Roles of GABAA and GABAB receptors in regulating thalamic activity by the zona incerta: A computational study Abbreviated Title: GABA receptors in incerto-thalamic circuit

The posterior thalamic nucleus (PO) is a higher order nucleus heavily implicated in the processing of somatosensory information. We have previously shown in rodent models that activity in PO is tightly regulated by inhibitory inputs from a GABAergic nucleus known as the zona incerta (ZI). The level of incertal inhibition varies under both physiological and pathological conditions, leading to concomitant changes in PO activity. These changes are causally linked to variety of phenomena from altered sensory perception to pathological pain. ZI regulation of PO is mediated by GABAA and GABAB receptors (GABAAR and GABABR) that differ in their binding kinetics and their electrophysiological properties, suggesting that each may have distinct roles in incerto-thalamic regulation. We develop a computational model to test this hypothesis. We created a two-cell Hodgkin-Huxley model representing PO and ZI with kinetically realistic GABAAR and GABABR mediated synapses. We simulated spontaneous and evoked firing in PO, and observed how these activities were affected by inhibition mediated by each receptor type. Our model predicts that spontaneous PO activity is preferentially regulated by GABABR mediated mechanisms, while evoked activity is preferentially regulated by GABAAR. Our model also predicts that modulation of ZI firing rate and synaptic GABA concentrations are effective means to regulate the incerto-thalamic circuit. The coupling of distinct functions to GABAAR and GABABR presents an opportunity for the development of therapeutics, as particular aspects of incerto-thalamic regulation can be targeted by manipulating the corresponding receptor class. Thus, these findings may provide interventions for pathologies of sensory processing.