HDAC3 inhibitors(Birla Institute of Technology & Science)

Schizophrenia is a complex neurodevelopmental disorder with cognitive impairment being one of the core features that remains largely unresponsive to current antipsychotic treatments. Histone deacetylase 3 (HDAC3), a negative regulator of memory and synaptic plasticity, has been implicated in neurodegenerative conditions, but its role remains underexplored in psychosis. Here, we hypothesized that aberrant HDAC3 activity contributes to hippocampal dysfunction and learning deficits in schizophrenia. Pregnant SD rats were administered methylazoxymethanol (MAM; 20 mg/kg) and vehicle on GD 17. We characterized the pharmacokinetic profile of selective HDAC3 inhibitor, SP108, to ensure adequate BBB penetration and systemic exposure. Next, adult male offspring were administered SP108 (25 mg/kg, i.p.) and vehicle every day for 3 weeks, followed by behavioral analysis. The MAM-exposed group showed schizophrenia-like behavioral patterns with increased hippocampal HDAC3 expression and activity. HDAC3 inhibitor treatment selectively ameliorated avoidance learning and MK801-induced hyperlocomotion. At the molecular level, HDAC3 inhibition elevated hippocampal H3K9 acetylation and increased the expression of synaptic plasticity markers BDNF and PSD95. To establish a neurodevelopmental link, HDAC3 knockdown was performed in differentiating neurons from mouse embryonic stem cells (mESCs) exposed to MAM at the early differentiating phase in vitro. HDAC3 knockdown in MAM-exposed differentiating neurons enhanced MAP2 intensity and neurite length with improved levels of MAP2, NeuN, TUBB3 (neuronal differentiation and maturation markers), BDNF, and PSD95 (neuroplasticity markers). Collectively, these findings identify HDAC3 as an important regulator of hippocampal dysfunction and cognitive impairment in a schizophrenia-like preclinical model, highlighting its potential to augment the therapeutic outcomes beyond current antipsychotic treatments.