Orexinergic regulation of GABAergic input onto pyramidal neurons in the anterior cingulate cortex

Orexin, a neuropeptide synthesized exclusively in the hypothalamus, projects its efferent fibers widely across nearly all brain regions and plays a role in the pathophysiology of psychiatric disorders by binding to and activating orexin receptor 1 (OX1R) and/or orexin receptor 2 (OX2R). The anterior cingulate cortex (ACC), particularly its pyramidal neurons, is known to play a critical role in fundamental cognitive and social processes. In this study, we investigated the effects of orexin-A on GABAergic transmission onto pyramidal neurons in the ACC of juvenile rats. Orexin-A was found to enhance both the frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs). This increase in mIPSC frequency depended on Ca²⁺ influx through T-type voltage-gated Ca²⁺ channels. Additionally, orexin-A facilitated GABA release probability and the number of releasable vesicles by modulating T-type Ca²⁺ channels. While orexin-A depolarized GABAergic fast-spiking interneurons, it did not alter their action potential firing rate. This depolarization was mediated by the inhibition of inward rectifier K⁺ (Kir) channels. Collectively, our findings suggest that orexin-A enhances GABA release by interacting with Kir channels and T-type Ca²⁺ channels.