EFFECTS OF VITAMIN A ON BEHAVIOR AND CORTICAL NEURONAL POPULATIONS IN A GENETIC MOUSE MODEL OF AUTISM

Vitamin A (VA) and its active metabolite retinoic acid (RA) play essential roles during brain development, and altered VA serum levels has been implicated in autism spectrum disorders (ASD). Here, we investigated the effects of different gestational VA levels on postnatal behavior and cortical neuronal populations in a genetic mouse model of syndromic autism, Pitt-Hopkins syndrome (PTHS, TCF4 deficiency). Using this model, we analyzed excitatory and inhibitory neuronal populations in the cerebral cortex, assessed postnatal behavioral outcomes, and quantified serum retinol levels. The expression of genes related to VA metabolism was evaluated in the cerebral cortex at postnatal days (P) 0–7 and P90. In parallel, oral gavage (OG) supplementation with RA was performed at embryonic days E12 and E14, and VA deprivation (VAD) during gestation was used to assess early postnatal behavioral changes. PTHS mice exhibited an altered balance between excitatory SATB2-positive neurons at P0, and inhibitory interneurons at P14, which was associated with significant impairments in early postnatal olfactory memory and reflex behaviors. Gene expression analyses revealed reduced cortical expression of VA metabolism-related enzymes at P7 and P90. Contrary to expectations for ASD models, PTHS mice displayed increased serum retinol levels compared to controls at P7 and P90, and high-dose gestational VA supplementation failed to improve behavioral outcomes. In contrast, gestational VAD showed trends toward partial recovery of early postnatal olfactory memory. These findings suggest an atypical regulation of VA metabolism in PTHS and identify gestational VA modulation as a potential therapeutic avenue for this ASD model.