Regulation of excitation and inhibition in early stages of neuronal differentiation and arborisation

Abstract

Neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD), schizophrenia (SCZ) and attention deficit hyperactivity disorder (ADHD), have been extensively linked to early-life excitatory/inhibitory (E/I) imbalances. These imbalances are particularly associated with alterations in the GABAergic inhibitory system. Numerous studies in neurodevelopmental research have reported a decreased expression of cortical GABAergic interneurons, which are responsible for releasing gamma-aminobutyric acid (GABA), in patients with NDDs. However, the precise mechanisms underlying this reduction in GABAergic interneurons remain unclear. This study investigated the effects of early-life prolonged GABA-a receptor activation on cortical GABAergic interneuron development in mice. Muscimol, a GABA-a receptor agonist, was injected intraperitoneally (0.5 mg/kg) to mice on post-natal days 3 to 5 (P3-P5). At P10, we employed immunohistochemistry and imaging analyses to assess three distinct GABAergic interneuron populations in the somatosensory cortex: parvalbumin-expressing (PV+), somatostatin-expressing (SST+), and calretinin-expressing (CR+). Our main results revealed a significant increase in PV+ interneuron density (cells/layer) within cortical layer V following muscimol treatment. Additionally, non-significant but consistent trends towards elevation were observed for all interneuron population densities (cells/mm²). These findings suggest that early-life GABA circuit disruption may initially increase GABAergic interneuron expression, potentially offering insight into the trajectory leading to the eventual decrease observed in NDDs. While limited by sample size, this research contributes to understanding the developmental processes that may lead to GABAergic deficits in NDDs. Further research with larger samples and longitudinal designs is needed to elucidate the long-term impacts of early GABAergic perturbations on interneuron populations and their potential relevance to NDD pathology.