Hippocampus/amygdala alterations, loss of heparan sulfates, fractones and ventricle wall reduction in adult BTBR T+ tf/J mice, animal model for autism

Mercier, Frédéric; Kwon, Youngsu Cho; Douet, Vanessa

doi:10.1016/j.neulet.2011.11.007

Cited by 46 publications

(35 citation statements)

References 25 publications

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“…In addition, a genome-wide scan for rare copy number variation (CNV) in 996 autism cases has identified four independent CNVs in the GPC5/ GPC6 gene cluster, which encodes the glypican-5 and glypican-6 HSPGs in tandem array, on chromosome 13q22 (22). Finally, data from mouse models of autism also suggest the possible connection between autism and HS: Recently it has been shown that the level of HS immunoreactivity is reduced in the brain tissue of BTBR T +tf/J mice (23,24), a strain that exhibits a host of behaviors recapitulating the major symptoms of autism (25,26).…”

mentioning

confidence: 99%

Autism-like socio-communicative deficits and stereotypies in mice lacking heparan sulfate

Irie

Badie-Mahdavi

Yamaguchi

2012

Proc. Natl. Acad. Sci. U.S.A.

134

113

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Heparan sulfate regulates diverse cell-surface signaling events, and its roles in the development of the nervous system recently have been increasingly uncovered by studies using genetic models carrying mutations of genes encoding enzymes for its synthesis. On the other hand, the role of heparan sulfate in the physiological function of the adult brain has been poorly characterized, despite several pieces of evidence suggesting its role in the regulation of synaptic function. To address this issue, we eliminated heparan sulfate from postnatal neurons by conditionally inactivating Ext1, the gene encoding an enzyme essential for heparan sulfate synthesis. Resultant conditional mutant mice show no detectable morphological defects in the cytoarchitecture of the brain. Remarkably, these mutant mice recapitulate almost the full range of autistic symptoms, including impairments in social interaction, expression of stereotyped, repetitive behavior, and impairments in ultrasonic vocalization, as well as some associated features. Mapping of neuronal activation by c-Fos immunohistochemistry demonstrates that neuronal activation in response to social stimulation is attenuated in the amygdala in these mice. Electrophysiology in amygdala pyramidal neurons shows an attenuation of excitatory synaptic transmission, presumably because of the reduction in the level of synaptically localized AMPA-type glutamate receptors. Our results demonstrate that heparan sulfate is critical for normal functioning of glutamatergic synapses and that its deficiency mediates socio-communicative deficits and stereotypies characteristic for autism.glycosaminoglycan | conditional knockout | multiple hereditary exostoses

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mentioning

confidence: 99%

Autism-like socio-communicative deficits and stereotypies in mice lacking heparan sulfate

Irie

Badie-Mahdavi

Yamaguchi

2012

Proc. Natl. Acad. Sci. U.S.A.

134

113

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“…Mice engineered to be impaired in the ability to sulfate heparan-sulfate chains in the brain suffered from all of the pathologies associated with "mouse-autism" [127]. Structural pathologies in the hippocampi were associated with depletion of heparan sulfate in the lateral ventricles in the brains at autopsy of mice exhibiting a mouse-model of autism [128]. Similar heparan sulfate deficiencies were also observed in postmortem analyses of human brains of individuals with autism [129].…”

Section: Sulfate Synthesis By Nitric Oxide Synthasesmentioning

confidence: 69%

Aluminum?s Role in CNS-immune System Interactions leading to Neurological Disorders

CA¹

2013

Immunome Res

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Multisystem interactions are well established in neurological disorders, in spite of conventional views that only the central nervous system (CNS) is impacted. We review evidence for mutual interactions between the immune and nervous systems and show how these seem to be implicated in the origin and progression of nervous system disorders. Well-established immune system triggers leading to autoimmune reactions are considered. Of these, aluminum, a known neurotoxicant, may be of particular importance. We have demonstrated elsewhere that aluminum has the potential to induce damage at a range of levels in the CNS leading to neuronal death, circuit malfunction and ultimately, system failure. Aluminum is widely used as an adjuvant in various vaccine formulations and has been implicated in a multisystem disorder termed "autoimmune/inflammatory syndrome induced by adjuvants" (ASIA). The implications of aluminum-induced ASIA in some disorders of the CNS are considered. We propose a unified theory capturing a progression from a local response to a systemic response initiated by disruption of water-based interfaces of exposed cells.

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“…Autism is a neurodevelopmental disorder resulting from neural alterations that occur during development and post-natal life (Mercier et al, 2012), thereby providing a small window of opportunity for therapeutic intervention early in life. Identification of 'at risk' infants, e.g.…”

Section: Autismmentioning

confidence: 99%

“…For example, pharmaceutical intervention could interfere with neural plasticity in order to prevent the development of autism-related deficits. A genetic animal model that is used to study autism is the inbred BTBR T+ tf/J mouse strain, because it exhibits several symptoms of the disease including reduced social interactions, impaired play and diminished exploratory behavior (Mercier et al, 2012). These mice display severe forebrain alterations, collapsed lateral ventricles and shrunken CPs in the anterior portions of the lateral ventricles (Mercier et al, 2012).…”

Section: Autismmentioning

confidence: 99%

“…A genetic animal model that is used to study autism is the inbred BTBR T+ tf/J mouse strain, because it exhibits several symptoms of the disease including reduced social interactions, impaired play and diminished exploratory behavior (Mercier et al, 2012). These mice display severe forebrain alterations, collapsed lateral ventricles and shrunken CPs in the anterior portions of the lateral ventricles (Mercier et al, 2012). As the CP has important immunological, neuroendocrine and secretory roles, its atrophy probably has many, yet unknown, consequences.…”

Section: Autismmentioning

confidence: 99%

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Therapeutic implications of the choroid plexus–cerebrospinal fluid interface in neuropsychiatric disorders

Demeestere

Libert

Vandenbroucke

2015

Brain, Behavior, and Immunity

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Hippocampus/amygdala alterations, loss of heparan sulfates, fractones and ventricle wall reduction in adult BTBR T+ tf/J mice, animal model for autism

Cited by 46 publications

References 25 publications

Autism-like socio-communicative deficits and stereotypies in mice lacking heparan sulfate

Autism-like socio-communicative deficits and stereotypies in mice lacking heparan sulfate

Aluminum?s Role in CNS-immune System Interactions leading to Neurological Disorders

Therapeutic implications of the choroid plexus–cerebrospinal fluid interface in neuropsychiatric disorders

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