Absence of Prenatal Forebrain Defects in the Dp(16)1Yey/+ Mouse Model of down Syndrome.
Open accessAbstract
Studies in humans with Down syndrome (DS) show that alterations in fetal brain development are followed by postnatal deficits in neuronal numbers, synaptic plasticity, and cognitive and motor function. This same progression is replicated in several mouse models of DS. Dp(16)1Yey/+ (hereafter called Dp16) is a recently developed mouse model of DS in which the entire region of mouse chromosome 16 that is homologous to human chromosome 21 has been triplicated. As such, Dp16 mice may more closely reproduce neurodevelopmental changes occurring in humans with DS. Here, we present the first comprehensive cellular and behavioral study of the Dp16 forebrain from embryonic to adult stages. Unexpectedly, our results demonstrate that Dp16 mice do not have prenatal brain defects previously reported in human fetal neocortex and in the developing forebrains of other mouse models, including microcephaly, reduced neurogenesis, and abnormal cell proliferation. Nevertheless, we found impairments in postnatal developmental milestones, fewer inhibitory forebrain neurons, and deficits in motor and cognitive performance in Dp16 mice. Therefore, although this new model does not express prenatal morphological phenotypes associated with DS, abnormalities in the postnatal period appear sufficient to produce significant cognitive deficits in Dp16. SIGNIFICANCE STATEMENT Down syndrome (DS) leads to intellectual disability. Several mouse models have increased our understanding of the neuropathology of DS and are currently being used to test therapeutic strategies. A new mouse model that contains an expanded number of DS-related genes, known as Dp(16)1Yey/+ (Dp16), has been generated recently. We sought to determine whether the extended triplication creates a better phenocopy of DS-related brain pathologies. We measured embryonic development, forebrain maturation, and perinatal/adult behavior and revealed an absence of prenatal phenotypes in Dp16 fetal brain, but specific cellular and behavioral deficits after the first 2 postnatal weeks. These results uncover important differences in prenatal phenotype between Dp16 animals and humans with DS and other DS mouse models.
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Recent studies indicate an increased ratio of inhibitory to excitatory neurons in the cortex and hippocampus in Dp16 mice that is associated with deficits in learning, memory, and motor function.
“recent studies that indicate an increased ratio of inhibitory to excitatory neurons in the cortex and hippocampus in Dp16 mice that is associated with deficits in learning, memory, and motor function.”
From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [44]
The section on P15 neuronal populations reports fewer PV-positive and Sst-positive inhibitory interneurons in Dp16 somatosensory cortex, not an increased inhibitory-to-excitatory ratio; it attributes higher inhibition in cortex and hippocampus to prior findings in Ts65Dn mice. The Motor assessment and Cognitive assessment sections do report motor, learning, and memory deficits in Dp16 mice, but do not establish the claimed association with an increased ratio. Page numbers were not provided in our copy. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredDp16 mice exhibit hyperactive IFN signaling and recapitulate many phenotypes of DS including developmental delays, cranial malformations, and cognitive deficits.
“Notably, Dp16 mice exhibit hyperactive IFN signaling and recapitulate many phenotypes of DS including developmental delays, cranial malformations, and cognitive deficits.38,40,42,43,44,45”
From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [44]
The Introduction reports craniofacial dysmorphology in Dp16 mice, and the paper reports delayed postnatal developmental milestones and impaired adult cognitive performance. Neither the supplied passages nor a search of our copy for IFN and interferon signaling supports the claim of hyperactive IFN signaling. Page numbers were not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSeveral commonly used cognitive tests employed here, including RAWM, rotarod, and the open field task, could be partially a function of non-neurological contributors to motor function that have been reported in Dp16 mice.
“Several commonly used cognitive tests employed here, including RAWM, rotarod, and the open field task, could be partially a function of non-neurological contributors to motor function that have been reported in Dp16 mice.44”
From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [44]
The Motor assessment section (page not provided) reports reduced open-field locomotion, impaired hindlimb reflexes, and motor weakness in adult Dp16 mice. It does not identify non-neurological causes of those impairments or test whether they affect RAWM or rotarod performance; the proposed contribution to those tests remains an inference. (LLM, conf=0.83)
Experimental — accuracy not yet measuredDp(16)1Yey show no change in brain volume, NPC proliferation, neurogenesis, or neuronal density in the developing forebrain; Dp1Tyb show no changes in cerebellar anatomy.
“No change in brain volume, NPC proliferation, neurogenesis, or neuronal density was identified in the developing forebrain (Goodliffe et al., 2016) nor any changes in cerebellar anatomy in Dp1Tyb (Watson-Scales et al., 2018).”
From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Goodliffe et al., 2016
The sections on gross embryo and brain size, neural precursors, and neurogenesis report comparable prenatal forebrain dimensions, proliferation, and neuronal production in Dp16 and controls (page unavailable). They do not establish unchanged brain volume or prenatal neuronal density; the paper also reports changes in some cortical neuronal populations at P15. The Dp1Tyb cerebellum clause is attributed to Watson-Scales et al., not Goodliffe et al., and is outside this verdict. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe Ts65Dn DS mouse model demonstrates embryonic and early postnatal gene expression, neuroanatomical, and developmental behavioral deficits like those observed in DS.
“The Ts65Dn DS mouse model demonstrates embryonic and early postnatal gene expression, neuroanatomical, and developmental behavioral deficits like those observed in DS, whereas other DS models, including Dp1Yey and TcMAC21, do not have or have not yet been tested for these phenotypes (Aziz et al., 2018; Goodliffe et al., 2016).”
From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Goodliffe et al., 2016
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).”
From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Goodliffe et al., 2016
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).”
From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Goodliffe et al., 2016
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“No change in brain volume, NPC proliferation, neurogenesis, or neuronal density was identified in the developing forebrain (Goodliffe et al., 2016) nor any changes in cerebellar anatomy in Dp1Tyb (WatsonScales et al.”
BackgroundMethodSelf-citationModeling Down syndrome in animals from the early stage to the 4.0 models and next
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“…embryonic and early postnatal gene expression, neuroanatomical, and developmental behavioral deficits like those observed in DS, whereas other DS models, including Dp1Yey and TcMAC21, do not have or have not yet been tested for these phenotypes (Aziz et al., 2018; Goodliffe et al., 2016).”
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- Authors
- Goodliffe, J. W., Olmos-Serrano, J. L., Aziz, N. M., Pennings, J. L. A., Guedj, F., Bianchi, D. W., & Haydar, T. F.
- Affiliations
- Boston University (US)
- National Institute for Public Health and the Environment (NL)
- Tufts Medical Center (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2016-03-09
- Volume
- 36
- Issue
- 10
- Pages
- 2926-2944
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4783496
- OpenAlex
- W2306947905
- Cited by
- 65
- References
- 73
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 5 · 2023: 5 · 2022: 6 · 2021: 8 · 2020: 8 · 2019: 5 · 2018: 4 · 2017: 5 · 2016: 3
- FWCI
- 5.62
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Rivm (National Institute for Public Health and the Environment) (submittedVersion)
- Funders
- National Institute of Mental Health
- National Institute of Child Health and Human Development
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD05780)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- Down syndrome, forebrain development, postnatal neurodevelopment, inhibitory neurons, motor impairment, cognitive impairment, intellectual disability, mouse models of Down syndrome, neurodevelopmental disorders
- MeSH terms
- Age Factors, Animals, Animals, Newborn, Brain, Developmental Disabilities, Chromosomes, Human, Pair 16, Disease Models, Animal, Down Syndrome, Embryo, Mammalian, Exploratory Behavior, Female, Genotype, Humans, Male, Mice, Inbred C57BL, Mice, Mutant Strains, Trisomy, Maze Learning, Craniofacial Abnormalities, Mice, Muscle Strength, Neurogenesis, Nestin, Spatial Memory
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