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The stem cell transcription factor SOX2 is essential for astrocyte maturation and controls animal hyperactive behavior

ABSTRACT: Children with SOX2-deficiency develop anophthalmia/microphthalmia and display neurological impairment. Here we report an essential role for astroglial SOX2 in brain anomalies and neurological defects. Sox2-deficiency inhibited postnatal astrocyte maturation without affecting astroglial proliferation and population expansion. Mechanistically, we found that SOX2 directly bound to a cohort of astrocytic signature genes such as those involving in glutamate transport and that Sox2-deficiency remarkably reduced glutamate transporter expression and compromised astrocyte function of glutamate uptake. Behaviorally, astroglial Sox2-deficient mice developed hyperactivity in locomotion while their motor skills, social capability, and learning abilities were unaffected. We found that astroglial Sox2-deficiency results in elevated glutamatergic synapse formation and elevated excitability of striatal medium spiny neurons, which has been shown to trigger hyperactive locomotion. Our study provides new insights into the biological mechanisms underlying brain defects in children with SOX2 mutations and unveils a novel connection between astrocyte SOX2 and brain development and behavior.

ORGANISM(S): Mus musculus

PROVIDER: GSE182032 | GEO | 2021/08/14

REPOSITORIES: GEO

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Project description:Succinate semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder effecting approximately 350 people around the world. Patients suffering from SSADH deficiency experience language acquisition failure, memory deficiencies, autism, increased aggressive behaviors, and seizures. There is a chemical buildup of both gamma-aminobutyric acid (GABA) and gamma-hydroxybutyric acid (GHB) in the neurological system of these patients. The Aldh5a1-/- knock out mouse model of SSADH deficiency shows the same chemical imbalances as the human disease, with additional fatal tonic-clonic seizures at three weeks of age. The elucidation of seizure causing pathways will facilitate treatment of seizure phenotypes in diseases with related epilepsy. Gene expression patterns within the hippocampus, cerebellum, and cortex of SSADH deficient mice (Aldh5a1-/- mice) will be compared to wild type mice at a time point immediately prior to fatal seizures. We hypothesis that the SSADH deficient mice experience a dysfunction of glutamate/GABA/ glutamine neurotransmitter cycle linked to astroglial metabolism and/or uptake of neuronally-released glutamate. The increased levels of GHB and GABA lead to down regulation of GABA-B-Receptor leading to seizures. The SSADH deficient phenotype may also be caused by ongoing oxidative damage and the pathological role of succinic semialdehyde. SSADH deficient mice (Aldh5a1-/- knock out) exhibit fatal seizures around three weeks of age. Mutant and wild type mice will be sacrificed between 17 and 19 days of life, and brain sections will be extracted and frozen (using a standard protocol). Hippocampus, cerebellum, and cortex from three mutant mice and three wild type mice will individually be expression profiled on the Affymetrix platform, giving a total of eighteen arrays. Comparative analysis will then be carried out, evaluating the transcript differences between mutant and wild type mice in each brain region. Keywords: other

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The stem cell transcription factor SOX2 is essential for astrocyte maturation and controls animal hyperactive behavior

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