Neurodevelopment in Down syndrome: Concordance in humans and models

An increased number of astrocytes has been observed in the frontal lobe, fusiform gyrus, and inferior temporal gyrus of developing fetuses with Down syndrome compared to those without (17-21 weeks).

“An increased number of astrocytes has been observed in the frontal lobe (Zdaniuk et al., 2011), fusiform gyrus, and inferior temporal gyrus (Guidi et al., 2018) of developing fetuses with DS compared to those without (17–21 weeks).”

• cites Zdaniuk et al., 2011Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Guidi et al., 2018 sourceDisputed

  The Results section, “Density and percentage of neurons and astrocytes in the FG and ITG of fetuses with DS,” reports a similar absolute number of cells with an astrocytic phenotype in DS and euploid fetuses, not an increased number. It reports a higher percentage of astrocytes in both gyri. The frontal-lobe finding is attributed to a different citation in the citing sentence. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

A significant increase in the number of inhibitory synapses without any changes in excitatory synapses identified in Ts65Dn.

“Finally, a significant increase in the number of inhibitory synapses without any changes in excitatory synapses identified (Belichenko et al., 2009).”

• cites Belichenko et al., 2009 sourceDisputed

  The Results section, “Selective changes in the ultrastructure of symmetric synapses in the Ts65Dn FD” (page unavailable), reports no significant difference in total synapse density or in the ratio of asymmetric to symmetric synapses. It found longer symmetric synapses, not a significant increase in their number. The Discussion reports more puncta for inhibitory-synapse markers, but those puncta are not a count of synapses. (LLM, conf=0.89)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

During 17-21 weeks gestation, fewer neurons were found in the hippocampus, cerebellum, and multiple thalamic nuclei in fetuses with Down syndrome.

“During the same time period (17–21 weeks gestation) fewer neurons were found in the hippocampus (Guidi et al., 2008), cerebellum (Guidi et al., 2011), and multiple thalamic nuclei (Stagni et al., 2020).”

• cites Guidi et al., 2008 sourceNot checked — no full text of the source
• cites Guidi et al., 2011 sourceSupported
• cites Stagni et al., 2020 sourcePartly supported

  Section 4.1 reports fewer neurons in the mediodorsal, centromedian, and parafascicular thalamic nuclei of fetuses with Down syndrome. Section 2.1 describes the study's gestational range as 17–22 weeks, not 17–21 weeks; the hippocampus and cerebellum are attributed to other citations in the citing sentence. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

Reductions in the number of proliferating neural progenitor cells in the dentate gyrus, germinal matrix of the lateral ventricle, and third ventricle have been observed in tissue derived from fetuses diagnosed with Down syndrome (17-21 weeks gestation) prior to the initial observations of volumetric changes.

“Reductions in the number of proliferating neural progenitor cells (NPCs) in the dentate gyrus, germinal matrix of the lateral ventricle, and third ventricle have all been observed in tissue derived from fetuses diagnosed with DS (17–21 weeks gestation) prior to the initial observations of volumetric changes (Contestabile et al., 2007; Stagni et al., 2020).”

• cites Contestabile et al., 2007 sourceNot checked — no full text of the source
• cites Stagni et al., 2020 sourcePartly supported

  Section 3.4 (page unavailable) reports fewer proliferating cells in the third-ventricle ventricular zone of fetuses with Down syndrome, although that difference did not reach statistical significance. Section 4.1 (page unavailable) also reports earlier findings in the dentate gyrus. The paper does not establish the claimed reduction in the lateral-ventricle germinal matrix or that these findings preceded the initial observations of volumetric changes; its study included fetuses at 17–22, rather than specifically 17–21, gestational weeks. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

Fetal brain MRIs show that the cortical plate, subcortical parenchyma, and cerebellar hemispheres have significantly decreased growth trajectories in fetuses with Down syndrome compared to typically developing controls beginning at 28 weeks of gestation.

“Analysis of fetal brain MRIs show that the cortical plate, subcortical parenchyma, and cerebellar hemispheres have significantly decreased growth trajectories in fetuses with DS compared to typically developing controls beginning at 28 weeks of gestation (Tarui et al., 2020).”

• cites Tarui et al., 2020 sourceSupported

A third study found no difference in the density of interneurons in thalamic nuclei of fetuses (17-21 weeks gestation) with Down syndrome compared to those without.

“A third study also found no difference in the density of interneurons in thalamic nuclei of fetuses (17–21 weeks gestation) with DS compared to those without (Stagni et al., 2020).”

• cites Stagni et al., 2020 sourcePartly supported

  The Abstract reports no change in interneuron density in the mediodorsal, centromedian, and parafascicular thalamic nuclei of fetuses with Down syndrome compared with controls. However, the Abstract and §2.1 (Subjects) give the gestational range as 17–22 weeks, not 17–21 weeks. Page numbers were not available in our copy. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

Another study analyzing a similar age group and area found no difference in parvalbumin or calretinin positive interneurons in Down syndrome.

“However, another study analyzing a similar age group and area found no difference in parvalbumin or calretinin positive interneurons (Giffin-Rao et al., 2020).”

• cites Giffin-Rao et al., 2020 sourcePartly supported

  In “Fewer neurons in DS cortex” (page unavailable), the paper reports no difference in parvalbumin-positive cell density in age-matched superior temporal gyrus samples (ages 15–35). It does not make the same unqualified finding for calretinin-positive cells: it reports a lower measured density in Down syndrome that may indicate a reduction, although the comparison was not statistically significant (p=0.11). (LLM, conf=0.88)

  Experimental — accuracy not yet measured

The intellectual disability in Down syndrome ranges from moderate to severe as measured by intelligence quotient (IQ 10-70) with a median IQ of 40.

“The ID in DS ranges from moderate to severe as measured by intelligence quotient (IQ 10–70) with a median IQ of 40 (Guéant et al., 2005).”

• cites Guéant et al., 2005 sourcePartly supported

  The Results report IQs of 10–70 among 131 patients with Down syndrome, with a median of 40. But the same section identifies patients with IQs below 25 as having profound, rather than severe, intellectual disability; the stated severity range therefore omits a category present in the sample. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

The finding of increased calretinin positive interneuron proportion without increases in interneuron number was repeated in the entorhinal cortex and hippocampus in Down syndrome.

“This finding of increased calretinin positive interneuron proportion without increases in interneuron number, was repeated in the entorhinal cortex and hippocampus (Guidi et al., 2018).”

• cites Guidi et al., 2018 sourcePartly supported

  The section “Increased number of calretinin-positive cells in the ventral temporal lobe of DS fetuses” reports a higher proportion of calretinin-positive cells in the entorhinal cortex and parts of the hippocampal region. It also reports an exception to the claim that their number did not increase: DS fetuses had more calretinin-positive cells in the dentate gyrus granule cell layer and CA1 stratum pyramidale. No page number is provided in the supplied passages. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Hypocellularity persists with fewer total neurons being identified in the superior temporal gyrus in adolescents and adults with Down syndrome (15-35 years).

“The hypocellularity persists with fewer total neurons being identified in the superior temporal gyrus in adolescents and adults with DS (15–35 years) (Ross et al., 1984; Giffin-Rao et al., 2020).”

• cites Ross et al., 1984 sourceNot checked — no full text of the source
• cites Giffin-Rao et al., 2020 sourceSupported

Neuroanatomical differences in brain size in Down syndrome are present starting at birth.

“The neuroanatomical differences in size are present starting at birth; changes in volume were identified in multiple cohorts consisting of individuals ranging from 0 months to 5 years of age (Schmidt-Sidor et al., 1990; McCann et al., 2021) implicating onset during fetal development.”

• cites Schmidt-Sidor et al., 1990Not checked — no full text of the source
• cites McCann et al., 2021 sourcePartly supported

  The Results and Discussion report volumetric differences in a 0–5-year cohort, including findings in a 0–2-year subgroup. But Table 1 (Materials and methods > Participants) gives 0.62 years as the youngest age for a participant with Down syndrome, so this study does not establish that the differences are present at birth. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

In an MRI study, the youngest cohort (0-5 years) with Down syndrome showed a smaller effect size compared to older cohorts (5-10, 10-15, and 15-20 years), indicating more similarity between individuals with Down syndrome and controls at the younger age.

“in a detailed MRI study, the youngest cohort (0–5 years) showed a smaller effect size compared to older cohorts (5–10, 10–15, and 15–20 years) indicating more similarly between the individuals with DS and controls at the younger age (McCann et al., 2021).”

• cites McCann et al., 2021 sourceSupported

Dp1Tyb/Dp(16)1Yey replicate some developmental and learning and memory deficits of DS.

“These mouse models have quickly become popular models of DS and replicate some of the same developmental and learning and memory deficits as individuals with DS (Goodliffe et al., 2016; Pinto et al., 2020; Lana-Elola et al., 2021).”

• cites Goodliffe et al., 2016 sourceSupported
• cites Pinto et al., 2020 sourcePartly supported

  The Introduction says Dp(16) mice recapitulate characteristics of Down syndrome, including cognitive deficits, and the Results report deficits on cognitive tests in juvenile Dp(16) mice (pages not supplied). The paper does not establish the claim for Dp1Tyb or that both models have quickly become popular. Its Discussion also says Dp(16) mice lack marked prenatal defects in neuronal-precursor proliferation and neurogenesis, so the developmental-deficits claim needs qualification. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites Lana-Elola et al., 2021 sourceSupported

A decrease in choline acetyltransferase (ChAT)-positive motor neurons was identified in cervical sections of the spinal cord from older adults with Down syndrome (58-70 years).

“A decrease in choline acetyltransferase (ChAT)-positive motor neurons was identified in cervical sections of the spinal cord from older adults with DS (58–70 years) (Watson-Scales et al., 2018).”

• cites Watson-Scales et al., 2018 sourcePartly supported

  The Results section reports fewer motor neurons in cervical spinal cord sections from adults with Down syndrome than in controls, and the human-autopsy Methods give the participants’ ages as 58–70 years. However, the Methods say the researchers counted neurons with intense Nissl staining; they do not identify the counted cells as ChAT-positive. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

In Ts65Dn, there is an increase in astrocytes (S100β) in both cortex and hippocampus.

“Additionally, an increase in astrocytes as identified by S100β staining has been found in both the cortex and the hippocampus (Illouz et al., 2019).”

• cites Illouz et al., 2019 sourceSupported

In Ts65Dn hippocampus, long-term potentiation (LTP) induction fails due to excessive GABA-mediated inhibition.

“A seminal study in the field found failure of induction of long-term potentiation (LTP) in the Ts65Dn hippocampus due to excessive GABA-mediated inhibition and a wide array of following studies have confirmed this finding (Siarey et al., 1997, 1999; Kleschevnikov et al., 2004; Costa and Grybko, 2005; Fernandez et al., 2007).”

• cites Siarey et al., 1997, 1999Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Kleschevnikov et al., 2004 sourceSupported
• cites Costa and Grybko, 2005 sourceNot checked — no full text of the source

Behaviorally, Ts65Dn appears to capture many of the features of Down syndrome including developmental delays and learning and memory deficits.

“Behaviorally, Ts65Dn appears to capture many of the features of DS including developmental delays and learning and memory deficits (Reeves et al., 1995; Olmos-Serrano et al., 2016b; Shaw et al., 2020).”

• cites Reeves et al., 1995 sourceNot checked — no full text of the source
• cites Olmos-Serrano et al., 2016bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Shaw et al., 2020 sourceSupported

These recapitulated phenotypes appear to be subject to phenotypic drift.

“However, these recapitulated phenotypes appear to be subject to phenotypic drift.”

• cites Shaw et al., 2020 sourceSupported

In an older cohort (36-67 years), deficits in microglia morphology including decreased ramification and increased cell body size were identified in samples from individuals with Down syndrome.

“In an older cohort (36–67 years), deficits in microglia morphology including decreased ramification and increased cell body size were identified in samples from individuals with DS (Pinto et al., 2020).”

• cites Pinto et al., 2020 sourceSupported

Contrary to the existing human data, these proliferation changes in Ts65Dn appear to be region specific as an increase in number of actively proliferating cells was observed in the embryonic medial ganglionic eminence, the site of interneuron production.

“Contrary to the existing human data, these proliferation changes appear to be region specific as an increase in number of actively proliferating cells was observed in the embryonic medial ganglionic eminence, the site of interneuron production (Chakrabarti et al., 2010; Aziz et al., 2018).”

• cites Chakrabarti et al., 2010 sourceSupported
• cites Aziz et al., 2018 sourceSupported

Like the majority of individuals with Down syndrome, Ts65Dn has an extra freely segregating marker chromosome that carries ∼119 genes triplicated from MMU16.

“Therefore, like the majority of individuals with DS, Ts65Dn has an extra freely segregating marker chromosome that carries ∼119 genes triplicated from MMU16 (Duchon et al., 2011).”

• cites Duchon et al., 2011 sourceSupported

Many phenotypes described in Ts65Dn are susceptible to phenotypic drift and are variable between cohorts.

“However, many of the phenotypes that have been described in Ts65Dn have recently been found to be susceptible to phenotypic drift and are variable between cohorts (Shaw et al., 2020).”

• cites Shaw et al., 2020 sourceSupported

In Dp(16)1Yey, there is a decrease in parvalbumin and somatostatin interneurons at postnatal day 15 in the cortex.

“A change in interneuron populations have been identified, but unlike the increases found in Ts65Dn and likely in humans, a decrease in parvalbumin and somatostatin interneurons was found at postnatal day 15 in the cortex (Goodliffe et al., 2016).”

• cites Goodliffe et al., 2016 sourceSupported

Human studies show decreased cerebral volume due in part to hypocellularity driven by decreased NPC proliferation.

“One of the best documented phenotypes observed from human studies is the decreased cerebral volume thought to be due in part to hypocellularity driven by a decrease in NPC proliferation (Contestabile et al., 2007; Stagni et al., 2020).”

• cites Contestabile et al., 2007 sourceNot checked — no full text of the source
• cites Stagni et al., 2020 sourcePartly supported

  Section 4.5 (page unavailable) describes reduced cerebral-hemisphere size and hypocellularity in Down syndrome. Section 4.1 (page unavailable) reports reduced proliferation and suggests it underlies hypocellularity in the three fetal thalamic nuclei studied. The paper does not establish that decreased NPC proliferation causes the reduction in overall cerebral volume. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Trisomic neurons exhibit decreased neurite length.

“Finally in a third study using age matched iPSC lines, trisomic neurons again exhibited significantly decreased neurite length compared to control lines (Chen et al., 2014).”

• cites Chen et al., 2014 sourceSupported

Trisomic iPSCs show significant increase in astrocyte differentiation.

“A significant increase in astrocytes differentiated from trisomic iPSCs has been reported many times (Briggs et al., 2013; Chen et al., 2014; Hibaoui et al., 2014; Real et al., 2018; Mollo et al., 2021).”

• cites Briggs et al., 2013 sourceNot checked — no full text of the source
• cites Chen et al., 2014 sourcePartly supported

  In Results (‘Confirmation of phenotypes of DS astroglia by isogenic iPSCs’; page not provided), the paper reports significantly more astroglia from trisomic than disomic cells under spontaneous differentiation. But Results (‘Generation and differentiation of DS patient-specific hiPSCs’; page not provided) reports no significant difference under directed differentiation, so the unqualified claim is broader than the finding. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Hibaoui et al., 2014 sourceSupported

Two other studies found decreased number of neurons from trisomic iPSCs.

“However, two other studies, one using a separate isogenic line and one using non-isogenic matched iPSCs found that the trisomic line produced a decreased number of neurons compared to the euploid control (Lu et al., 2013; Hibaoui et al., 2014).”

• cites Lu et al., 2013Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Hibaoui et al., 2014 sourceSupported

In Ts65Dn, NPC subtype may be shifted during development.

“Reports in the Ts65Dn mouse model indicate that NPC subtype may be shifted during development (Tyler and Haydar, 2013).”

• cites Tyler and Haydar, 2013 sourceSupported

MAC21 recapitulates some phenotypes described in individuals with DS.

“The transchromosomic mouse model, MAC21, has undergone preliminary characterization and recapitulates some of the phenotypes described in individuals with DS (Kazuki et al., 2020).”

• cites Kazuki et al., 2020 sourceSupported

MAC21 recapitulate non-neuronal phenotypes such as skeletal changes and cardiovascular abnormalities.

“Like Dp1Tyb/Dp(16)1Yey, they appear to recapitulate some of the non-neuronal phenotypes associated with DS such as skeletal changes and cardiovascular abnormalities.”

• cites Kazuki et al., 2020 sourceSupported

In 2D culture, there is an increase in OLIG2 expressing ventral NPCs.

“This increase in percentage of OLIG2 expressing ventral NPCs was also found in two dimensional culture where two isogenic lines of iPSCs were differentiated to brain-like NPCs and ventralized (Klein et al., 2022).”

• cites Klein et al., 2022 sourceSupported

Two studies found no changes in differentiation of excitatory cortical neurons from trisomic iPSCs.

“Two studies using isogenic pairs of iPSCs did not identify any changes in differentiation of excitatory cortical neurons (Weick et al., 2013; Murray et al., 2015).”

• cites Weick et al., 2013 sourceNot checked — no full text of the source
• cites Murray et al., 2015 sourcePartly supported

  In the Results (page unavailable), Murray et al. report that both isogenic trisomic and disomic iPSCs produced neurons, and that the cortical-neuron protocol yielded predominantly neuronal cells. But their statement that cortical-layer subpopulations did not differ refers to an earlier study; they say they cannot fully rule out cell-type differences in their own cultures. Thus their findings support comparable neuronal differentiation in part, not an unqualified finding of no changes in excitatory cortical-neuron differentiation. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

DS iPSC-derived astrocytes have changes in cell adhesion and motility dynamics.

“Astrocytes differentiated from iPSCs derived from individuals with DS had changes in cell adhesion and motility dynamics compared to matched euploid controls (Bally et al., 2020).”

• cites Bally et al., 2020 sourceSupported

No difference in electrical properties between trisomic and euploid neurons.

“This finding was repeated using age-matched cell lines that again found no difference in electrical properties between trisomic and euploid neurons (Chen et al., 2014).”

• cites Chen et al., 2014 sourceSupported

Trisomic iPSC-derived NPCs show a proliferation deficit compared to controls.

“In two different isogenic pairs, the trisomic NPCs showed a proliferation deficit compared to their control (Hibaoui et al., 2014; Murray et al., 2015).”

• cites Hibaoui et al., 2014 sourceSupported
• cites Murray et al., 2015 sourceSupported

Engrafted trisomic neurons show increased spine density.

“A novel study where NPCs and neurons derived from iPSCs were engrafted into mouse cortex and allowed to mature found an increase in spine density in the trisomic neurons compared to euploid controls (Real et al., 2018).”

• cites Real et al., 2018 sourceSupported

In 2D culture, there is a significant decrease in calretinin and calbindin positive interneurons.

“However, another study using a 2D culture method identified a significant decrease in calretinin positive interneurons along with a significant decrease in calbindin positive interneurons (Huo et al., 2018).”

• cites Huo et al., 2018 sourceSupported

Trisomic iPSC-derived NPCs exhibit more ventral and fewer caudal characteristics compared to euploid controls.

“The trisomic NPCs exhibited more ventral and fewer caudal characteristics compared to their euploid controls exposed to the same patterning agents (Giffin-Rao et al., 2020).”

• cites Giffin-Rao et al., 2020 sourceSupported

MAC21 show learning and memory deficits.

“In addition to modeling the genetics of DS, they also show some of the same behavioral deficits in learning and memory.”

• cites Kazuki et al., 2020 sourceSupported

Alterations in circuitry rather than intrinsic neuronal properties may be responsible for altered neuronal activity.

“These activity changes indicate that it may be alterations in circuitry rather than changes in intrinsic neuronal properties that may be responsible for altered neuronal activity.”

• cites Real et al., 2018 sourcePartly supported

  The section “Imaging human neuron structural and functional dynamics in Down syndrome” reports reduced burst and global activity in trisomy 21 grafts, supporting the network-activity part of the claim. The Conclusion describes cell-intrinsic deficits, but the paper does not establish that circuitry changes, rather than changes in intrinsic neuronal properties, caused the altered activity. Page numbers were not provided in our copy. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

Dp1Tyb shows a decrease in motor neurons in the spinal cord at six months of age, same as aged Ts65Dn and humans.

“Additionally, Dp1Tyb shows the same decrease in motor neurons in the spinal cord at six month of age that has been observed in aged Ts65Dn and humans (Watson-Scales et al., 2018).”

• cites Watson-Scales et al., 2018 sourcePartly supported

  The Results (Fig. 6; page unavailable) report reduced spinal motor-neuron numbers in Tc1 and Dp(16)1Yey mice, including measurements at six months, while the human Results report reduced numbers in adults with Down syndrome. The cited paper discusses Dp1Tyb in its sensory-function Results, but does not report a six-month spinal motor-neuron decrease in Dp1Tyb or establish the claimed comparison with aged Ts65Dn mice. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Distinct brain size differences in Down syndrome are more apparent after 3-5 months of age.

“Though present at birth, distinct size differences were more apparent after 3–5 months of age (Schmidt-Sidor et al., 1990)”

• cites Schmidt-Sidor et al., 1990Not checked — no full text of the source

The density of the final myelinated axons is decreased in Down syndrome.

“In addition to the developmental delay, the density of the final myelinated axons is decreased in DS (Ábrahám et al., 2012; Olmos-Serrano et al., 2016a).”

• cites Ábrahám et al., 2012 sourceNot checked — no full text of the source
• cites Olmos-Serrano et al., 2016aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

A decreased number of dendritic spines on pyramidal neurons were found in children and young adults (3-23 years) with Down syndrome compared to age matched controls.

“a decreased number of dendritic spines on pyramidal neurons were found both in children and young adults (3–23 years) (Suetsugu and Mehraein, 1980)”

• cites Suetsugu and Mehraein, 1980 sourceNot checked — no full text of the source

Analysis of RNA isolated from cortical samples across the developmental lifespan (14 weeks gestation-40 years) identified the downregulation of a module enriched for genes expressed in the oligodendrocyte lineage in Down syndrome.

“analysis of RNA isolated from cortical samples across the developmental lifespan (14 weeks gestation–40 years), identified the downregulation of a module enriched for genes expressed in the OL lineage (Olmos-Serrano et al., 2016a).”

• cites Olmos-Serrano et al., 2016aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

General hypocellularity has consistently been identified in multiple structures at numerous points of development in Down syndrome.

“General hypocellularity has consistently been identified in multiple structures at numerous points of development.”

Brain measurement studies consistently indicate differences in Down syndrome by the early second trimester of gestation.

“Together, brain measurement studies consistently indicate differences by the early second trimester of gestation, a developmental phase when critical processes such as cellular maturation, synapse formation, and dendrite growth occur.”

The myelination delay in Down syndrome predominantly affects associated and intercortical fibers in the fronto-temporal lobes, tracts that typically display late initiation of myelination.

“The delay predominantly affects associated and intercortical fibers in the fronto-temporal lobes, tracts that typically display late initiation of myelination (Wisniewski and Schmidt-Sidor, 1989).”

• cites Wisniewski and Schmidt-Sidor, 1989Not checked — no full text of the source

There remain significant conflicting data between human studies and models of Down syndrome neurodevelopment.

“However, there remain significant conflicting data between human studies and the models.”

At 19 weeks gestation, a significant decrease in total cells was found in the forebrain of fetuses with Down syndrome.

“At 19 weeks gestation, a significant decrease in total cells was found the forebrain (Larsen et al., 2008).”

• cites Larsen et al., 2008 sourceNot checked — no full text of the source

In infants aged 0-6 months, the total dendritic length was longer in samples from individuals with Down syndrome compared to controls.

“Initially, in infants aged 0–6 months, the total dendritic length was longer in samples from individuals with DS compared to controls.”

• cites Becker et al., 1986 sourceNot checked — no full text of the source

No volumetric changes were observed in fetuses with Down syndrome at 15-22 weeks of gestation.

“while no changes were observed in fetuses 15–22 weeks of gestation (Schmidt-Sidor et al., 1990).”

• cites Schmidt-Sidor et al., 1990Not checked — no full text of the source

Fetuses (14-40 weeks gestation) with Down syndrome had similar dendritic spine counts compared to controls.

“another study showed that fetuses (14–40 weeks gestation) with DS had similar dendritic spine counts compared to controls.”

• cites Takashima et al., 1981 sourceNot checked — no full text of the source

A decreased number of dendritic spines on pyramidal neurons were found in middle aged adults (47-55 years) with Down syndrome compared to age matched controls.

“and middle aged adults (47–55 years) compared to age matched controls (Ferrer and Gullotta, 1990).”

• cites Ferrer and Gullotta, 1990 sourceNot checked — no full text of the source

The cerebral cortical hemispheres, cerebellum, and hippocampal formations are significantly reduced in size in people with Down syndrome.

“In particular, the cerebral cortical hemispheres, cerebellum, and hippocampal formations are significantly reduced in size (Wisniewski, 1990; Golden and Hyman, 1994; Kesslak et al., 1994; Raz et al., 1995; Pinter et al., 2001; Tarui et al., 2020; McCann et al., 2021).”

• cites Wisniewski, 1990 sourceNot checked — no full text of the source
• cites Golden and Hyman, 1994 sourceNot checked — no full text of the source
• cites Kesslak et al., 1994 sourceNot checked — no full text of the source

Myelination is also delayed in the hippocampus in Down syndrome.

“Myelination is also delayed in the hippocampus in DS (Ábrahám et al., 2012).”

• cites Ábrahám et al., 2012 sourceNot checked — no full text of the source

One study has identified a decreased number of aspinous stellate interneurons in young adults with Down syndrome.

“Broadly, one study has identified a decreased number of aspinous stellate interneurons in young adults with DS (Ross et al., 1984).”

• cites Ross et al., 1984 sourceNot checked — no full text of the source

Lower levels of 2′,3′-cyclic nucleotide-3′-phosphodiesterase (CNP), an oligodendrocyte specific protein, have been detected in the front and temporal lobes of tissue samples from Down syndrome versus controls.

“In addition, lower levels of 2′,3′-cyclic nucleotide-3′-phosphodiesterase (CNP), an OL specific protein, have also been detected in the front and temporal lobes of tissue samples from DS versus controls (Vlkolinský et al., 2001).”

• cites Vlkolinský et al., 2001 sourceNot checked — no full text of the source

Volumetric differences in Down syndrome become more disparate with age.

“Additionally, it appears that these volumetric differences become more disparate with age.”

Post-mortem and magnetic resonance imaging studies consistently show that overall brain size is decreased in people with Down syndrome compared to age-matched controls.

“Post-mortem and magnetic resonance imaging (MRI) studies consistently show that the overall size of the brain is decreased compared to age-matched controls.”

Volumetric changes in Down syndrome are apparent as early as 23 weeks gestation in developing fetuses.

“Indeed, as early as 23 weeks gestation, volumetric changes are apparent in developing fetuses with DS (Golden and Hyman, 1994)”

• cites Golden and Hyman, 1994 sourceNot checked — no full text of the source

Delayed myelination was identified in children with Down syndrome (2 months-6 years), with an average delay of 12 months compared to typically developing controls.

“Delayed myelination was identified in children with DS (2 months–6 years), with an average delay of 12 months compared to typically developing controls (Wisniewski and Schmidt-Sidor, 1989).”

• cites Wisniewski and Schmidt-Sidor, 1989Not checked — no full text of the source

The intellectual disability in Down syndrome presents with predominant deficits in executive functioning and memory.

“It presents as a range of impairments including predominant deficits in executive functioning and memory (Vicari et al., 2005, 2000; Lanfranchi et al., 2010; Costanzo et al., 2013; Grieco et al., 2015).”

• cites Vicari et al., 2005 sourceNot checked — no full text of the source
• cites Lanfranchi et al., 2010 sourceNot checked — no full text of the source
• cites Costanzo et al., 2013 sourceNot checked — no full text of the source

There is an increase in the number of ramified microglia in developing fetuses with Down syndrome compared to controls (18-22 weeks).

“There is an increase in the number of ramified microglia in developing fetuses with DS compared to controls (18–22 weeks) (Wierzba-Bobrowicz et al., 1999).”

• cites Wierzba-Bobrowicz et al., 1999Not checked — no full text of the source

Ts65Dn is the result of a translocation of the distal region of MMU16 onto the centromeric region of mouse chromosome 17 (MMU17).

“Unlike the triplication of a full MMU16, Ts65Dn is the result of a translocation of the distal region of MMU16 onto the centromeric region of mouse chromosome 17 (MMU17).”

The Ts65Dn mouse model recapitulates some of the anatomical and cellular phenotypes found in human studies that are thought to underlie the development of the intellectual disability.

“The Ts65Dn mouse model recapitulates some of the anatomical and cellular phenotypes found in human studies that are thought to underlie the development of the ID.”

Similar to human studies, neuronal hypocellularity has been detected in multiple structures including the cortex, cerebellum, and hippocampus in postnatal trisomic Ts65Dn animals.

“Similar to human studies, neuronal hypocellularity has been detected in multiple structures including the cortex, cerebellum, and hippocampus in postnatal trisomic animals (Insausti et al., 1998; Baxter et al., 2000; Olson et al., 2004; Roper et al., 2006; Chakrabarti et al., 2010; Aziz et al., 2018).”

• cites Insausti et al., 1998 sourceNot checked — no full text of the source
• cites Baxter et al., 2000 sourceNot checked — no full text of the source
• cites Olson et al., 2004 sourceNot checked — no full text of the source

Much of what is known of neurodevelopment in Down syndrome during late gestation and childhood is derived from tissue samples from individuals that died prematurely.

“It should be noted that much of what we know of neurodevelopment in DS during late gestation and childhood is derived from tissue samples from individuals that died prematurely.”

Another phenotype consistently observed in tissue samples from individuals with Down syndrome is a decrease in neurite arborization and synaptic density.

“Finally, another phenotype consistently observed in tissue samples from individuals with DS is a decrease in neurite arborization and synaptic density.”

The length of symmetric synapses appears to be significantly longer in the Ts65Dn hippocampus indicating an alteration of structure of typically inhibitory connections.

“Additionally, the length of symmetric synapses appears to be significantly longer in the Ts65Dn hippocampus indicating an alteration of structure of typically inhibitory connections.”

• cites Belichenko et al., 2004 sourceNot checked — no full text of the source

Some observed neurodevelopmental phenotypes in Down syndrome are inconsistent either within human studies or between humans and model systems.

“Some of the observed phenotypes are inconsistent either from human studies or between humans and model systems.”

Several clinical trials have tested the effect of GABA antagonists on cognition in people with Down syndrome.

“several different clinical trials have tested the effect of GABA antagonists on cognition in people with DS (Hart et al., 2017)”

• cites Hart et al., 2017 sourceNot checked — no full text of the source

An increase in astrocyte density has consistently appeared in all human tissue studied and in mouse models and iPSCs.

“There are some neurodevelopmental phenotypes that have consistently appeared not only in all human tissue studied but also in mouse models and iPSCs. These phenotypes include a decrease in NPC proliferation, changes in synaptic density, and an increase in astrocyte density.”

Changes in synaptic density in Down syndrome are age dependent.

“*The up and down arrows in the changes in synaptic density indicate an age dependent phenotype.”

Decreased brain volume has been consistently observed in individuals with Down syndrome across their lifespan.

“decreased brain volume has been consistently observed in individuals with DS across their lifespan.”

Decreased brain volume has not been well recapitulated in rodent studies.

“The phenotype has not been well recapitulated in rodent studies.”

A decrease in NPC proliferation has consistently appeared in all human tissue studied and in mouse models and iPSCs.

“There are some neurodevelopmental phenotypes that have consistently appeared not only in all human tissue studied but also in mouse models and iPSCs. These phenotypes include a decrease in NPC proliferation, changes in synaptic density, and an increase in astrocyte density.”

Neuronal hypocellularity has been consistently described in samples from individuals with Down syndrome.

“neuronal hypocellularity has been consistently described in samples from individuals with DS.”

None of the clinical trials of GABA antagonists have resulted in an improvement in cognition in people with Down syndrome.

“none of these trials have resulted in an improvement.”

• cites Hart et al., 2017 sourceNot checked — no full text of the source

Changes in synaptic density have consistently appeared in all human tissue studied and in mouse models and iPSCs.

“There are some neurodevelopmental phenotypes that have consistently appeared not only in all human tissue studied but also in mouse models and iPSCs. These phenotypes include a decrease in NPC proliferation, changes in synaptic density, and an increase in astrocyte density.”

Down syndrome is caused by triplication of chromosome 21 (HSA21).

“Jerome Lejeune identified triplication of chromosome 21 (HSA21) as its cause (Down, 1866; Lejeune et al., 1959).”

• cites Lejeune et al., 1959Not checked — no full text of the source

The neurodevelopmental changes underlying intellectual disability in Down syndrome include changes in neurogenesis, synaptic connectivity, and myelination that drive anatomical and physiological changes resulting in the disability.

“Detailed studies of human tissue coupled with findings from rodent and induced pluripotent stem cells (iPSCs) model systems have uncovered the changes in neurogenesis, synaptic connectivity, and myelination that drive the anatomical and physiological changes resulting in the disability.”

The decrease in production of neurons is the initial neurodevelopmental deficit identified in the gray matter in Down syndrome.

“The decrease in production of neurons is just the initial neurodevelopmental deficit identified in the gray matter in DS.”

The opposing changes based on developmental origin may explain the conflicting results identifying an increase or decrease in interneurons in different studies.

“The opposing changes based on developmental origin may explain the conflicting results identifying an increase or decrease in interneurons in different studies.”

The structural brain changes in Down syndrome correlate with some specific deficits in cognitive function.

“These structural changes correlate with some of the specific deficits noted in cognitive function in DS.”

Ts65Dn has been considered a good model to understand the cellular underpinnings that connect the genetics of Down syndrome to the intellectual disability.

“Therefore, Ts65Dn has been considered a good model to understand the cellular underpinnings that connect the genetics of DS to the ID.”

In humans with DS, the only described cellular change in the spinal cord is reduction in motor neurons.

“Currently, the only described cellular changes in the spinal cord in humans with DS is the reduction in motor neurons.”

Decreased myelin in Ts65Dn is explained by a maturation deficit of oligodendrocyte precursor cells (OPCs).

“Analysis of Ts65Dn provides an explanation for this decreased myelin via a maturation deficit of the OL precursor cells (OPCs).”

• cites Olmos-Serrano et al., 2016bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The OPC maturation defect in Ts65Dn is cell autonomous.

“This defect appears to be cell autonomous as purified trisomic OPCs from Ts65Dn differentiate into fewer mature MBP+ cells in culture compared to OPCs isolated from control euploid mice (Olmos-Serrano et al., 2016b).”

• cites Olmos-Serrano et al., 2016bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Similar to humans, the neuronal hypocellularity in Ts65Dn is thought to be driven by changes in neural progenitor cell proliferation during development.

“Similar to humans, the neuronal hypocellularity in Ts65Dn is thought to be driven by changes in NPC proliferation during development.”

Pharmaceutical interventions translating these findings back into humans have not been successful.

“However, translating these findings back into humans in the form of pharmaceutical interventions has yet to prove successful (Hart et al., 2017).”

• cites Hart et al., 2017 sourceNot checked — no full text of the source

Ts65Dn has historically recapitulated glial changes seen in humans.

“Importantly, Ts65Dn has historically recapitulated these glial changes and has provided insight into the mechanisms driving them in people.”

In Ts65Dn mice, action potential transmission is slower along myelinated axons.

“In the mice, action potential transmission is slower along myelinated axons, perhaps contributing to the ID in DS.”

• cites Olmos-Serrano et al., 2016bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Human studies have consistently identified an increase in astrocytes at the expense of neuronal generation in DS.

“Opposed to the decrease in white matter, human studies have consistently identified an increase in astrocytes as the expense of neuronal generation.”

The changes observed directly in human samples from individuals with Down syndrome are the most reliable information about different neurodevelopmental phenotypes that may be underlying the intellectual disability.

“The changes observed directly in human samples from individuals with DS are the most reliable information about different neurodevelopmental phenotypes that may be underlying the ID.”

Ts65Dn show an increased percentage of cells with astroglial morphology in the hippocampus.

“This astroglia shift has also been observed in Ts65Dn with an increased percentage of cells showing astroglial morphology in the hippocampus (Contestabile et al., 2007).”

• cites Contestabile et al., 2007 sourceNot checked — no full text of the source

Trisomic Ts65Dn display a similar white matter phenotype to humans with thinner myelin sheaths and decreased amounts of MAG and MBP in the corpus callosum.

“Trisomic Ts65Dn display a similar white matter phenotype to humans with thinner myelin sheaths and decreased amounts of MAG and MBP in the corpus callosum (Olmos-Serrano et al., 2016b).”

• cites Olmos-Serrano et al., 2016bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

As the volumetric changes and hypocellularity are some of the most consistent phenotypes described in individuals with Down syndrome, the disappearance of them in various cohorts of Ts65Dn currently calls into question their utility as a model to capture key neurodevelopmental aspects of Down syndrome.

“However, as the volumetric changes and hypocellularity are some of the most consistent phenotypes described in individuals with DS, the disappearance of them in various cohorts of Ts65Dn currently calls into question their utility as a model to capture key neurodevelopmental aspects of DS.”

Animal models that live into adulthood and cellular models derived from healthy people with Down syndrome may not fully capture some of the neurodevelopmental changes observed in the most affected individuals.

“Animal models that live into adulthood and cellular models derived from healthy people with DS may not fully capture some of the neurodevelopmental changes observed in the most affected individuals.”

The phenotypic drift and variability call into question the current utility of Ts65Dn for studying the molecular and cellular underpinnings of DS.

“This calls into question the current utility of the model to study the molecular and cellular underpinnings of DS.”

Human studies have identified changes in all types of glia in DS.

“Human studies have identified changes in all types of glia in addition to the neuronal changes found in the CNS.”

Human tissue studies consistently identify changes in dendritic spine density in DS.

“While the nature of any excitatory and inhibitory neurons imbalance is still up for debate, human tissue studies have consistently identified changes in dendritic spine density indicating lifelong alteration of synaptic connections.”

Dp1Tyb/Dp(16)1Yey is not a good model of the neurodevelopmental changes thought to underlie ID in DS.

“While not as extensively studied as the Ts65Dn model, the collected data do not suggest that Dp1Tyb/Dp(16)1Yey is a good model of the neurodevelopmental changes that are thought to underlie the ID in DS.”

Ts65Dn has never consistently shown volumetric changes that persist into adulthood except in the cerebellum.

“It has also never consistently shown volumetric changes that persist into adulthood except in the cerebellum.”

No animal models fully recapitulate the known anatomical and cellular changes observed in individuals with DS that are hypothesized to underlie ID.

“While there are many models that mimic both the initial genetics (triplication of HSA21 genes) and ID (deficits in learning and memory), to the best of our knowledge, there are no models that fully recapitulate the known anatomical and cellular changes observed in individuals with DS that are hypothesized to underlie the ID.”

Human equivalent age of engrafted neurons (5-8 months) is comparable to samples showing increased spine number in human tissue.

“However, the human equivalent age of the engrafted neurons (5–8 months) during this time period is comparable to the samples that show an increase spine number in human tissue (Becker et al., 1986).”

• cites Becker et al., 1986 sourceNot checked — no full text of the source

Neither study precisely matches the human data.

“In addition to contradicting each other, neither study precisely matches the human data indicating there is still much work to do, both in understanding the human phenotype and modeling it to understand its molecular origin.”

Increased astrocyte differentiation at the expense of neuronal differentiation is a strong glial phenotype in iPSC culture.

“Once of the strongest glial phenotypes observed in iPSC culture is increased astrocyte differentiation at the expense of neuronal differentiation.”

No change in electrical properties of trisomic early cortical neurons.

“One study found no change in the electrical properties of either excitatory or inhibitory trisomic early cortical neurons indicating that at that stage, there is no difference in intrinsic ability to communicate (Weick et al., 2013).”

• cites Weick et al., 2013 sourceNot checked — no full text of the source

iPSC studies of neurogenesis in DS have produced conflicting results.

“However, using iPSCs to model changes in neurogenesis has produced conflicting results.”

Decreased NPC pool leads to neuronal hypocellularity observed in tissue samples from individuals with DS.

“This consistent phenotype, found in humans, mice, and iPSCs, further supports the hypothesis that a decreased NPC pool leads to the neuronal hypocellularity observed in tissue samples from individuals with DS.”

A range of cellular phenotypes have been observed from differentiated trisomic cells.

“Due to this wide array of methodologies and cell lines used to generate a variety of cell types, a range of cellular phenotypes have been observed from the differentiated trisomic cells.”

Differentiation protocol is important when examining neurodevelopment in DS.

“These discordant results reported with the same cell lines perhaps explain the divergent results in previous studies and emphasize the importance of differentiation protocol when examining neurodevelopment in DS.”

In trisomic organoids, there is a significant increase in GABAergic interneurons, specifically calretinin and somatostatin positive.

“Similar to studies in Ts65Dn, a significant increase in GABAergic interneurons was identified in both isogenic and matched lines of trisomic organoids differentiated to a ventral forebrain fate (Xu et al., 2019). Specifically, an increase in calretinin and somatostatin positive interneurons was identified.”

• cites Xu et al., 2019Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Dp1Tyb/Dp(16)1Yey has not shown any of the well-described neurodevelopmental phenotypes.

“Meanwhile Dp1Tyb/Dp(16)1Yey has not shown any of these well described phenotypes even though it models both the genetics and the learning and memory deficits.”

The Yamanaka factors Oct3/4, Sox2, c-Myc, and Klf4 are sufficient to reprogram terminally differentiated cells back to a pluripotent state.

“With the discovery of the “Yamanaka factors,” Oct3/4, Sox2, c-Myc, and Klf4, that are sufficient to reprogram terminally differentiated cells back to a pluripotent state (Takahashi and Yamanaka, 2006), iPSCs derived from individuals with DS have been produced to study cellular and molecular underpinnings of DS while circumnavigating the drawbacks of mouse models.”

• cites Takahashi and Yamanaka, 2006 sourceNot checked — no full text of the source

Multiple changes in neural and glial development have been identified in Down syndrome through combined studies of human tissue and model systems.

“Through these combined studies, multiple changes in neural and glial development have been identified.”

Neurodevelopmental phenotypes that arise above the noise of human variability and model systems are likely to represent key phenotypes that strongly underlie intellectual disability in Down syndrome.

“These phenotypes that arise above the noise of human variability and model system are likely to represent key phenotypes that strongly underlie the ID and now need to be expanded upon.”

Early reports suggest that MAC21 and TsHSA21rat recapitulate some DS related phenotypes.

“Early reports suggest that the mouse and rat do recapitulate some DS related phenotypes and more work is eagerly awaited in hopes that these new models will provide insights into the some of the open questions regarding the etiology and development of well characterized DS related phenotypes.”

• cites Kazuki et al., 2020, 2022Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In trisomic organoids, there is an increased proportion of OLIG2 expressing NPCs.

“A similar study examining changes in the production of interneurons but in an organoid system found an increase in proportion of OLIG2 expressing NPCs in the trisomic organoids differentiated toward a ventral forebrain fate (Xu et al., 2019).”

• cites Xu et al., 2019Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

It is difficult to study the underlying mechanism or elucidate the role the decrease in brain volume plays in the intellectual disability in individuals with Down syndrome because the phenotype is not present in rodent models.

“as this phenotype is not present in the rodent models it is difficult to study the underlying mechanism or elucidate the role the decrease in brain volume plays in the ID in individuals with DS.”

No studies differentiating iPSCs to oligodendrocytes or microglia in DS have been reported.

“While many studies have examined iPSC derived astrocytes, currently, no studies differentiating iPSCs to oligodendrocytes or microglia have been reported in the context of DS though changes in both of these glia types have been reported in humans and mice.”

These models faithfully recapitulate some non-neuronal phenotypes.

“As mentioned, these models do appear to faithfully recapitulate some of the non-neuronal phenotypes and so would be useful in studying those important issues as they also affect quality of life in individuals with DS.”

• cites Li et al., 2007Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Lana-Elola et al., 2016, 2021Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Alterations in glia have been described in DS.

“Alterations in glia have been described in DS in addition to changes in neuronal development.”

Variable and discordant results in the Down syndrome neurodevelopment literature hamper using the data to elucidate molecular mechanisms or identify pharmacological targets.

“using it as a jumping off point to either elucidate the molecular mechanisms driving the phenotypes or identify pharmacological targets is hampered by the variable and discordant results.”

• AssumptionRests on an assumption: The discordant results in the Down syndrome neurodevelopment literature are due to a combination of technical limitations and true underlying biological variability.

The field has a broad understanding of multiple cellular phenotypes that are likely driving the intellectual disability in Down syndrome.

“We have a broad understanding of multiple cellular phenotypes that are likely driving the ID in DS.”