Background: Schizophrenia (SZ) is a long-term psychiatric condition that affects cognition, thought processing, emotional regulation, and behavior. Epigenetic modifications during pregnancy or early postnatal development increase vulnerability to SZ by disrupting the balance of GABAergic-glutamatergic neurotransmission. Objective: The association between GABAergic interneurons and inflammation has been increasingly investigated. Systemic inflammation alters the expression of GABAergic interneuron markers, including somatostatin and parvalbumin, in various brain regions. These modifications contribute to microglial reactivity and neuronal damage. Neuroinflammation, driven by reactive microglia, is recognized as a pathophysiological mechanism associated with SZ and its cognitive domain. Methods: In this review, we addressed the role of GABAergic interneurons and examined how neuroinflammation interacts with epigenetic changes, contributing to SZ development. Network analysis was used to reveal potential molecular targets for pharmacological studies. Results: Functional analysis of TLR4 and NF-κB1 revealed molecular factors relevant to inflammatory processes and gene regulation. Network analysis of GABA receptor A type 1 and TNF identified molecular targets suitable for pharmacological intervention. Protein-chemical interaction analysis showed that TLR4 and NF-κB1 interact with the polyphenols quercetin, epigallocatechin gallate, and resveratrol, all of which exert anti-inflammatory effects via epigenetic mechanisms, as well as the HDAC inhibitor valproic acid. Conclusion: Epigenetic changes in GABAergic interneurons may facilitate circuit imbalance and exacerbate psychotic symptoms. Epigenetic alterations in cortical parvalbumin-positive GABAergic interneurons and modifications in glutamate-mediated excitatory neurotransmission during early neurodevelopment contribute to the pathogenesis of SZ, alongside concomitant neuroinflammation. Targeting these epigenetic modifications and neuroinflammation may reveal new treatment strategies for the pharmacological management of SZ.
Matrisciano et al. (2026) studied this question.