyses were at PND25, and stereological quantification focused on selected regions (mPFC, SSC, striatum), with some regional comparisons assessed only qualitatively.
- Evident from the text: the study reports correlational down-regulation of PV and does not test whether restoring PV expression or Pvalb neuron function reverses ASD-relevant phenotypes.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
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- Findingown data
An average of the three regions resulted in VVA+ values of 98% and 99% of WT control for PV+/- and PV-/-, respectively.
“An average of the three regions resulted in values of 98 % and 99 % of WT control for PV+/- and PV-/-, respectively”
Quote in the paperSubstantial claim - Findingown data
In PV+/- mice, VVA+ cells showing PV staining were on average 45%, approximately one third fewer double-labeled cells compared to WT.
“Values were clearly lower in PV+/- mice, on average 45 %, i.e., approximately one third fewer double-labeled cells compared to WT (Fig. 3a, right).”
Quote in the paperSubstantial claim - Findingown data
No positive staining for PV was detectable in sections from PV-/- mice.
“no positive staining for PV was detectable in the sections from PV-/- mice (Fig. 1).”
Quote in the paperSubstantial claim - Findingown data
On average, PV+ cells in PV+/- mice were reduced to 60% of PV+/+ controls.
“On average, PV+ cells in PV+/- mice were reduced to 60 % of PV+/+ controls”
Quote in the paperNot a substantial claim - Findingown data
There was a significant reduction in the number of PV+ interneurons in PV+/- and PV-/- mice compared to PV+/+ in all ROIs.
“We observed a significant reduction in the number of PV+ interneurons in PV+/- and PV-/- mice compared to PV+/+ in all ROIs.”
Quote in the paperNot a substantial claim
- Findingown data
The count of PV+ cells in PV-/- mice was essentially zero.
“Evidently, the count in PV-/- cells was essentially zero.”
Quote in the paperSubstantial claim - Findingown data
VVA+ cells that also showed PV staining accounted for around 68% in PV+/+ mice for all three ROIs.
“Vice versa, VVA+ cells that also showed PV staining accounted for around 68 % in PV+/+ mice for all the three ROIs.”
Quote in the paperNot a substantial claim - Findingown data
In Shank3B-/- striatum, the number of PV+ cells also expressing VVA was even slightly increased.
“Interestingly, in the Shank3B-/- mice, the number of PV+ cells also expressing VVA was even slightly increased (Fig. 6a, right).”
Quote in the paperNot a substantial claim - Findingown data
The percentage of double-labeled (PV+VVA+) cells was in the order of 70% in PV+/+ and 55% in PV+/- brains.
“The percentage of double-labeled cells was rather homogeneous among brain regions and in the order of 70 % in PV+/+ and 55 % in PV+/- brains (Fig. 3a, middle).”
Quote in the paperSubstantial claim - Findingown data
PV protein levels in the forebrain of PND25 PV+/- mice were reduced by approximately 50% determined by semi-quantitative Western blot analyses.
“PV protein levels in the forebrain of PND25 PV+/- mice were reduced by approximately 50 % determined by semi-quantitative Western blot analyses (Fig. 3b)”
Quote in the paperSubstantial claim - Findingown data
In Shank3B-/- striatum, PV mRNA and protein expression levels were significantly lower, to 53 ± 8 and 50 ± 9 % of PV+/+ levels for mRNA and protein, respectively.
“Both RT-PCR and Western blot analysis revealed the PV mRNA and protein expression levels to be significantly lower, i.e., to 53 ± 8 and 50 ± 9 % of PV+/+ levels for mRNA and protein, respectively (Fig. 7b, c).”
Quote in the paperSubstantial claim - Findingown data
In Shank3B-/- cortex and hippocampus, qualitative immunofluorescence images revealed no obvious differences.
“Qualitatively, immunofluorescence images of cortex (Fig. 7a, b) and hippocampus (Fig. 7c, d) revealed no obvious differences”
Quote in the paperNot a substantial claim - Findingown data
Pvalb mRNA levels were decreased to a similar extent (≈50%) in PV+/- mice.
“Pvalb mRNA levels were decreased to a similar extent (≈50 %)”
Quote in the paperSubstantial claim - Findingown data
In Shank3B-/- striatum, co-localization studies revealed a decrease of double-labeled cells, mostly resulting from a reduction in PV+ cells showing VVA staining.
“The co-localization studies also revealed a decrease of double-labeled cells, again mostly resulting from a reduction in PV+ cells showing VVA staining (Fig. 6a, middle).”
Quote in the paperSubstantial claim - Findingown data
Cell counts of EGFP+ cells in PV+/+EGFP mice revealed the number of positive cells to be nearly identical to either PV+ or VVA+ cell numbers in the three ROIs.
“Cell counts of EGFP+ cells in PV+/+EGFP mice revealed the number of positive cells to be nearly identical to either PV+ or VVA+ cell numbers in the three ROIs, i.e., mPFC, SSC and striatum (Table 3).”
Quote in the paperSubstantial claim - Findingown data
The difference in double-labeled cells between genotypes was significant in all ROIs.
“The difference between genotypes was significant in all ROIs.”
Quote in the paperSubstantial claim - Findingown data
There were no significant differences in the number of VVA+ cells between all three genotypes and all three ROIs.
“With respect to the number of VVA+ cells, no significant differences existed between all three genotypes and all three ROIs (Fig. 3a, left).”
Quote in the paperSubstantial claim - Findingown data
A decrease in PV protein levels and Pvalb mRNA levels to approximately 50% of WT occurred in both Shank mutants.
“A decrease in PV protein levels and Pvalb mRNA levels to approximately 50 % of WT in both Shank mutants are in full support of a down-regulation of PV.”
- Also stated in: § Conclusions · plain
“while PV protein and Pvalb mRNA levels were decreased by approximately 50 %.”
Quote in the paperSubstantial claim- Rests on an assumption: CB expression levels were unchanged in Shank3B-/- mice.
- Also stated in: § Conclusions · plain
- Findingown data
Qualitatively, immunofluorescence images of cortex and hippocampus revealed no obvious differences in PV+ neurons between WT and Shank3B-/- mice.
“Qualitatively, immunofluorescence images of cortex (Fig. 7a, b) and hippocampus (Fig. 7c, d) revealed no obvious differences between WT (a, c) and Shank3B-/- (b, d) mice.”
Quote in the paperSubstantial claim - Findingown data
In both Shank ASD models, the number of PV+ cells was decreased.
“and the number of PV+ cells was decreased”
Quote in the paperSubstantial claim - Findingown data
In both Shank knockout ASD models, PV protein expression levels were decreased in brain regions normally expressing high levels of either Shank1 or Shank3 in WT mice.
“Thus, in both Shank knockout ASD models, PV protein expression levels were decreased in those brain regions normally expressing high levels of either Shank1 or Shank3 in WT mice”
Quote in the paperSubstantial claim- Rests on an assumption: CB expression levels were unchanged in Shank3B-/- mice.
- Findingown data
In Shank3B-/- mice, PV Western blot signals in cortex and hippocampus were not significantly different from WT (100 ± 15% in WT vs. 103 ± 25% in Shank3B-/-; n = 5 mice per genotype; p = 0.78).
“Quantitatively, the PV Western blot signals (Fig. 7e) were not significantly different between genotypes (100 ± 15 % in WT vs. 103 ± 25 %; in Shank3B-/-; mean ± S.D., n = 5 mice per genotype; p = 0.78).”
Quote in the paperSubstantial claim- Rests on an assumption: CB expression levels were unchanged in Shank3B-/- mice.
- Findingown data
The percentage of PV+ cells enwrapped by PNN (VVA+) was not different between sections from WT and PV+/- mice.
“While the percentage of PV+ cells enwrapped by PNN (VVA+) was not different between sections from WT and PV+/- mice”
Quote in the paperSubstantial claim - Findingown data
In all three ASD models there was no evidence for a Pvalb neuron loss.
“Importantly, in all three ASD models there was no evidence for a Pvalb neuron loss.”
Quote in the paperSubstantial claim - Findingown data
In both Shank ASD models, the VVA+ cell number was unchanged.
“In both ASD models, the VVA+ cell number was unchanged”
Quote in the paperSubstantial claim - Findingcitation
In agreement with previous results in cortex and hippocampus of adult PV-/- mice, there was no indication of a cell decrease/loss of Pvalb neurons.
“In agreement with previous results obtained in the cortex and hippocampus of adult PV-/- mice [55, 57], there was no indication of a cell decrease/loss of Pvalb neurons.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [55] Vreugdenhil M, Jefferys JG, Celio MR, Schwaller B. Parvalbumin-deficiency facilitates repetitive IPSCs and gamma oscillations in the hippocampus. J Neurophysiol. 2003;89(3):1414–22. source
Not checked in the free run.
- cites [57] Schwaller B, Tetko IV, Tandon P, Silveira DC, Vreugdenhil M, Henzi T, et al. Parvalbumin deficiency affects network properties resulting in increased susceptibility to epileptic seizures. Mol Cell Neurosci. 2004;25(4):650–63. source
Not checked in the free run.
- Findingcitation
In the first step, stereology showed that the number of VVA+ cells was unchanged in mice with reduced (PV+/-) or absent (PV-/-) PV expression in the mPFC, SSC and striatum.
“Thus, in the first step we ascertained by stereology [60] that the number of VVA+ cells was unchanged in mice with reduced (PV+/-) or absent (PV-/-) PV expression in the mPFC, SSC and striatum.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [60] West MJ, Slomianka L, Gundersen HJ. Unbiased stereological estimation of the total number of neurons in thesubdivisions of the rat hippocampus using the optical fractionator. Anat Rec. 1991;231(4):482–97. doi: 10.1002/ar.1092310411 . source
Not checked in the free run.
- Findingown data
In both Shank ASD models, the percentage of PV+ cells among all VVA+ cells was decreased.
“also evidenced by the decreased percentage of PV+ cells among all VVA+ cells.”
Quote in the paperSubstantial claim - Findingown data
The morphology of PNNs in PV-/- animals does not differ from that of WT mice.
“The morphology of PNNs in PV-/- animals does not differ from the one of WT mice.”
Quote in the paperNot a substantial claim - Findingown data
Analyses of double-labeled (VVA+ and PV+) cells revealed approximately 70-80% of co-stained cells within the mPFC, SSC and striatum of WT mice.
“Analyses of double-labeled (VVA+ and PV+) cells using either the total of PV+ or VVA+ cells for normalization revealed approximately 70–80 % of co-stained cells within the mPFC, SSC and striatum of WT mice.”
Quote in the paperSubstantial claim - Findingown data
Stereological analysis of Pvalb neurons in PV+/- and PV-/- mice revealed their numbers to be unaltered in comparison to WT mice.
“Stereological analysis of Pvalb neurons in mice heterozygous and homozygous for a deletion of the functional Pvalb gene (PV+/- and PV-/- mice, respectively, both showing an ASD-like phenotype) revealed their numbers to be unaltered in comparison to WT mice.”
Quote in the paperSubstantial claim - Premisecitation
A decrease in PV staining intensity and puncta density of PV-ir neurons contacting pyramidal cells in the mouse insular cortex has been reported in Shank3B-/- mice.
“a decrease in PV staining intensity and puncta density of PV-ir neurons contacting pyramidal cells in the mouse insular cortex has been reported in Shank3B-/- mice [76].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [76] Gogolla N, Takesian AE, Feng G, Fagiolini M, Hensch TK. Sensory integration in mouse insular cortex reflects GABA circuit maturation. Neuron. 2014;83(4):894–905. doi: 10.1016/j.neuron.2014.06.033 . source
Not checked in the free run.
- Premisecitation
Shank1-/- and Shank3B-/- mice display behavioral phenotypes with relevance to all core symptoms of ASD in humans.
“The two models display behavioral phenotypes with relevance to all core symptoms of ASD in humans [38–40]”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [38] Jiang YH, Ehlers MD. Modeling autism by SHANK gene mutations in mice. Neuron. 2013;78(1):8–27. doi: 10.1016/j.neuron.2013.03.016 . source
Not checked in the free run.
- cites [39] Herbert MR. SHANK3, the synapse, and autism. N Engl J Med. 2011;365(2):173–5. doi: 10.1056/NEJMcibr1104261 . source
Not checked in the free run.
- cites [40] Wohr M. Ultrasonic vocalizations in Shank mouse models for autism spectrum disorders: detailed spectrographic analyses and developmental profiles. Neurosci Biobehav Rev. 2014;43:199–212. doi: 10.1016/j.neubiorev.2014.03.021 . source
Not checked in the free run.
- Interpretationown data
In Shank1-/- SSC, PV down-regulation occurs at the transcriptional level.
“demonstrating that the PV down-regulation occurs at the transcriptional level.”
Quote in the paperSubstantial claim - Interpretationown data
The PV system might represent a convergent downstream endpoint for some forms of ASD.
“Our findings suggest that the PV system might represent a convergent downstream endpoint for some forms of ASD”
Quote in the paperSubstantial claim - Interpretationnone given
The excitation/inhibition balance is shifted towards enhanced inhibition due to the down-regulation of PV.
“with the excitation/inhibition balance shifted towards enhanced inhibition due to the down-regulation of PV”
Quote in the paperNot a substantial claim - Premisenone given
Decreased PV expression results in enhanced inhibition.
“decreased PV expression results in enhanced inhibition.”
Quote in the paperSubstantial claim - Interpretationown data
The number of VVA+ cells represents a reliable estimate of the Pvalb cells.
“This indicates that the number of VVA+ cells represents a reliable estimate of the Pvalb cells.”
Quote in the paperSubstantial claim - Interpretationown data
The decrease in Pvalb mRNA and PV protein in PV+/- mice is indicative of regulation at the transcriptional level.
“indicative of a regulation at the transcriptional level (Fig. 3c).”
Quote in the paperNot a substantial claim - Interpretationown data
Co-localization results in Shank1-/- are essentially identical to PV+/- strongly indicative of PV down-regulation and not PV+ cell loss.
“Also results from the co-localization experiments (Fig. 4a, middle & right) are essentially identical to the ones of PV+/- strongly indicative of PV down-regulation and not PV+ cell loss.”
Quote in the paperSubstantial claim - Study design and conductcitation
VVA staining was used as a reliable marker for visualizing Pvalb neurons, irrespective of reduced or absent PV expression.
“Since neither the morphology nor the distribution of PNNs were shown to be altered in PV+/- and PV-/- mice in comparison to PV+/+ mice [57, 69], VVA staining was used as reliable marker for visualizing the specific neuronal subpopulation of “PV-FSI” cells, defined as Pvalb neurons, irrespective of reduced or absent PV expression in PV+/- and PV-/- mice, respectively.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [57] Schwaller B, Tetko IV, Tandon P, Silveira DC, Vreugdenhil M, Henzi T, et al. Parvalbumin deficiency affects network properties resulting in increased susceptibility to epileptic seizures. Mol Cell Neurosci. 2004;25(4):650–63. source
Not checked in the free run.
- cites [69] Haunso A, Ibrahim M, Bartsch U, Letiembre M, Celio MR, Menoud P. Morphology of perineuronal nets in tenascin-R and parvalbumin single and double knockout mice. Brain Res. 2000;864(1):142–5. source
Not checked in the free run.
- Premisecitation
Mice with reduced PV expression (PV+/-) or without PV (PV-/-) display a robust ASD-like phenotype.
“mice with reduced PV expression (PV+/-) or without PV (PV-/-) display a robust ASD-like phenotype [48]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [48] Wohr M, Orduz D, Gregory P, Moreno H, Khan U, Vorckel KJ, et al. Lack of parvalbumin in mice leads to behavioral deficits relevant to all human autism core symptoms and related neural morphofunctional abnormalities. Translat Psychiatry. 2015;5, e525. doi: 10.1038/tp.2015.19 . source
Not checked in the free run.
- Interpretationown data
Results in SSC of Shank1-/- mice were highly similar to the ones observed in SSC of PV+/- mice.
“Results in the SSC of Shank1-/- mice were highly similar to the ones observed in the SSC of PV+/- mice.”
Quote in the paperSubstantial claim - Interpretationreasoning
The impairment in GABAergic function reported in both Shank models is likely to impact on the Ca2+-dependent excitability-transcription (E/T) coupling including transcription of the Pvalb gene.
“Thus, the impairment in GABAergic function reported in both Shank models is likely to impact on the Ca2+-dependent excitability-transcription (E/T) coupling including transcription of the Pvalb gene.”
Quote in the paperSubstantial claim - Premisecitation
In Shank3 knockout mice, a reduction in PV+ puncta staining (intensity and puncta numbers) around pyramidal cells in the insular cortex of Shank3B-/- mice was associated with weakened GABAergic circuit function and impaired postnatal pruning.
“In Shank3 knockout mice, a reduction in PV+ puncta staining (intensity and puncta numbers) around pyramidal cells in the insular cortex of Shank3B-/- mice was associated with weakened GABAergic circuit function and impaired postnatal pruning [76].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [76] Gogolla N, Takesian AE, Feng G, Fagiolini M, Hensch TK. Sensory integration in mouse insular cortex reflects GABA circuit maturation. Neuron. 2014;83(4):894–905. doi: 10.1016/j.neuron.2014.06.033 . source
Not checked in the free run.
- Premisecitation
Canonical ASD mouse models were shown to display a reduction in the number of PV-immunoreactive cells in various brain regions.
“As already reported in several studies [47, 72–74] canonical ASD mouse models were shown to display a reduction in the number of PV-immunoreactive cells in various brain regions.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [47] Gogolla N, Leblanc JJ, Quast KB, Sudhof TC, Fagiolini M, Hensch TK. Common circuit defect of excitatory-inhibitory balance in mouse models of autism. J Neurodev Disord. 2009;1(2):172–81. doi: 10.1007/s11689-009-9023-x . source
Not checked in the free run.
- cites [72] Selby L, Zhang C, Sun QQ. Major defects in neocortical GABAergic inhibitory circuits in mice lacking the fragile X mental retardation protein. Neurosci Lett. 2007;412(3):227–32. doi: 10.1016/j.neulet.2006.11.062 . source
Not checked in the free run.
- cites [73] Sadakata T, Washida M, Iwayama Y, Shoji S, Sato Y, Ohkura T, et al. Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients. J Clin Invest. 2007;117(4):931–43. doi: 10.1172/JCI29031 . source
Not checked in the free run.
- cites [74] Tripathi PP, Sgado P, Scali M, Viaggi C, Casarosa S, Simon HH, et al. Increased susceptibility to kainic acid-induced seizures in Engrailed-2 knockout mice. Neuroscience. 2009;159(2):842–9. doi: 10.1016/j.neuroscience.2009.01.007 . source
Not checked in the free run.
- Interpretationown data
The decrease in PV protein and Pvalb mRNA levels in both Shank mutants supports a down-regulation of PV.
“A decrease in PV protein levels and Pvalb mRNA levels to approximately 50 % of WT in both Shank mutants are in full support of a down-regulation of PV.”
Quote in the paperSubstantial claim - Interpretationown data
The decrease in PV protein expression in both Shank knockout ASD models likely arises from alterations at the transcriptional level, in view of the similar decrease in Pvalb mRNA.
“Thus, in both Shank knockout ASD models, PV protein expression levels were decreased in those brain regions normally expressing high levels of either Shank1 or Shank3 in WT mice likely arising from alterations at the transcriptional level, in view of the similar decrease in Pvalb mRNA.”
- Also stated in: § Discussion · hedged
“The similar magnitude in down-regulation of PV and Pvalb mRNA in both Shank mutants is indicative of a regulation at the transcriptional level.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · hedged
- Interpretationown data
The weaker PV staining results in a lower number of neurons considered as positive for PV.
“The weaker staining results in a lower number of neurons considered as positive for PV as shown in Figs. 3, 4 & 6.”
Quote in the paperSubstantial claim - Interpretationreasoning
PV-/- mice likely belong to the group 1 ASD models.
“indicating that PV-/- likely belongs to the group 1 ASD models.”
Quote in the paperSubstantial claim - Interpretationcitation
The demonstration that PV levels are decreased may indicate a shift in the E/I balance towards increased inhibition, taking into account the proven role of PV in synaptic transmission.
“In addition, the demonstration that PV levels are decreased may indicate a shift in the E/I balance towards an increased inhibition, taking into account the proven role of PV in synaptic transmission [52, 53, 55, 97, 98].”
Quote in the paperNot a substantial claim0 of 5 sources checked- cites [52] Manseau F, Marinelli S, Mendez P, Schwaller B, Prince DA, Huguenard JR, et al. Desynchronization of neocortical networks by asynchronous release of GABA at autaptic and synaptic contacts from fast-spiking interneurons. PLoS Biol. 2010. doi: 10.1371/journal.pbio.1000492 .
Not checked in the free run.
- cites [53] Orduz D, Bischop DP, Schwaller B, Schiffmann SN, Gall D. Parvalbumin tunes spike-timing and efferent short-term plasticity in striatal fast spiking interneurons. J Physiol. 2013;591(Pt 13):3215–32. doi: 10.1113/jphysiol.2012.250795 . source
Not checked in the free run.
- cites [55] Vreugdenhil M, Jefferys JG, Celio MR, Schwaller B. Parvalbumin-deficiency facilitates repetitive IPSCs and gamma oscillations in the hippocampus. J Neurophysiol. 2003;89(3):1414–22. source
Not checked in the free run.
- cites [97] Eggermann E, Jonas P. How the ‘slow’ Ca2+ buffer parvalbumin affects transmitter release in nanodomain-coupling regimes. Nat Neurosci. 2012;15(1):20–2. doi: 10.1038/nn.3002 . source
Not checked in the free run.
- cites [98] Alberi L, Lintas A, Kretz R, Schwaller B, Villa AE. The calcium-binding protein parvalbumin modulates the firing 1 properties of the reticular thalamic nucleus bursting neurons. J Neurophysiol. 2013;109(11):2827–41. doi: 10.1152/jn.00375.2012 . source
Not checked in the free run.
- Interpretationown data
In Shank1-/- and Shank3B-/- mice, the number of Pvalb neurons was unchanged in brain regions with high expression of either protein.
“A similar situation as in PV+/- mice prevailed in the two ASD mouse models Shank1-/- and Shank3B-/-: the number of Pvalb neurons was unchanged in brain regions with high expression of either protein”
Quote in the paperSubstantial claim
- May combine two claims. 22
- Classified as probably not a substantial claim. 29
May combine two claims.
Findingown dataThe percentage of PV+ cells surrounded by VVA+ PNNs was ~75% in all ROIs and there were no significant differences between PV+/+ and PV+/- mice.
“This percentage was found to be ~75 % in all the ROIs and there were no significant differences between PV+/+ and PV+/- mice (Fig. 3a, right).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn Shank1-/- striatum, there were no prominent differences in staining intensity and PV+ neuron density between WT and Shank1-/- mice.
“Qualitatively, immunofluorescence images revealed no prominent differences with respect to staining intensity and PV+ neuron density between WT and Shank1-/- mice in the striatum (Fig. 5).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn Shank1-/- SSC, the number of PV+ cells was significantly reduced to 62% of PV+/+ while the number of VVA+ cells was unaltered.
“The number of PV+ cells was significantly reduced to 62 % of PV+/+ in Shank1-/- mice, while the number of VVA+ cells was unaltered (Fig. 4a, left & Table 4)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn Shank3B-/- striatum, the number of VVA+ cells was unchanged, while the number of PV+ cells was reduced to approximately 58%.
“While the number of VVA+ cells was unchanged, the number of PV+ cells was reduced to approximately 58 % (Fig. 6a, left & Table 4).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn Shank1-/- SSC, both PV mRNA and protein levels were significantly decreased.
“quantitative RT-PCR results and moreover Western blots showed that both PV mRNA level and protein levels, respectively (Fig. 4b, c), were significantly decreased”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn PV+/- mice, both the total number of PV+ cells and the percentage of VVA+ cells expressing PV were significantly decreased in all regions analyzed.
“as the result of decreased PV protein expression levels in PV+/- mice, both the total number of PV+ cells, as well as the percentage of VVA+ cells expressing PV was significantly decreased in all regions analyzed in our study.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningAll identified PV+ cells were highly likely to show VVA staining, while in a fraction of VVA+ cells, PV expression levels, more prominently in PV+/- mice, were below the predefined PV expression threshold and were thus not considered as double-labeled cells.
“This indicates that all identified PV+ cells were highly likely to show VVA staining, while in a fraction of VVA+ cells, PV expression levels, more prominently in PV+/- mice were below the predefined PV expression threshold and were thus not considered as double-labeled cells.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisereasoningA quantitative and systematic analysis of Pvalb neurons by unbiased stereology in mPFC, SSC and striatum was still missing.
“a quantitative and systematic analysis of Pvalb neurons by unbiased stereology in different brain regions including ASD-implicated regions such as the medial prefrontal cortex (mPFC), somatosensory cortex (SSC) and striatum was still missing.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [55] Vreugdenhil M, Jefferys JG, Celio MR, Schwaller B. Parvalbumin-deficiency facilitates repetitive IPSCs and gamma oscillations in the hippocampus. J Neurophysiol. 2003;89(3):1414–22. source
Not checked in the free run.
- cites [57] Schwaller B, Tetko IV, Tandon P, Silveira DC, Vreugdenhil M, Henzi T, et al. Parvalbumin deficiency affects network properties resulting in increased susceptibility to epileptic seizures. Mol Cell Neurosci. 2004;25(4):650–63. source
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisereasoningGenetic Shank mouse models display behavioral alterations with relevance to all human ASD core symptoms.
“genetic Shank mouse models display behavioral alterations with relevance to all human ASD core symptoms.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationPV plays a key role in the regulation of local inhibitory effects on pyramidal neurons and other interneurons.
“all together provide evidence that PV plays a key role in the regulation of local inhibitory effects on pyramidal neurons, as well as on other interneurons (for more details, see [56]).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [56] Schwaller B. The use of transgenic mouse models to reveal the functions of Ca2+ buffer proteins in excitable cells. Biochim Biophys Acta. 2012;1820(8):1294–303. doi: 10.1016/j.bbagen.2011.11.008 . source
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Classified as probably not a substantial claim.
PremisecitationA reduction of about 20-25% in the number of PV-immunoreactive (PV+) neurons has been reported in ASD individuals and mouse ASD models.
“a reduction in the order of 20–25 % in the number of PV-immunoreactive (PV+) neurons has been reported in ASD individuals [46] and mouse ASD models [47]”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [46] Zikopoulos B, Barbas H. Altered neural connectivity in excitatory and inhibitory cortical circuits in autism. Front Hum Neurosci. 2013;7:609. doi: 10.3389/fnhum.2013.00609 . source
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- cites [47] Gogolla N, Leblanc JJ, Quast KB, Sudhof TC, Fagiolini M, Hensch TK. Common circuit defect of excitatory-inhibitory balance in mouse models of autism. J Neurodev Disord. 2009;1(2):172–81. doi: 10.1007/s11689-009-9023-x . source
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May combine two claims.
PremisecitationExpression patterns of Shank1 and Shank3 are different: high mRNA levels of Shank1 in cortex and hippocampus and of Shank3 in striatum and cortex.
“high mRNA levels of Shank1 in cortex and hippocampus and of Shank3 in striatum and cortex [36, 77]”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [36] Peca J, Feliciano C, Ting JT, Wang W, Wells MF, Venkatraman TN, et al. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature. 2011;472(7344):437–42. doi: 10.1038/nature09965 . source
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- cites [77] Bockers TM, Segger-Junius M, Iglauer P, Bockmann J, Gundelfinger ED, Kreutz MR, et al. Differential expression and dendritic transcript localization of Shank family members: identification of a dendritic targeting element in the 3’ untranslated region of Shank1 mRNA. Mol Cell Neurosci. 2004;26(1):182–90. doi: 10.1016/j.mcn.2004.01.009 . source
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May combine two claims.
Interpretationown dataWhile PV expression levels were decreased, the number of Pvalb cells was unchanged.
“indicating that while PV expression levels were decreased, the number of Pvalb cells was unchanged (Table 3).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe SHANK gene family is one of the most important gene families mutated in ASD.
“One of the most important gene families mutated in ASD is the SHANK gene family [9]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [9] Leblond CS, Nava C, Polge A, Gauthier J, Huguet G, Lumbroso S, et al. Meta-analysis of SHANK mutations in autism spectrum disorders: a gradient of severity in cognitive impairments. PLoS Genet. 2014;10(9), e1004580. doi: 10.1371/journal.pgen.1004580 . source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPV-expressing interneurons seem to be highly impacted in several neuropsychiatric disorders including schizophrenia, bipolar disorder and ASD.
“Among these specific subpopulations, PV-expressing interneurons seem to be highly impacted in several neuropsychiatric disorders including schizophrenia, bipolar disorder and ASD [45].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [45] Marin O. Interneuron dysfunction in psychiatric disorders. Nat Rev Neurosci. 2012;13(2):107–20. doi: 10.1038/nrn3155 . source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationShank1-/- and Shank3B-/- mice cover the extremes of the ASD spectrum with a gradient in severity in mental retardation.
“Shank1-/- and Shank3B-/- mice, covering the extremes of the spectrum with a gradient in severity in mental retardation.”
- Also stated in: § PV expression levels are reduced in two canonical ASD models, Shank1-/- and Shank3B-/-, while VVA+ Pvalb neuron numbers are unaltered · plain
“cover the extremes of the spectrum with a gradient in severity in mental retardation [9].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [9] Leblond CS, Nava C, Polge A, Gauthier J, Huguet G, Lumbroso S, et al. Meta-analysis of SHANK mutations in autism spectrum disorders: a gradient of severity in cognitive impairments. PLoS Genet. 2014;10(9), e1004580. doi: 10.1371/journal.pgen.1004580 . source
Not checked in the free run.
- Also stated in: § PV expression levels are reduced in two canonical ASD models, Shank1-/- and Shank3B-/-, while VVA+ Pvalb neuron numbers are unaltered · plain
May combine two claims.
Interpretationown dataIn Shank3B-/- striatum, counting and co-localization results show globally similar results as for PV+/- and Shank1-/- mice, i.e., a reduction of PV expression in the unchanged number of striatal VVA+ cells.
“However, counting and co-localization results show globally similar results as for PV+/- and Shank1-/- mice, i.e., a reduction of PV expression in the unchanged number of striatal VVA+ cells.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationCE values ranged from 0.06 to 0.10, indicating sufficient precision of the estimates for both cell populations.
“CE values ranged from 0.06 to 0.10 (Table 1) indicating a sufficient precision of the estimates for both cell populations [63].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [63] Gundersen HJ, Jensen EB, Kieu K, Nielsen J. The efficiency of systematic sampling in stereology--reconsidered. J Microsc. 1999;193(Pt 3):199–211. source
Not checked in the free run.
Classified as probably not a substantial claim.
Premisenone givenGlobal PV expression levels as well as the ones in PV+ neurons in various brain regions are currently unknown in Shank1-/- and Shank3B-/- mouse mutants.
“Global PV expression levels as well as the ones in PV+ neurons in various brain regions are currently unknown in these two mouse mutants”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataData from the two hemispheres were pooled because no differences were encountered when comparing ROIs of the two hemispheres in the same animal.
“Since no differences were encountered when comparing the ROIs of the two hemispheres in the same animal, data were pooled together and analyzed.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductreasoningThe optical fractionator method does not require measurement of tissue volume, so the cell number estimate is valid even if tissue volume changes during processing.
“Since the fractionator method does not require a measurement of tissue volume or any other dimensional quality, the cell number estimate is valid, even if the tissue volume changes during processing.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [60] West MJ, Slomianka L, Gundersen HJ. Unbiased stereological estimation of the total number of neurons in thesubdivisions of the rat hippocampus using the optical fractionator. Anat Rec. 1991;231(4):482–97. doi: 10.1002/ar.1092310411 . source
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- cites [62] West MJ, Ostergaard K, Andreassen OA, Finsen B. Estimation of the number of somatostatin neurons in the striatum: an in situ hybridization study using the optical fractionator method. J Comp Neurol. 1996;370(1):11–22. doi: 10.1002/(SICI)1096-9861(19960617)370:1<11::AID-CNE2>3.0.CO;2-O . source
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May combine two claims.
PremisecitationAbsence of PV in PV-/- Pvalb neurons does not affect basal synaptic transmission but enhances facilitation and shortens delayed transmitter release.
“The absence of PV in PV-/- Pvalb neurons does not affect basal synaptic transmission, but enhances facilitation [49, 50] and shortens delayed transmitter release [51].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [49] Caillard O, Moreno H, Schwaller B, Llano I, Celio MR, Marty A. Role of the calcium-binding protein parvalbumin in short-term synaptic plasticity. Proc Natl Acad Sci U S A. 2000;97(24):13372–7. source
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- cites [50] Muller M, Felmy F, Schwaller B, Schneggenburger R. Parvalbumin is a mobile presynaptic Ca2+ buffer in the calyx of held that accelerates the decay of Ca2+ and short-term facilitation. J Neurosci. 2007;27(9):2261–71. source
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- cites [51] Collin T, Chat M, Lucas MG, Moreno H, Racay P, Schwaller B, et al. Developmental changes in parvalbumin regulate presynaptic Ca2+ signaling. J Neurosci. 2005;25(1):96–107. source
Not checked in the free run.
Probably not a substantial claim: may not pass S4 (based).
Premisenone givenLoss of the Pvalb neuron subpopulation is likely to result in reduced inhibition.
“while loss of the Pvalb neuron subpopulation is likely to result in reduced inhibition”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductown dataCalbindin D-28k (CB) levels were unaltered in PV-/- mice and in Shank1-/- and Shank3B-/- brains, supporting their use as loading controls.
“The levels of PV signals were normalized to calbindin D-28k (CB) signals, a protein previously shown to be unaltered in PV-/- mice [57, 66] to control for differences in loading. CB levels were found to be unaltered in Shank1-/- and Shank3B-/- brains (data not shown).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [57] Schwaller B, Tetko IV, Tandon P, Silveira DC, Vreugdenhil M, Henzi T, et al. Parvalbumin deficiency affects network properties resulting in increased susceptibility to epileptic seizures. Mol Cell Neurosci. 2004;25(4):650–63. source
Not checked in the free run.
- cites [66] Chen G, Racay P, Bichet S, Celio MR, Eggli P, Schwaller B. Deficiency in parvalbumin, but not in calbindin D-28k upregulates mitochondrial volume and decreases smooth endoplasmic reticulum surface selectively in a peripheral, subplasmalemmal region in the soma of Purkinje cells. Neuroscience. 2006;142(1):97–105. source
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Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataNo significant differences existed between PV signals quantitatively evaluated by either normalization method.
“No significant differences existed between PV signals quantitatively evaluated by either normalization method (not shown).”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationcitationThe enfeebled GABAergic circuit function reported in Shank3B-/- and Shank1-/- mice is likely to decrease somatic Ca2+ signals and subsequently modify the Ca2+ signaling components of Pvalb neurons.
“The enfeebled GABAergic circuit function reported in Shank3B-/- [76] and Shank1-/- mice [96] is likely to decrease somatic Ca2+ signals and subsequently modify the Ca2+ signaling components of Pvalb neurons”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [76] Gogolla N, Takesian AE, Feng G, Fagiolini M, Hensch TK. Sensory integration in mouse insular cortex reflects GABA circuit maturation. Neuron. 2014;83(4):894–905. doi: 10.1016/j.neuron.2014.06.033 . source
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- cites [96] Mao W, Watanabe T, Cho S, Frost JL, Truong T, Zhao X, et al. Shank1 regulates excitatory synaptic transmission in mouse hippocampal parvalbumin-expressing inhibitory interneurons. Eur J Neurosci. 2015;41(8):1025–35. doi: 10.1111/ejn.12877 . source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationA neuronal activity-related Ca2+-dependent transcriptional regulation of PV expression was proposed before.
“a neuronal activity-related Ca2+-dependent transcriptional regulation of PV expression was proposed before [100].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [100] Berridge MJ. Calcium signalling and psychiatric disease: bipolar disorder and schizophrenia. Cell Tissue Res. 2014;357(2):477–92. doi: 10.1007/s00441-014-1806-z . source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA further link exists between Shank protein expression and Pvalb neurons.
“A further link exists between Shank protein expression and Pvalb neurons [76, 96].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [76] Gogolla N, Takesian AE, Feng G, Fagiolini M, Hensch TK. Sensory integration in mouse insular cortex reflects GABA circuit maturation. Neuron. 2014;83(4):894–905. doi: 10.1016/j.neuron.2014.06.033 . source
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- cites [96] Mao W, Watanabe T, Cho S, Frost JL, Truong T, Zhao X, et al. Shank1 regulates excitatory synaptic transmission in mouse hippocampal parvalbumin-expressing inhibitory interneurons. Eur J Neurosci. 2015;41(8):1025–35. doi: 10.1111/ejn.12877 . source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn the few human studies, a decrease in PV+ cells and/or PVALB mRNA was reported.
“Also in the few human studies, a decrease in PV+ cells and/or PVALB mRNA was reported [46, 86].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [46] Zikopoulos B, Barbas H. Altered neural connectivity in excitatory and inhibitory cortical circuits in autism. Front Hum Neurosci. 2013;7:609. doi: 10.3389/fnhum.2013.00609 . source
Not checked in the free run.
- cites [86] Stoner R, Chow ML, Boyle MP, Sunkin SM, Mouton PR, Roy S, et al. Patches of disorganization in the neocortex of children with autism. N Engl J Med. 2014;370(13):1209–19. doi: 10.1056/NEJMoa1307491 . source
Not checked in the free run.
May combine two claims.
PremisecitationAbsence/down-regulation of PV in PV-/- and PV+/- mice affects the properties of Pvalb neurons and of neurons impacting on Pvalb cells, and leads to a robust ASD-like behavioral phenotype characterized by impaired social interaction behavior, reduced pro-social ultrasonic vocalizations and deficits in reversal learning.
“Absence/down-regulation of PV in PV-/- and PV+/- mice, respectively, not only affects the properties of the Pvalb neurons, but also of neurons impacting on Pvalb cells, and leads to a robust ASD-like behavioral phenotype characterized by impaired social interaction behavior, reduced pro-social ultrasonic vocalizations and deficits in reversal learning [48].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [48] Wohr M, Orduz D, Gregory P, Moreno H, Khan U, Vorckel KJ, et al. Lack of parvalbumin in mice leads to behavioral deficits relevant to all human autism core symptoms and related neural morphofunctional abnormalities. Translat Psychiatry. 2015;5, e525. doi: 10.1038/tp.2015.19 . source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAlterations in other genes implicated in E/T coupling have been observed before in ASD individuals and include Ca2+ signaling components such as Cav1.2 (CACNA1C), Cav1.3 (CACNA1D) and the α-δ auxiliary subunit of L-type voltage-gated Ca2+ channels (CACNA2D3).
“Alterations in other genes implicated in E/T coupling have been observed before in ASD individuals and include Ca2+ signaling components such as the voltage-dependent channels Cav1.2 (CACNA1C), Cav1.3 (CACNA1D) and the α-δ auxiliary subunit of L-type voltage-gated Ca2+ channels (CACNA2D3) [102, 103].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [102] De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014;515(7526):209–15. doi: 10.1038/nature13772 . source
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- cites [103] Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet. 2013;381(9875):1371–9. doi: 10.1016/S0140-6736(12)62129-1 . source
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PremisecitationIn striatal PV+ FSI, the increased facilitation (increased inhibition) between FSI and medium spiny neurons (MSN) caused by the absence of PV in PV-/- mice is partly compensated by a decrease in the excitatory synaptic input from cortical pyramidal cells, a mechanism hypothesized to compensate for the increased output of PV-/- neurons.
“In striatal PV+ FSI the increased facilitation (increased inhibition) between FSI and medium spiny neurons (MSN) caused by the absence of PV in PV-/-mice [53] is partly compensated by a decrease in the excitatory synaptic input from cortical pyramidal cells, a mechanism hypothesized to compensate for the increased output of PV-/- neurons [48].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [53] Orduz D, Bischop DP, Schwaller B, Schiffmann SN, Gall D. Parvalbumin tunes spike-timing and efferent short-term plasticity in striatal fast spiking interneurons. J Physiol. 2013;591(Pt 13):3215–32. doi: 10.1113/jphysiol.2012.250795 . source
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- cites [48] Wohr M, Orduz D, Gregory P, Moreno H, Khan U, Vorckel KJ, et al. Lack of parvalbumin in mice leads to behavioral deficits relevant to all human autism core symptoms and related neural morphofunctional abnormalities. Translat Psychiatry. 2015;5, e525. doi: 10.1038/tp.2015.19 . source
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Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).
PremisecitationThe networks containing Pvalb neurons were hypothesized to be strongly implicated in ASD.
“Thus, the networks containing Pvalb neurons were hypothesized to be strongly implicated in ASD [45].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [45] Marin O. Interneuron dysfunction in psychiatric disorders. Nat Rev Neurosci. 2012;13(2):107–20. doi: 10.1038/nrn3155 . source
Not checked in the free run.
Classified as probably not a substantial claim.
Premisenone givenIn most studies the reduction in PV-immunoreactive cells was assumed to result from a cell loss of the PV+ subpopulation.
“In most studies this was assumed to result from a cell loss of the PV+ subpopulation.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationMore than 900 patients with genetic alterations in SHANK genes were identified, with the SHANK gene family being the primary gene family implicated in ASD.
“The selection among the many ASD mouse models available was based on the fact that more than 900 patients with genetic alterations in SHANK genes were identified, with the SHANK gene family being the primary gene family implicated in ASD [9].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [9] Leblond CS, Nava C, Polge A, Gauthier J, Huguet G, Lumbroso S, et al. Meta-analysis of SHANK mutations in autism spectrum disorders: a gradient of severity in cognitive impairments. PLoS Genet. 2014;10(9), e1004580. doi: 10.1371/journal.pgen.1004580 . source
Not checked in the free run.
May combine two claims.
PremisecitationSimilar to the most consistent finding in humans, an increase in the frontal and parieto-temporal lobes and decreased volume of the cerebellar cortex were observed in one of three subgroups (group 1) identified among 26 investigated ASD mouse models.
“Similar to the most consistent finding in humans [94, 95], an increase in the frontal and parieto-temporal lobes and decreased volume of the cerebellar cortex were observed in one of the three subgroups (“group 1”) identified among the 26 investigated models [75].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [75] Ellegood J, Anagnostou E, Babineau BA, Crawley JN, Lin L, Genestine M, et al. Clustering autism: using neuroanatomical differences in 26 mouse models to gain insight into the heterogeneity. Mol Psychiatry. 2014;20(1):118–25. doi: 10.1038/mp.2014.98 . source
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- cites [94] Palmen SJ, van Engeland H, Hof PR, Schmitz C. Neuropathological findings in autism. Brain. 2004;127(Pt 12):2572–83. doi: 10.1093/brain/awh287 . source
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- cites [95] Amaral DG, Schumann CM, Nordahl CW. Neuroanatomy of autism. Trends Neurosci. 2008;31(3):137–45. doi: 10.1016/j.tins.2007.12.005 . source
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Classified as probably not a substantial claim.
PremisecitationA decrease in the number of PV+ cells has been reported in many genetic ASD mouse models in various brain regions including mPFC, SSC and striatum.
“a decrease in the number of PV+ cells has been reported in many genetic ASD mouse models in various brain regions including mPFC, SSC and striatum; (see Table S1 in [48])”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [48] Wohr M, Orduz D, Gregory P, Moreno H, Khan U, Vorckel KJ, et al. Lack of parvalbumin in mice leads to behavioral deficits relevant to all human autism core symptoms and related neural morphofunctional abnormalities. Translat Psychiatry. 2015;5, e525. doi: 10.1038/tp.2015.19 . source
Not checked in the free run.
May combine two claims.
PremisecitationIn Shank1-/- hippocampal PV+ FSI, the absence of Shank1 functionally leads to a decrease in excitatory synaptic inputs and inhibitory synaptic outputs to pyramidal neurons and to molecular changes including down-regulation of postsynaptic proteins GKAP, PSD-95 and gephyrin.
“In Shank1-/- hippocampal PV+ FSI the absence of Shank1 functionally leads to a decrease in excitatory synaptic inputs and inhibitory synaptic outputs to pyramidal neurons and furthermore to molecular changes including the down-regulation of the postsynaptic proteins GKAP, PSD-95 and gephyrin [96].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [96] Mao W, Watanabe T, Cho S, Frost JL, Truong T, Zhao X, et al. Shank1 regulates excitatory synaptic transmission in mouse hippocampal parvalbumin-expressing inhibitory interneurons. Eur J Neurosci. 2015;41(8):1025–35. doi: 10.1111/ejn.12877 . source
Not checked in the free run.
May combine two claims.
PremisecitationSimilar neuroanatomical changes are present in PV-/- (Pvalb) mice, i.e., a transient cortical hypertrophy and a decrease in cerebellar volume at young age.
“Similar neuroanatomical changes are present in PV-/- (Pvalb) mice, i.e., a transient cortical hypertrophy and a decrease in cerebellar volume at young age [48]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [48] Wohr M, Orduz D, Gregory P, Moreno H, Khan U, Vorckel KJ, et al. Lack of parvalbumin in mice leads to behavioral deficits relevant to all human autism core symptoms and related neural morphofunctional abnormalities. Translat Psychiatry. 2015;5, e525. doi: 10.1038/tp.2015.19 . source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPV plays an important role in Ca2+ homeostasis regulating many aspects of neuronal signaling (short-term plasticity, synchronization, precision of spike timing, etc.) in the subpopulation of PV+ interneurons.
“PV plays an important role in the Ca2+ homeostasis regulating many aspects of neuronal signaling (short-term plasticity, synchronization, precision of spike timing, etc.) in the subpopulation of PV+ interneurons [56].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [56] Schwaller B. The use of transgenic mouse models to reveal the functions of Ca2+ buffer proteins in excitable cells. Biochim Biophys Acta. 2012;1820(8):1294–303. doi: 10.1016/j.bbagen.2011.11.008 . source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationKnockout mice in group 1 including null mutants for En2, Fmr1 and Shank3 show an increase in the frontal and parieto-temporal lobes and a volume decrease in the cerebellum, as well as a decrease in PV staining.
“Knockout mice in group 1 including null mutants for En2, Fmr1 and Shank3 show an increase in the frontal and parieto-temporal lobes and a volume decrease in the cerebellum, as well as a decrease in PV staining.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [75] Ellegood J, Anagnostou E, Babineau BA, Crawley JN, Lin L, Genestine M, et al. Clustering autism: using neuroanatomical differences in 26 mouse models to gain insight into the heterogeneity. Mol Psychiatry. 2014;20(1):118–25. doi: 10.1038/mp.2014.98 . source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn the mouse cortical V1 region, 82% of all VVA+ cells were found to also express PV.
“Similar numbers were reported in the mouse cortical V1 region, where 82 % of all VVA+ cells were found to also express PV [87].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [87] Ye Q, Miao QL. Experience-dependent development of perineuronal nets and chondroitin sulfate proteoglycan receptors in mouse visual cortex. Matrix Bio. 2013;32(6):352–63. doi: 10.1016/j.matbio.2013.04.001 . source
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May combine two claims.
PremisecitationShank1 and Shank3 mouse models were selected to cover both extremes of the spectrum, namely SHANK1 mutations found in individuals with ASD and normal intelligence and SHANK3 mutations associated with severe mental retardation.
“Shank1 and Shank3 mouse models were selected to cover both extremes of the spectrum, namely SHANK1 mutations found in individuals with ASD and normal intelligence and SHANK3 mutations associated with severe mental retardation [9].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [9] Leblond CS, Nava C, Polge A, Gauthier J, Huguet G, Lumbroso S, et al. Meta-analysis of SHANK mutations in autism spectrum disorders: a gradient of severity in cognitive impairments. PLoS Genet. 2014;10(9), e1004580. doi: 10.1371/journal.pgen.1004580 . source
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe modification of the E/I balance within the PV-circuitry in PV-/- mice is reminiscent of the situation in schizophrenia, where NMDA receptor hypofunction leads to the reduction of GAD67 levels and thus GABA synthesis.
“The modification of the E/I balance within the PV-circuitry in PV-/- mice is reminiscent of the situation in schizophrenia, where NMDA receptor hypofunction leads to the reduction of glutamic acid decarboxylase 67 (GAD67) levels and thus GABA synthesis.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [99] Gonzalez-Burgos G, Lewis DA. NMDA receptor hypofunction, parvalbumin-positive neurons, and cortical gamma oscillations in schizophrenia. Schizophr Bull. 2012;38(5):950–7. doi: 10.1093/schbul/sbs010 . source
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- cites [100] Berridge MJ. Calcium signalling and psychiatric disease: bipolar disorder and schizophrenia. Cell Tissue Res. 2014;357(2):477–92. doi: 10.1007/s00441-014-1806-z . source
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- cites [101] Lewis DA. Inhibitory neurons in human cortical circuits: substrate for cognitive dysfunction in schizophrenia. Curr Opin Neurobiol. 2014;26:22–6. doi: 10.1016/j.conb.2013.11.003 . source
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PremisecitationMorphological changes in PV-/- mice follow the same pattern as group 1: increased neocortical volume and decreased size of the cerebellum.
“Importantly, however, also the morphological changes in PV-/- mice follow the same pattern, as we recently demonstrated: increased neocortical volume and a decreased size of the cerebellum [48].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [48] Wohr M, Orduz D, Gregory P, Moreno H, Khan U, Vorckel KJ, et al. Lack of parvalbumin in mice leads to behavioral deficits relevant to all human autism core symptoms and related neural morphofunctional abnormalities. Translat Psychiatry. 2015;5, e525. doi: 10.1038/tp.2015.19 . source
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Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).
InterpretationcitationThe observed decrease in PV expression in Shank mutant mice might be viewed as an adaptive or compensatory mechanism to possibly restore (increase) synaptic output according to the concept of the Ca2+ homeostasome.
“In summary, the observed decrease in PV expression in Shank mutant mice might be viewed as an adaptive or compensatory mechanism to possibly restore (increase) synaptic output according to the concept of the Ca2+ homeostasome [104].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [104] Schwaller B. The Regulation of a Cell’s Ca2+ Signaling Toolkit: The Ca2+ Homeostasome. Adv Exp Med Biol. 2012;740:1–25. doi: 10.1007/978-94-007-2888-2_1 . source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationEvidence has accumulated that mutated ASD risk genes are critical components of activity-regulated signaling networks often controlling synapse development and morphology, as well as structural and functional plasticity.
“Evidence has accumulated that mutated ASD risk genes are critical components of activity-regulated signaling networks often controlling synapse development and morphology, as well as structural and functional plasticity [8].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [8] Ebert DH, Greenberg ME. Activity-dependent neuronal signalling and autism spectrum disorder. Nature. 2013;493(7432):327–37. doi: 10.1038/nature11860 . source
Not checked in the free run.
Classified as probably not a substantial claim.
InterpretationreasoningBased on the similar magnitude in PV down-regulation and impairment in the E/I balance reported before in all three models, the PV system, in particular reduced PV expression levels, might represent a convergent downstream endpoint for some forms of ASD.
“Based on the similar magnitude in PV down-regulation and impairment in the E/I balance reported before in all three models we hypothesize that the PV system, in particular reduced PV expression levels, might represent a convergent downstream endpoint for some forms of ASD.”
Quote in the paperSubstantial claim
The paper relies on this without support.
CB expression levels were unchanged in Shank3B-/- mice.
“CB was used as loading control for the normalization of the PV signal, since CB expression levels were unchanged in Shank3B-/- mice (data not shown).”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In other mouse models of autism spectrum disorder, reduced PV-INs or decreased PV immunoreactivity has been reported.
“In other mouse models of ASD, a reduction in PV-INs or a decrease in PV immunoreactivity has been reported [20].”
From Parvalbumin interneuron vulnerability and brain disorders (2021) · cites this paper as [20]
Both increase and decrease in the number of PV-IR cells are reported in these models.
“Both increase and decrease in number of PV-IR cells are reported.”
From Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia (2017) · cites this paper as [27]
Shank1 and Shank3B knockout mice show a reduced number of PV-IR cells but no deficit in WFA-labeled perineuronal nets in the somatosensory cortex.
“Moreover, Shank1 and Shank3B KO mice show a reduced number of PV-IR cells but no deficit in WFA-labeled PNN in the somatosensory cortex.27”
From Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia (2017) · cites this paper as [27]
Manipulations of other genes associated with intellectual disability and ASD (e.g., MECP2, NLGN3, Shank3, CNTNAP2) reveal diverse abnormalities within cortical GABAergic circuits.
“Manipulations of other genes associated with intellectual disability and ASD (for example, MECP2, NLGN3, Shank3; CNTNAP2) reveal diverse abnormalities within cortical GABAergic circuits.27, 28, 113, 114, 115”
From Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia (2017) · cites this paper as [27]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Figure 6 caption switches the Shank3B-/- analysis from striatum to SSC
MinorThe caption identifies the left-hand Shank3B-/- counts as striatal but calls the middle-panel double-label counts SSC counts. The results state that the Shank3B-/- analysis focused on the striatum.
“Middle: estimation of double-labeled cells in SSC of PND25 WT and Shank3B-/- mice.”
“For the Shank3B-/- mice we focused on the striatum, a region with high Shank3 expression levels”
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“In addition, the demonstration that PV levels are decreased may indicate a shift in the E/I balance towards an increased inhibition, taking into account the proven role of PV in synaptic transmission [52, 53, 55, 97, 98].”
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“This is consistent with previous findings that show a reduction in PV expression in cortex of mouse models of autism (Filice et al. 2016).”
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A postnatal molecular switch drives activity-dependent maturation of parvalbumin interneurons
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Altered Relationship Between Parvalbumin and Perineuronal Nets in an Autism Model
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The integration site of the APP transgene in the J20 mouse model of Alzheimer’s disease
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Parvalbumin neurons as a hub in autism spectrum disorders
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“…study, it is important to note that the data presented here offer important indications of distinct molecular signatures in well-characterized suicidal individuals, without any major in fl uence of psychotrophic medication, and that they can serve as the basis for designing future targeted studies.”
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- Authors
- Filice, F., Vörckel, K. J., Sungur, A. Ö., Wöhr, M., & Schwaller, B.
- Affiliations
- University of Fribourg (CH)
- Philipps University of Marburg (DE)
- Corresponding author
- Schwaller, Beat
- Venue
- Molecular Brain
- Published
- 2016-01-27
- Volume
- 9
- Issue
- 1
- Pages
- 10-10
- ISSN
- 1756-6606 (ISSN-L)
- PMC
- PMC4729132
- OpenAlex
- W2276586942
- Cited by
- 240
- References
- 109
- Citations by year
- 2026: 15 · 2025: 22 · 2024: 24 · 2023: 30 · 2022: 24 · 2021: 25 · 2020: 26 · 2019: 27 · 2018: 22 · 2017: 19 · 2016: 6
- FWCI
- 15.70
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Brain (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- reroDoc Digital Library (submittedVersion)
- Lirias (submittedVersion, other-oa)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (155952, 130680)
- Deutsche Forschungsgemeinschaft (DFG) (DFG WO 17327/1-1)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- parvalbumin, autism spectrum disorder, Shank1, Shank3B, GABAergic interneurons, excitation-inhibition balance, medial prefrontal cortex, somatosensory cortex, striatum, mouse models of autism
- MeSH terms
- Animals, Autistic Disorder, Cell Count, Cerebral Cortex, Disease Models, Animal, Fluorescent Antibody Technique, Interneurons, Mice, Inbred C57BL, Mice, Mutant Strains, Microfilament Proteins, Nerve Tissue Proteins, Parvalbumins, Prefrontal Cortex, GABAergic Neurons
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.
Statistics and arithmetic are recomputed, not judged.
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