Deficits in Morphofunctional Maturation of Hippocampal Mossy Fiber Synapses in a Mouse Model of Intellectual Disability

Kabuki syndrome is a Mendelian intellectual disability syndrome caused by mutations in either of two genes (KMT2D and KDM6A) involved in chromatin accessibility. We previously showed that an agent that promotes chromatin opening, the histone deacetylase inhibitor (HDACi) AR-42, ameliorates the deficiency of adult neurogenesis in the granule cell layer of the dentate gyrus and rescues hippocampal memory defects in a mouse model of Kabuki syndrome (Kmt2d+/βGeo). Unlike a drug, a dietary intervention could be quickly transitioned to the clinic. Therefore, we have explored whether treatment with a ketogenic diet could lead to a similar rescue through increased amounts of beta-hydroxybutyrate, an endogenous HDACi. Here, we report that a ketogenic diet in Kmt2d+/βGeo mice modulates H3ac and H3K4me3 in the granule cell layer, with concomitant rescue of both the neurogenesis defect and hippocampal memory abnormalities seen in Kmt2d+/βGeo mice; similar effects on neurogenesis were observed on exogenous administration of beta-hydroxybutyrate. These data suggest that dietary modulation of epigenetic modifications through elevation of beta-hydroxybutyrate may provide a feasible strategy to treat the intellectual disability seen in Kabuki syndrome and related disorders.

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The intellectual disability PAK3 R67C mutation impacts cognitive functions and adult hippocampal neurogenesis

Human Molecular Genetics ◽

10.1093/hmg/ddz296 ◽

2020 ◽

Vol 29 (12) ◽

pp. 1950-1968

Author(s):

Charlotte Castillon ◽

Laurine Gonzalez ◽

Florence Domenichini ◽

Sandrine Guyon ◽

Kevin Da Silva ◽

...

Keyword(s):

Intellectual Disability ◽

Mouse Model ◽

Spatial Memory ◽

Adult Neurogenesis ◽

Hippocampal Neurons ◽

Memory Task ◽

Clinical Signs ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Adult Born Neurons

Abstract The link between mutations associated with intellectual disability (ID) and the mechanisms underlying cognitive dysfunctions remains largely unknown. Here, we focused on PAK3, a serine/threonine kinase whose gene mutations cause X-linked ID. We generated a new mutant mouse model bearing the missense R67C mutation of the Pak3 gene (Pak3-R67C), known to cause moderate to severe ID in humans without other clinical signs and investigated hippocampal-dependent memory and adult hippocampal neurogenesis. Adult male Pak3-R67C mice exhibited selective impairments in long-term spatial memory and pattern separation function, suggestive of altered hippocampal neurogenesis. A delayed non-matching to place paradigm testing memory flexibility and proactive interference, reported here as being adult neurogenesis-dependent, revealed a hypersensitivity to high interference in Pak3-R67C mice. Analyzing adult hippocampal neurogenesis in Pak3-R67C mice reveals no alteration in the first steps of adult neurogenesis, but an accelerated death of a population of adult-born neurons during the critical period of 18–28 days after their birth. We then investigated the recruitment of hippocampal adult-born neurons after spatial memory recall. Post-recall activation of mature dentate granule cells in Pak3-R67C mice was unaffected, but a complete failure of activation of young DCX + newborn neurons was found, suggesting they were not recruited during the memory task. Decreased expression of the KCC2b chloride cotransporter and altered dendritic development indicate that young adult-born neurons are not fully functional in Pak3-R67C mice. We suggest that these defects in the dynamics and learning-associated recruitment of newborn hippocampal neurons may contribute to the selective cognitive deficits observed in this mouse model of ID.

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Nr2f1 heterozygous knockout mice recapitulate neurological phenotypes of Bosch-Boonstra-Schaaf optic atrophy syndrome and show impaired hippocampal synaptic plasticity

Human Molecular Genetics ◽

10.1093/hmg/ddz233 ◽

2019 ◽

Vol 29 (5) ◽

pp. 705-715 ◽

Cited By ~ 2

Author(s):

Chun-An Chen ◽

Wei Wang ◽

Steen E Pedersen ◽

Ayush Raman ◽

Michelle L Seymour ◽

...

Keyword(s):

Synaptic Plasticity ◽

Intellectual Disability ◽

Mouse Model ◽

Optic Atrophy ◽

Hippocampal Slices ◽

Long Term Potentiation ◽

Matrix Metalloproteases ◽

Autosomal Dominant Disorder ◽

Hippocampal Synaptic Plasticity

Abstract Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) has been identified as an autosomal-dominant disorder characterized by a complex neurological phenotype, with high prevalence of intellectual disability and optic nerve atrophy/hypoplasia. The syndrome is caused by loss-of-function mutations in NR2F1, which encodes a highly conserved nuclear receptor that serves as a transcriptional regulator. Previous investigations to understand the protein’s role in neurodevelopment have mostly used mouse models with constitutive and tissue-specific homozygous knockout of Nr2f1. In order to represent the human disease more accurately, which is caused by heterozygous NR2F1 mutations, we investigated a heterozygous knockout mouse model and found that this model recapitulates some of the neurological phenotypes of BBSOAS, including altered learning/memory, hearing defects, neonatal hypotonia and decreased hippocampal volume. The mice showed altered fear memory, and further electrophysiological investigation in hippocampal slices revealed significantly reduced long-term potentiation and long-term depression. These results suggest that a deficit or alteration in hippocampal synaptic plasticity may contribute to the intellectual disability frequently seen in BBSOAS. RNA-sequencing (RNA-Seq) analysis revealed significant differential gene expression in the adult Nr2f1+/− hippocampus, including the up-regulation of multiple matrix metalloproteases, which are known to be critical for the development and the plasticity of the nervous system. Taken together, our studies highlight the important role of Nr2f1 in neurodevelopment. The discovery of impaired hippocampal synaptic plasticity in the heterozygous mouse model sheds light on the pathophysiology of altered memory and cognitive function in BBSOAS.

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Specific Disruption of Hippocampal Mossy Fiber Synapses in a Mouse Model of Familial Alzheimer's Disease

PLoS ONE ◽

10.1371/journal.pone.0084349 ◽

2014 ◽

Vol 9 (1) ◽

pp. e84349 ◽

Cited By ~ 16

Author(s):

Scott A. Wilke ◽

Tara Raam ◽

Joseph K. Antonios ◽

Eric A. Bushong ◽

Edward H. Koo ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Mossy Fiber ◽

Familial Alzheimer’S Disease ◽

Familial Alzheimer's Disease

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Altered fronto-striatal functions in the Gdi1 -null mouse model of X-linked Intellectual Disability

Neuroscience ◽

10.1016/j.neuroscience.2016.12.043 ◽

2017 ◽

Vol 344 ◽

pp. 346-359 ◽

Cited By ~ 4

Author(s):

Lorenzo Morè ◽

Basil Künnecke ◽

Latefa Yekhlef ◽

Andreas Bruns ◽

Antonella Marte ◽

...

Keyword(s):

Intellectual Disability ◽

Mouse Model ◽

Null Mouse

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Mossy fiber sprouting and pyramidal cell dispersion in the hippocampal CA2 region in a mouse model of temporal lobe epilepsy

Hippocampus ◽

10.1002/hipo.22543 ◽

2015 ◽

Vol 26 (5) ◽

pp. 577-588 ◽

Cited By ~ 21

Author(s):

Ute Häussler ◽

Katrin Rinas ◽

Antje Kilias ◽

Ulrich Egert ◽

Carola A. Haas

Keyword(s):

Mouse Model ◽

Temporal Lobe Epilepsy ◽

Temporal Lobe ◽

Pyramidal Cell ◽

Mossy Fiber ◽

Mossy Fiber Sprouting ◽

Cell Dispersion

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Biallelic truncation variants in ATP9A are associated with a novel autosomal recessive neurodevelopmental disorder

10.1101/2021.05.31.21257832 ◽

2021 ◽

Author(s):

Francesca Mattioli ◽

Hossein Darvish ◽

Sohail Aziz Paracha ◽

Abbas Tafakhori ◽

Saghar Ghasemi Firouzabadi ◽

...

Keyword(s):

Intellectual Disability ◽

Mouse Model ◽

Autosomal Recessive ◽

High Throughput Sequencing ◽

Neurodevelopmental Disorder ◽

Behavioral Changes ◽

Causative Role ◽

Speech Impairment ◽

Lipid Flippase

Intellectual disability (ID) is a highly heterogeneous disorder with hundreds of associated genes. Despite progress in the identification of the genetic causes of ID following the introduction of high-throughput sequencing, about half of affected individuals still remain without a molecular diagnosis. Consanguineous families with affected individuals provide a unique opportunity to identify novel recessive causative genes. In this report we describe a novel autosomal recessive neurodevelopmental disorder. We identified two consanguineous families with homozygous variants predicted to alter the splicing of ATP9A which encodes a transmembrane lipid flippase of the class II P4-ATPases. The three individuals homozygous for these putatively truncating variants presented with severe ID, motor and speech impairment, and behavioral anomalies. Consistent with a causative role of ATP9A in these patients, a previously described Atp9a-/- mouse model showed behavioral changes.

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Male-specific CREB signaling in the hippocampus controls spatial memory deficits in a mouse model of autism and intellectual disability

10.1101/249649 ◽

2018 ◽

Cited By ~ 1

Author(s):

Marta Zamarbide ◽

Adele Mossa ◽

Molly K. Wilkinson ◽

Heather L. Pond ◽

Adam W. Oaks ◽

...

Keyword(s):

Intellectual Disability ◽

Mouse Model ◽

Neurodevelopmental Disorders ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Coiled Coil ◽

Autism Spectrum ◽

Behavioral Studies ◽

Males And Females ◽

Male Specific

ABSTRACTBackgroundThe prevalence of neurodevelopmental disorders is biased towards males with male: female ratios of 2:1 in intellectual disability (ID) and 4:1 in autism spectrum disorder (ASD). However, the molecular mechanisms of such bias remain unknown. While characterizing a mouse model for loss of the signaling scaffold coiled-coil and C2 domain containing 1A (CC2D1A), which is mutated in ID and ASD, we identified biochemical and behavioral differences between males and females, and explored whether CC2D1A controls male-specific intracellular signaling.MethodsCC2D1A is known to regulate phosphodiesterase 4D (PDE4D). We tested for activation PDE4D and downstream signaling molecules such as CREB in the hippocampus of Cc2d1a-deficient mice. We then performed behavioral studies in females to analyze learning and memory, social interactions, anxiety and hyperactivity. Finally, we targeted PDE4D activation with a PDE4D inhibitor to define how changes in PDE4D and CREB activity affect behavior in males and females.ResultsWe found that in Cc2d1a-deficient males PDE4D is hyperactive leading to a reduction in CREB signaling, but this molecular deficit is not present in females. Cc2d1a-deficient females only show impairment in novel object recognition, and no other cognitive and social deficits that have been found in males. Restoring PDE4D activity using an inhibitor rescues male-specific cognitive deficits, but has no effect on females.ConclusionsOur findings show that CC2D1A regulates intracellular signaling in a male-specific manner in the hippocampus leading to male-specific behavioral deficits. We propose that male-specific signaling mechanisms are involved in establishing sex bias in neurodevelopmental disorders.

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