CoChat
Sign Up
Cited by 215Neuroscience and Neuropharmacology ResearchSchizophrenia research and treatmentNeural dynamics and brain function

Parvalbumin interneuron vulnerability and brain disorders

Open access
Ruden, Jacob B., Dugan, Laura L., Konradi, Christine·2021·Neuropsychopharmacology
DOI 10.1038/s41386-020-0778-9PMC PMC7852528
Open this paper in CoChat — free accountOpen PDF

Abstract

Parvalbumin-expressing interneurons (PV-INs) are highly vulnerable to stressors and have been implicated in many neuro-psychiatric diseases such as schizophrenia, Alzheimer's disease, autism spectrum disorder, and bipolar disorder. We examined the literature about the current knowledge of the physiological properties of PV-INs and gathered results from diverse research areas to provide insight into their vulnerability to stressors. Among the factors that confer heightened vulnerability are the substantial energy requirements, a strong excitatory drive, and a unique developmental trajectory. Understanding these stressors and elaborating on their impact on PV-IN health is a step toward developing therapies to protect these neurons in various disease states and to retain critical brain functions.

Integrity signals

Registry

Crossref · 10.1038/s41386-020-0778-9

Cites

148 of 148 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 143 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    People with schizophrenia have a lower density of excitatory synapses on PV-INs.

    “Furthermore, individuals with schizophrenia have a lower density of excitatory synapses on PV-INs [12] and exhibit alterations in gamma oscillations during a working memory task [13].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Chung DW, Fish KN, Lewis DA. Pathological basis for deficient excitatory drive to cortical parvalbumin interneurons in schizophrenia. Am J Psychiatry. 2016;173:1131–9. source

      Not checked in the free run.

  • Premisenone given

    Damage to or malfunction of PV-INs has been proposed to contribute to the pathophysiology of schizophrenia, autism spectrum disorder, bipolar disorder, neurodegenerative diseases, and aging-related cognitive changes.

    “Injury to, or dysfunction of, parvalbumin inhibitory interneurons (PV-INs) has been proposed to contribute to the pathophysiology of several important neuro-psychiatric disorders, including schizophrenia, autism spectrum disorder (ASD), bipolar disorder (BPD), various neurodegenerative diseases, and even aging-related cognitive changes.”
    Quote in the paperSubstantial claim
  • Premisecitation

    People with schizophrenia show altered gamma oscillations during a working memory task.

    “Furthermore, individuals with schizophrenia have a lower density of excitatory synapses on PV-INs [12] and exhibit alterations in gamma oscillations during a working memory task [13].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Barr MS, Farzan F, Tran LC, Chen R, Fitzgerald PB, Daskalakis ZJ. Evidence for excessive frontal evoked gamma oscillatory activity in schizophrenia during working memory. Schizophr Res. 2010;121:146–52. source

      Not checked in the free run.

  • Premisecitation

    Animal models that mimic schizophrenia reproduce the loss of PV-INs in the hippocampus.

    “Animal models that mimic schizophrenia replicate the loss of PV-INs in the hippocampus [6,14,15], and show a loss of PV fluorescence per cell in prelimbic regions [16].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [6] Lodge DJ, Behrens MM, Grace AA. A loss of parvalbumin-containing interneurons is associated with diminished oscillatory activity in an animal model of schizophrenia. J Neurosci. 2009;29:2344–54. source

      Not checked in the free run.

    • cites [14] Koh MT, Shao Y, Sherwood A, Smith DR. Impaired hippocampal-dependent memory and reduced parvalbumin-positive interneurons in a ketamine mouse model of schizophrenia. Schizophr Res. 2016;171:187–94. source

      Not checked in the free run.

    • cites [15] Harrington AJ, Raissi A, Rajkovich K, Berto S, Kumar J, Molinaro G, et al. MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders. eLife 2016;5:e20059. source

      Not checked in the free run.

  • Premisecitation

    Early intervention during the prepubertal period may prevent PV-IN loss in the MAM rat model of ventral hippocampal PV-IN loss.

    “Interestingly, early intervention during the prepubertal period might prevent loss of PV-INs, as shown in the methylazoxymethanol acetate (MAM) rat model of PV-IN loss in the ventral hippocampus [17].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Du Y, Grace AA. Loss of parvalbumin in the hippocampus of MAM schizophrenia model rats is attenuated by peripubertal diazepam. Int J Neuropsychopharmacol. 2016;19:pyw060. source

      Not checked in the free run.

  • May combine two claims. 34
  • Classified as probably not a substantial claim. 9

  • May combine two claims.

    Premisecitation

    PV-expressing interneurons are highly vulnerable to stressors and have been linked to several neuropsychiatric diseases, including schizophrenia, Alzheimer's disease, autism spectrum disorder, and bipolar disorder.

    “Parvalbumin-expressing interneurons (PV-INs) are highly vulnerable to stressors and have been implicated in many neuropsychiatric diseases such as schizophrenia, Alzheimer's disease, autism spectrum disorder, and bipolar disorder.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [1] Konradi C, Yang CK, Zimmerman EI, Lohmann KM, Gresch P, Pantazopoulos H, et al. Hippocampal interneurons are abnormal in schizophrenia. Schizophr Res. 2011;131:165–73. source

      Not checked in the free run.

    • cites [2] Lewis DA, Curley AA, Glausier JR, Volk DW. Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci. 2012;35:57–67. source

      Not checked in the free run.

    • cites [3] Marin O. Interneuron dysfunction in psychiatric disorders. Nat Rev Neurosci. 2012;13:107–20. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    The main factors that make PV-INs especially vulnerable are their large energy demands, strong excitatory input, and distinctive developmental path.

    “Among the factors that confer heightened vulnerability are the substantial energy requirements, a strong excitatory drive, and a unique developmental trajectory.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In schizophrenia, PVALB mRNA levels are lower in the hippocampus and in layer 4 of the dorsolateral prefrontal cortex, and DNA hypermethylation may partly account for this.

    “In schizophrenia, lower levels of PVALB mRNA, the gene coding for PV, were seen in the hippocampus and layer 4 of the dorsolateral prefrontal cortex, which might be partially explained by DNA hypermethylation [1,8].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Konradi C, Yang CK, Zimmerman EI, Lohmann KM, Gresch P, Pantazopoulos H, et al. Hippocampal interneurons are abnormal in schizophrenia. Schizophr Res. 2011;131:165–73. source

      Not checked in the free run.

    • cites [8] Fachim HA, Srisawat U, Dalton CF, Reynolds GP. Parvalbumin promoter hypermethylation in postmortem brain in schizophrenia. Epigenomics. 2018;10:519–24. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Many reports describe PV-IN-related changes in people with schizophrenia, and animal models that reproduce aspects of the disease support this finding.

    “Extensive accounts in the literature point to PV-IN-related changes in individuals with schizophrenia [1][2][3][4], a finding that is supported by various animal models that recapitulate aspects of the disease [5][6][7] (Table 1).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [1] Konradi C, Yang CK, Zimmerman EI, Lohmann KM, Gresch P, Pantazopoulos H, et al. Hippocampal interneurons are abnormal in schizophrenia. Schizophr Res. 2011;131:165–73. source

      Not checked in the free run.

    • cites [2] Lewis DA, Curley AA, Glausier JR, Volk DW. Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci. 2012;35:57–67. source

      Not checked in the free run.

    • cites [3] Marin O. Interneuron dysfunction in psychiatric disorders. Nat Rev Neurosci. 2012;13:107–20. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some human and animal data suggest that PV-INs may remain present but cease to express PV, although a definitive conclusion cannot yet be drawn.

    “Some human and animal model data suggest that formerly PV-INs are still present but cease to express PV, though a definitive conclusion cannot be drawn at this point [7,[18][19][20].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [7] Gill KM, Grace AA. Corresponding decrease in neuronal markers signals progressive parvalbumin neuron loss in MAM schizophrenia model. Int J Neuropsychopharmacol. 2014;17:1609–19. source

      Not checked in the free run.

    • cites [18] Powell SB, Sejnowski TJ, Behrens MM. Behavioral and neurochemical consequences of cortical oxidative stress on parvalbumin-interneuron maturation in rodent models of schizophrenia. Neuropharmacology. 2012;62:1322–31. source

      Not checked in the free run.

    • cites [19] Enwright JF, Sanapala S, Foglio A, Berry R, Fish KN, Lewis DA. Reduced labeling of parvalbumin neurons and perineuronal nets in the dorsolateral prefrontal cortex of subjects with schizophrenia. Neuropsychopharmacology. 2016;41:2206–14. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Stimulating PV-INs increases gamma oscillation patterns, whereas inhibiting PV-INs or downregulating PV at cortical synapses reduces gamma oscillations.

    “Stimulation of PV-INs leads to an increase in gamma oscillation patterns, while inhibition of PV-INs or downregulation of PV at cortical synapses reduces gamma oscillations [76][77][78].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [76] Cardin JA, Carlen M, Meletis K, Knoblich U, Zhang F, Deisseroth K, et al. Driving fast-spiking cells induces gamma rhythm and controls sensory responses. Nature. 2009;459:663–7. source

      Not checked in the free run.

    • cites [77] Sohal VS, Zhang F, Yizhar O, Deisseroth K. Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature. 2009;459:698–702. source

      Not checked in the free run.

    • cites [78] Volman V, Behrens MM, Sejnowski TJ. Downregulation of parvalbumin at cortical GABA synapses reduces network gamma oscillatory activity. J Neurosci. 2011;31:18137–48. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Transgenic mice with AD-like pathology have reduced gamma power, and in one model this reduction precedes cognitive impairment and amyloid plaque formation.

    “Transgenic mice with AD-like pathology were found to have reduced gamma power that, in one model, precedes cognitive impairment and amyloid plaque formation [21,22].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [21] Iaccarino HF, Singer AC, Martorell AJ, Rudenko A, Gao F, Gillingham TZ, et al. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature. 2016;540:230–5. source

      Not checked in the free run.

    • cites [22] Rubio SE, Vega-Flores G, Martinez A, Bosch C, Perez-Mediavilla A, del Rio J, et al. Accelerated aging of the GABAergic septohippocampal pathway and decreased hippocampal rhythms in a mouse model of Alzheimer’s disease. FASEB J. 2012;26:4458–67. source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Because PV rapidly sequesters calcium, it strongly reduces the calcium-activated potassium conductance responsible for postspike hyperpolarization, which partly explains why PV-INs repolarize and fire faster than other neurons.

    “Since PV rapidly sequesters Ca 2+ , it strongly attenuates the Ca 2+ -activated potassium conductance responsible for postspike hyperpolarization, which explains in part why PV-INs repolarize faster and fire faster than other neurons.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Individual PV-INs contact nearly every local pyramidal neuron, which allows them to synchronize networks.

    “Individual PV-INs contact nearly every local pyramidal neuron which enables them to synchronize networks [74].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] Packer AM, Yuste R. Dense, unspecific connectivity of neocortical parvalbumin-positive interneurons: a canonical microcircuit for inhibition? J Neurosci. 2011;31:13260–71. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PV-INs participate in feedforward and feedback inhibition, regulation of sensory responses, and learning and plasticity.

    “PV-INs have roles in both feedforward and feedback inhibition, regulation of sensory responses, and in learning and plasticity [66].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Hu H, Gan J, Jonas P. Interneurons. Fast-spiking, parvalbumin(+) GABAergic interneurons: from cellular design to microcircuit function. Science. 2014;345:1255263. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    There is ample evidence that PV-INs are vital for brain function and closely linked to brain malfunction.

    “There is therefore ample evidence that PV-INs are vital for brain function and intricately linked to brain malfunction.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Epilepsy and prion disease are among other disorders associated with alterations in PV-INs.

    “Epilepsy [63,64] and prion disease [65] are among other disorders that are associated with alterations in PV-INs.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [63] Sloviter RS, Sollas AL, Barbaro NM, Laxer KD. Calcium-binding protein (calbindin-D28K) and parvalbumin immunocytochemistry in the normal and epileptic human hippocampus. J Comp Neurol. 1991;308:381–96. source

      Not checked in the free run.

    • cites [64] Garbelli R, Meroni A, Magnaghi G, Beolchi MS, Ferrario A, Tassi L, et al. Architectural (Type IA) focal cortical dysplasia and parvalbumin immunostaining in temporal lobe epilepsy. Epilepsia. 2006;47:1074–8. source

      Not checked in the free run.

    • cites [65] Guentchev M, Hainfellner JA, Trabattoni GR, Budka H. Distribution of parvalbumin-immunoreactive neurons in brain correlates with hippocampal and temporal cortical pathology in Creutzfeldt-Jakob disease. J Neuropathol Exp Neurol. 1997;56:1119–24. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Schizophrenia shares significant overlap with bipolar disorder, including PV-IN pathology.

    “Schizophrenia also shares significant overlap with BPD [55,56], including PV-IN pathology.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [55] Consortium C-DGotPG, Lee SH, Ripke S, Neale BM, Faraone SV, Purcell SM, et al. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet. 2013;45:984–94. source

      Not checked in the free run.

    • cites [56] Cardno AG, Rijsdijk FV, Sham PC, Murray RM, McGuffin P. A twin study of genetic relationships between psychotic symptoms. Am J Psychiatry. 2002;159:539–45. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PV increases the rate of calcium sequestration, lowers presynaptic calcium levels, modulates short-term synaptic plasticity, and prevents cumulative facilitation.

    “PV increases the rate of Ca 2+ sequestration, reduces presynaptic Ca 2+ levels, modulates short-term synaptic plasticity, and prevents cumulative facilitation (Fig. 1), [67,68].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [67] 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 USA. 2000;97:13372–7. source

      Not checked in the free run.

    • cites [68] Wahr PA, Michele DE, Metzger JM. Parvalbumin gene transfer corrects diastolic dysfunction in diseased cardiac myocytes. Proc Natl Acad Sci USA. 1999;96:11982–5. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nav1.1, a voltage-gated sodium channel found largely on PV-IN axons, is decreased in a mouse model with amyloid pathology and in AD patients.

    “Separately, a voltage-gated sodium channel (Na v 1.1) that is largely found on axons of PV-INs was decreased in a mouse model with amyloid pathology, and in AD patients [24][25][26].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [24] Ogiwara I, Miyamoto H, Morita N, Atapour N, Mazaki E, Inoue I, et al. Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation. J Neurosci. 2007;27:5903–14. source

      Not checked in the free run.

    • cites [25] Wang W, Takashima S, Segawa Y, Itoh M, Shi X, Hwang SK, et al. The developmental changes of Na(v)1.1 and Na(v)1.2 expression in the human hippocampus and temporal lobe. Brain Res. 2011;1389:61–70. source

      Not checked in the free run.

    • cites [26] Verret L, Mann EO, Hang GB, Barth AM, Cobos I, Ho K, et al. Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell. 2012;149:708–21. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Autism spectrum disorder shares clinical overlap with schizophrenia and similar PV-IN abnormalities.

    “ASD shares many overlaps with schizophrenia, not just on a clinical scale, but also with similar PV-IN abnormalities [39].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] De Crescenzo F, Postorino V, Siracusano M, Riccioni A, Armando M, Curatolo P, et al. Autistic symptoms in schizophrenia spectrum disorders: a systematic review and meta-analysis. Front Psychiatry. 2019;10:78. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In humans, gamma oscillations are associated with increased working memory load.

    “Gamma oscillations in humans are also associated with increased working memory load [79].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Howard MW, Rizzuto DS, Caplan JB, Madsen JR, Lisman J, Aschenbrenner-Scheibe R, et al. Gamma oscillations correlate with working memory load in humans. Cereb Cortex. 2003;13:1369–74. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    It would be surprising if PV-IN densities in disease were uniform across all brain regions, because fast-spiking interneurons have different functions in different areas.

    “Indeed, it would be surprising to find that PV-IN densities in disease are uniform across every brain region given that fast-spiking interneurons have different functions in different brain areas.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Restoring Nav1.1 levels increased gamma oscillations and reduced memory deficits and premature deaths.

    “Restoration of the levels of this voltage-gated sodium channel increased gamma oscillations, while memory deficits and premature deaths decreased [26].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Verret L, Mann EO, Hang GB, Barth AM, Cobos I, Ho K, et al. Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell. 2012;149:708–21. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PV-INs have extraordinary energy requirements to support high metabolic activity and to protect against significant glutamatergic stress.

    “PV-INs have extraordinary energy requirements to support a high metabolic activity and to protect against significant glutamatergic stress [16,80,81].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [16] Behrens MM, Ali SS, Dao DN, Lucero J, Shekhtman G, Quick KL, et al. Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase. Science. 2007;318:1645–7. source

      Not checked in the free run.

    • cites [80] Gulyas AI, Megias M, Emri Z, Freund TF. Total number and ratio of excitatory and inhibitory synapses converging onto single interneurons of different types in the CA1 area of the rat hippocampus. J Neurosci. 1999;19:10082–97. source

      Not checked in the free run.

    • cites [81] Kann O, Papageorgiou IE, Draguhn A. Highly energized inhibitory interneurons are a central element for information processing in cortical networks. J Cereb Blood Flow Metab. 2014;34:1270–82. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A substantial amount of cytochrome c and cytochrome c oxidase supports the high bioenergetic needs of PV-INs, but cytochrome c is also central to apoptosis induction.

    “A substantial quantity of cytochrome c and cytochrome c oxidase supports the high bioenergetic needs of PV-INs [81,85], but comes at a price as cytochrome c is also central to the induction of apoptosis [86].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [81] Kann O, Papageorgiou IE, Draguhn A. Highly energized inhibitory interneurons are a central element for information processing in cortical networks. J Cereb Blood Flow Metab. 2014;34:1270–82. source

      Not checked in the free run.

    • cites [85] Gulyas AI, Buzsaki G, Freund TF, Hirase H. Populations of hippocampal inhibitory neurons express different levels of cytochrome c. Eur J Neurosci. 2006;23:2581–94. source

      Not checked in the free run.

    • cites [86] Liu X, Kim CN, Yang J, Jemmerson R, Wang X. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell. 1996;86:147–57. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The energy demands of PV-INs make them highly susceptible to loss of mitochondrial membrane potential and to metabolic and oxidative stress that accompanies disease states.

    “The energy requirements of PV-INs make them highly susceptible to the loss of mitochondrial membrane potential (a component of, and a proxy for, a decrease in mitochondrial function), and to metabolic and oxidative stress that accompanies disease states [81,91].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [81] Kann O, Papageorgiou IE, Draguhn A. Highly energized inhibitory interneurons are a central element for information processing in cortical networks. J Cereb Blood Flow Metab. 2014;34:1270–82. source

      Not checked in the free run.

    • cites [91] Whittaker RG, Turnbull DM, Whittington MA, Cunningham MO. Impaired mitochondrial function abolishes gamma oscillations in the hippocampus through an effect on fast-spiking interneurons. Brain. 2011;134:e180. author reply e81 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    If the pathological threshold is crossed, the electron transfer chain is disrupted, reactive oxygen species accumulate, the permeability transition pore opens, the outer mitochondrial membrane ruptures, cytochrome c is released, and an apoptotic program is activated.

    “If the pathological threshold is crossed, the electron transfer chain is disrupted, reactive oxygen species accumulate, the permeability transition pore opens, the outer mitochondrial membrane ruptures, cytochrome c is released, and an apoptotic cell death program is activated [86,109].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [86] Liu X, Kim CN, Yang J, Jemmerson R, Wang X. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell. 1996;86:147–57. source

      Not checked in the free run.

    • cites [109] Kwak S, Weiss JH. Calcium-permeable AMPA channels in neurodegenerative disease and ischemia. Curr Opin Neurobiol. 2006;16:281–7. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PV-INs have a higher density of inputs, more excitatory and inhibitory synapses, and a higher ratio of inhibitory to excitatory inputs than calbindin- and calretinin-positive interneurons.

    “PV-INs have a higher density of inputs, more excitatory and inhibitory synapses, and a higher ratio of inhibitory to excitatory inputs than calbindin-and calretinin-positive interneurons [80].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] Gulyas AI, Megias M, Emri Z, Freund TF. Total number and ratio of excitatory and inhibitory synapses converging onto single interneurons of different types in the CA1 area of the rat hippocampus. J Neurosci. 1999;19:10082–97. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Blocking calcium-permeable AMPA receptors reduces cortical neuron death in an in vitro traumatic brain injury model, hippocampal pyramidal neuron loss in an oxygen-glucose deprivation slice model, and retinal ganglion cell loss in a glaucoma rat model.

    “Consistent with the notion that the presence of Ca 2+ -permeable AMPA receptors contributes to the vulnerability of PV-INs, blocking of these receptors attenuates cortical neuron death in an in vitro model of traumatic brain injury; attenuates hippocampal pyramidal neuron loss in a mouse hippocampal slice model of oxygen-glucose deprivation; and attenuates retinal ganglion cells loss in a rat”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [111] Yin HZ, Sensi SL, Ogoshi F, Weiss JH. Blockade of Ca2+-permeable AMPA/kainate channels decreases oxygen-glucose deprivation-induced Zn2+ accumulation and neuronal loss in hippocampal pyramidal neurons. J Neurosci. 2002;22:1273–9. source

      Not checked in the free run.

    • cites [116] Cueva Vargas JL, Osswald IK, Unsain N, Aurousseau MR, Barker PA, Bowie D, et al. Soluble tumor necrosis factor alpha promotes retinal ganglion cell death in glaucoma via calcium-permeable AMPA receptor activation. J Neurosci. 2015;35:12088–102. source

      Not checked in the free run.

    • cites [117] Spaethling JM, Klein DM, Singh P, Meaney DF. Calcium-permeable AMPA receptors appear in cortical neurons after traumatic mechanical injury and contribute to neuronal fate. J Neurotrauma. 2008;25:1207–16. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the hippocampus, oxidative stress is associated with fewer PV-INs and reduced gamma oscillations.

    “In the hippocampus, oxidative stress was associated with a decrease in PV-INs as well as a reduction in gamma oscillations [94].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [94] Steullet P, Cabungcal JH, Kulak A, Kraftsik R, Chen Y, Dalton TP, et al. Redox dysregulation affects the ventral but not dorsal hippocampus: impairment of parvalbumin neurons, gamma oscillations, and related behaviors. J Neurosci. 2010;30:2547–58. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Animal studies suggest that a key mechanism of neural oscillations involves glutamatergic regulation.

    “Animal studies suggest that a key mechanism of neural oscillations is through glutamatergic regulation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    NMDA receptors in PV-INs regulate gamma rhythms and cognitive behaviors.

    “Importantly, NMDA receptors in PV-INs are regulating gamma rhythms and cognitive behaviors [121].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] Carlen M, Meletis K, Siegle JH, Cardin JA, Futai K, Vierling-Claassen D, et al. A critical role for NMDA receptors in parvalbumin interneurons for gamma rhythm induction and behavior. Mol Psychiatry. 2012;17:537–48. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PV-INs receive the greatest excitatory input of any inhibitory neuron population in the cortex, placing them under intense stress.

    “Indeed, PV-INs receive the greatest excitatory input of any population of inhibitory neurons in the cortex, which puts them under intense stress [16,80].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [16] Behrens MM, Ali SS, Dao DN, Lucero J, Shekhtman G, Quick KL, et al. Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase. Science. 2007;318:1645–7. source

      Not checked in the free run.

    • cites [80] Gulyas AI, Megias M, Emri Z, Freund TF. Total number and ratio of excitatory and inhibitory synapses converging onto single interneurons of different types in the CA1 area of the rat hippocampus. J Neurosci. 1999;19:10082–97. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    STAT3 can directly regulate mitochondrial function, and Nox2 can modulate mitochondrial activity.

    “STAT3 can directly regulate mitochondrial function [97,98], and Nox2 can modulate mitochondrial activity [99][100][101]”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [97] Gough DJ, Corlett A, Schlessinger K, Wegrzyn J, Larner AC, Levy DE. Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science. 2009;324:1713–6. source

      Not checked in the free run.

    • cites [98] Wegrzyn J, Potla R, Chwae YJ, Sepuri NB, Zhang Q, Koeck T, et al. Function of mitochondrial Stat3 in cellular respiration. Science. 2009;323:793–7. source

      Not checked in the free run.

    • cites [99] Kim YM, Kim SJ, Tatsunami R, Yamamura H, Fukai T, Ushio-Fukai M. ROS-induced ROS release orchestrated by Nox4, Nox2, and mitochondria in VEGF signaling and angiogenesis. Am J Physiol Cell Physiol. 2017;312:C749–64. source

      Not checked in the free run.

    • cites [100] Joseph LC, Barca E, Subramanyam P, Komrowski M, Pajvani U, Colecraft HM, et al. Inhibition of NAPDH oxidase 2 (NOX2) prevents oxidative stress and mitochondrial abnormalities caused by saturated fat in cardiomyocytes. PLoS ONE. 2016;11:e0145750. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ketamine, a pro-inflammatory stimulus, injures PV-INs in vitro and in vivo.

    “For example, the NMDA receptor antagonist ketamine, a pro-inflammatory stimulus, injures PV-INs in vitro and in vivo [16,95].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] Behrens MM, Ali SS, Dao DN, Lucero J, Shekhtman G, Quick KL, et al. Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase. Science. 2007;318:1645–7. source

      Not checked in the free run.

    • cites [95] Behrens MM, Ali SS, Dugan LL. Interleukin-6 mediates the increase in NADPH-oxidase in the ketamine model of schizophrenia. J Neurosci. 2008;28:13957–66. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Zinc influx into neurons leads to nitric oxide generation, PARP-1 activation, and cell death.

    “Like Ca 2+ influx, zinc influx into neurons leads to the generation of nitric oxide and subsequent activation of PARP-1 and cell death [114].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114] Kim YH, Koh JY. The role of NADPH oxidase and neuronal nitric oxide synthase in zinc-induced poly(ADP-ribose) polymerase activation and cell death in cortical culture. Exp Neurol. 2002;177:407–18. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    These receptors activate intraneuronal signaling cascades that remodel microtubule and actin cytoskeletal components to extend and retract processes that move cells toward their destination.

    “These receptors activate intraneuronal signaling cascades that dynamically remodel microtubule and actin cytoskeletal components to extend and retract processes that move the cells toward their destination [133].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [133] Peyre E, Silva CG, Nguyen L. Crosstalk between intracellular and extracellular signals regulating interneuron production, migration and integration into the cortex. Front Cell Neurosci. 2015;9:129. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In schizophrenia, NMDA receptors are believed to be hypo-functioning, and NMDA receptor inhibition reproduces many schizophrenia symptoms.

    “In schizophrenia, NMDA receptors are believed to be hypo-functioning, and the inhibition of NMDA receptors recapitulates many of the symptoms of schizophrenia [104, 122, 123].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [104] Timofeeva OA, Levin ED. Glutamate and nicotinic receptor interactions in working memory: importance for the cognitive impairment of schizophrenia. Neuroscience. 2011;195:21–36. source

      Not checked in the free run.

    • cites [122] Konradi C, Heckers S. Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment. Pharm Ther. 2003;97:153–79. source

      Not checked in the free run.

    • cites [123] Lisman JE, Coyle JT, Green RW, Javitt DC, Benes FM, Heckers S, et al. Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia. Trends Neurosci. 2008;31:234–42. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Working memory is notably impaired in schizophrenia and other neuropsychiatric diseases, likely because disinhibition changes gamma oscillation power.

    “Working memory is notably impaired in schizophrenia and in other neuro-psychiatric diseases likely due to the expected change in gamma oscillation power resulting from disinhibition”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    PV-INs, like other interneurons, arise from progenitor cells in the embryonic ganglionic eminences of the ventral telencephalon.

    “Like other interneurons, PV-INs are derived from progenitor cells in the embryonic ganglionic eminences of the ventral telencephalon of the developing brain (Fig. 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    PV-INs are implicated in neurodevelopmental diseases such as early-onset psychiatric disorders and in neurodegenerative diseases such as Alzheimer's disease, showing vulnerability throughout life.

    “PV-INs are implicated in neurodevelopmental diseases such as early-onset psychiatric disorders and in neurodegenerative diseases such as AD, demonstrating the vulnerability of this interneuron subset throughout life.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Attractant and repellant guidance factors from various brain regions guide migrating neurons to their destination.

    “Externally, an exquisite coordination of attractant and repellant guidance factors transmitted from various brain regions guide migrating neurons to their ultimate destination [132].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [132] Marin O, Valiente M, Ge X, Tsai LH. Guiding neuronal cell migrations. Cold Spring Harb Perspect Biol. 2010;2:a001834. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    PV-INs are important for proper brain function.

    “PV-INs are important for proper brain function.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    During migration, cell-intrinsic programs and external cues must be coordinated in a time- and location-sensitive way.

    “During migration, cellintrinsic programs and external cues must be coordinated in a time-and location-sensitive manner [131].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [131] Guo J, Anton ES. Decision making during interneuron migration in the developing cerebral cortex. Trends Cell Biol. 2014;24:342–51. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NMDA receptor antagonists such as ketamine and phencyclidine can transiently reproduce key clinical features of schizophrenia and are believed to reduce PV-IN excitation.

    “NMDA receptor antagonists, such as ketamine and phencyclidine, can transiently reproduce key clinical features of schizophrenia, and are believed to reduce PV-IN excitation [123].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] Lisman JE, Coyle JT, Green RW, Javitt DC, Benes FM, Heckers S, et al. Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia. Trends Neurosci. 2008;31:234–42. source

      Not checked in the free run.

41 of 41

  • The authors state this as an assumption.

    The developmental process by which interneurons migrate and integrate into cortical networks has vulnerabilities.

    “While there likely is some space to correct for minor variabilities, it seems reasonable to assume that the process also has some vulnerabilities.”
1 of 1

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?

  • Dysfunction and/or deficient inhibitory output from PV interneurons may be a common mechanism of multiple psychiatric disorders, such as schizophrenia, autism spectrum disorders and bipolar disorder.

    “Dysfunction and/or deficient inhibitory output from PV interneurons may be a common mechanism of multiple psychiatric disorders, such as schizophrenia (SCZ) (Lewis et al. 2005), autism spectrum disorders (ASD) (Gao and Penzes 2015) and bipolar disorder (BD) (Ruden et al. 2021).”

    From Neuronal pentraxins as biomarkers of synaptic activity: from physiological functions to pathological changes in neurodegeneration (2022) · cites this paper as Ruden et al. 2021

Cites

1 retracted

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Ruden, J. B., Dugan, L. L., & Konradi, C.
Affiliations
Vanderbilt University (US)
Corresponding author
Konradi, Christine
ORCID
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2020-07-28
Volume
46
Issue
2
Pages
279-287
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/s41386-020-0778-9
PMC
PMC7852528
OpenAlex
W3044343625
Semantic Scholar
2c4e5394f3b88323dda4206c07141d738c058a9c
Cited by
194
References
148
Citations by year
2026: 33 · 2025: 50 · 2024: 36 · 2023: 31 · 2022: 28 · 2021: 16
FWCI
2.59
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuropsychopharmacology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Veterans Affairs (I01 BX004321)
  • Vanderbilt University
  • Vanderbilt Institute for Clinical and Translational Research
  • Geriatric Research Education and Clinical Center
  • National Institute on Aging (R01AG058856)
  • National Center for Research Resources (KL2RR024977)
  • NIH Clinical Center
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
Keywords
parvalbumin interneurons, neuronal vulnerability, stressors, schizophrenia, Alzheimer's disease, autism spectrum disorder, bipolar disorder, excitatory drive, energy requirements, interneuron development, neuroprotection
MeSH terms
Autism Spectrum Disorder, Alzheimer Disease, Humans, Interneurons, Neurons, Parvalbumins

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.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review