Recruitment of the local GABAergic population engages complex network interactions in the ventral subiculum

Abstract

The ventral subiculum (vSub), a major output node of the hippocampal formation, has been implicated in diverse neurological disorders. Disruption of excitatory-inhibitory balance is a common feature of neurological disorders, with altered GABAergic signaling representing a critical component. More recently, the vSub has gained increasing attention as a component of neural circuits underlying emotional and motivational regulation, through its extensive connections with regions implicated in mental health disorders such as addiction and anxiety. Our previous work in models of alcohol use disorder and comorbid anxiety identified an important role for GABAergic inhibition in regulating vSub excitability, prompting us to investigate the functional consequences of recruiting the broader local GABAergic population. Although previous studies have examined individual interneuron subtypes, the network consequences of activating the global population of local GABAergic neurons remain poorly understood. To address this question, we expressed channelrhodopsin using an mDlx-dependent strategy to target GABAergic neurons in the ventral hippocampus and performed in vivo electrophysiological recordings from vSub neurons in anesthetized rats. Repeated activation of this GABAergic population at 20 Hz, a stimulation frequency commonly used in behavioral optogenetic studies, produced robust suppression of pyramidal neuron firing during stimulation. This direct inhibition was accompanied by network-dependent increases in post-stimulus activity that varied as a function of baseline activity, sex, and trial number. Complementary ex vivo electrophysiological experiments further supported network-dependent effects and revealed short-term synaptic plasticity that evolved across repeated stimulation trials, reflecting contributions from both pre- and postsynaptic mechanisms. Together, these findings demonstrate that recruitment of the broader GABAergic population produces effects extending beyond direct inhibition and can engage dynamic network responses that depend on stimulation history and circuit state. These findings highlight the importance of stimulation frequency, timing, and network context when interpreting the functional consequences of GABAergic circuit manipulation.