ArticleMolecular neurobiology2014
Pax6-dependent cortical glutamatergic neuronal differentiation regulates autism-like behavior in prenatally valproic acid-exposed rat offspring.
Article in Molecular neurobiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers.
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74 citing papers in PubMed, 131 citations in OpenAlex.
- Genetic and pharmacological evidence linking CB1R signaling to hippocampal GABAergic dysfunction in ASD mouse model.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- Multiomics analysis identifies VPA-induced changes in neural progenitor cells, ventricular-like regions, and cellular microenvironment in dorsal forebrain organoids.Molecular psychiatry · 2026Article
- Children with Autism Spectrum Disorder and Chronic Gastrointestinal Symptoms Have Alterations in Intestinal Neurotransmitter Pathways.Digestive diseases and sciences · 2026Article
- Targeting notch signaling to restore neural development and behavior in mouse models of ASD.Nature communications · 2026Article
- Digestive Neurobiology in Autism: From Enteric and Central Nervous System Interactions to Shared Genetic Pathways.International journal of molecular sciences · 2025Review
- Sulforaphane protects developing neural networks from VPA-induced synaptic alterations.Molecular psychiatry · 2025Article
- Contextual auditory processing in the inferior colliculus is affected in a sex- and age-dependent manner in the valproic acid-induced rat model of autism.PLoS biology · 2025Article
- Effects of Pharmacological Treatment on Telomere Length and the Expression of Telomerase/Shelterin-Related Genes in Rat Models of Autism.Journal of molecular neuroscience : MN · 2025Article
- Sex-Specific Behavioral Features of the Prenatal Valproic Acid Rat Model of Autism Spectrum Disorder.Brain sciences · 2025Article
- Gene expression differences in the olfactory bulb associated with differential social interactions and olfactory deficits in Pax6 heterozygous mice.Biology open · 2025Article
- Astrocytic gatekeeping of neural circuitry and synaptic balance in an autism mouse model: mechanistic insights beyondFrontiers in cell and developmental biology · 2025Article
- Altered prefrontal and cerebellar parvalbumin neuron counts are associated with cognitive changes in male rats.Experimental brain research · 2024Article
- VPA-induced autism impairs memory ability through disturbing neural oscillatory patterns in offspring rats.Cognitive neurodynamics · 2024Article
- Gestational valproic acid exposure enhances facial stimulation-evoked cerebellar mossy fiber-granule cell transmission via GluN2A subunit-containing NMDA receptor in offspring mice.Translational psychiatry · 2024Article
- N-Methyl-D-Aspartate (NMDA) Receptor Antagonists and their Pharmacological Implication: A Medicinal Chemistry-oriented Perspective Outline.Current medicinal chemistry · 2024Review
- Three Decades of Valproate: A Current Model for Studying Autism Spectrum Disorder.Current neuropharmacology · 2024Review
- Group I and group II metabotropic glutamate receptors are upregulated in the synapses of infant rats prenatally exposed to valproic acid.Psychopharmacology · 2023Article
- Saffron and crocin ameliorate prenatal valproic acid-induced autistic-like behaviors and brain oxidative stress in the male offspring rats.Metabolic brain disease · 2023Article
- Valproate-induced murine autism spectrum disorder is associated with dysfunction of amygdala parvalbumin interneurons and downregulation of AMPK/SIRT1/PGC1α signaling.Metabolic brain disease · 2023Article
- Hydroalcoholic extract of Passiflora incarnata improves the autistic-like behavior and neuronal damage in a valproic acid-induced rat model of autism.Journal of traditional and complementary medicine · 2023Article
14 more citing papers are in PubMed but not listed here.
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9 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Imbalance in excitatory/inhibitory signal in the brain has been proposed as one of the main pathological features in autism spectrum disorders, although the underlying cellular and molecular mechanism is unclear yet. Because excitatory/inhibitory imbalance can be induced by aberration in glutamatergic/GABAergic neuronal differentiation, we investigated the mechanism of dysregulated neuronal differentiation between excitatory and inhibitory neurons in the embryonic and postnatal brain of prenatally valproic acid-exposed rat offspring, which is often used as an animal model of autism spectrum disorders. Transcription factor Pax6, implicated in glutamatergic neuronal differentiation, was transiently increased in embryonic cortex by valproate exposure, which resulted in the increased expression of glutamatergic proteins in postnatal brain of offspring. Chromatin immunoprecipitation showed increased acetylated histone binding on Pax6 promoter region, which may underlie the transcriptional up-regulation of Pax6. Other histone deacetylase (HDAC) inhibitors including TSA and SB but not valpromide, which is devoid of HDAC inhibitor activity, induced Pax6 up-regulation. Silencing Pax6 expression in cultured rat primary neural progenitor cells demonstrated that up-regulation of Pax6 plays an essential role in valproate-induced glutamatergic differentiation. Blocking glutamatergic transmission with MK-801 or memantine treatment, and to a lesser extent with MPEP treatment, reversed the impaired social behaviors and seizure susceptibility of prenatally valproate-exposed offspring. Together, environmental factors may contribute to the imbalance in excitatory/inhibitory neuronal activity in autistic brain by altering expression of transcription factors governing glutamatergic/GABAergic differentiation during fetal neural development, in conjunction with the genetic preload.
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