(651) Prolonged GABAB receptor-mediated inhibition of dentate granule cell excitability

This abstract has been invited to present during the Better Patient Outcomes through Diversity Platform poster session

Rationale: Excessive activity of granule cells (GCs) in the dentate gyrus is associated with pathophysiological states such as temporal lobe epilepsy (TLE). In fact, the “dentate gate” theory of TLE proposes that seizures occur when the normally sparse response of GCs to afferent activity from the entorhinal cortex is disrupted.  This gating control is provided by both a heterogeneous network of interneurons that provides strong GABAergic inhibition and the low intrinsic excitability of GCs. We recently showed that GABA_B receptors coupled to G-protein-coupled inwardly rectifying potassium channels (GABA_B/GIRKs) contribute to both intrinsic excitability and synaptic inhibition, and that neural nitric oxide synthase (nNOS)-expressing interneurons are the primary source of GABA_B/GIRK inhibition (Gonzalez et al., 2018). As GABA_B receptor alterations are implicated with human epilepsy and animal models of TLE, and the GIRK1 subunit containing activator ML297 can suppress seizure activity, here we address how synaptic (phasic) and constitutive (tonic) GIRK-mediated inhibition regulates dentate GC excitability and dendritic integration.

Methods: We performed experiments in slices from adult wildtype and transgenic mice to show how GABA_B/GIRKs regulate synaptic integration at physiological stimulation frequencies. We made whole-cell recordings from GCs and interneurons to measure EPSPs and spike probability using single and train stimulation of the perforant path. We also used channelrhodopsin-2 (ChR2) targeted to parvalbumin (PV) and neuronal nitric oxide synthetase (nNOS) expressing interneurons to assess their contribution to GC inhibition.

Results: We found that tonic GABA_B/GIRK activity reduces GC excitability, decreasing the spike probability at all frequencies studied. In addition, we observed that phasic GABA_B/GIRK activation provides long-lasting control (around 350 ms) of GC excitability during gamma frequency trains. Studying how nNOS interneurons are recruited by the perforant path, we found that during gamma frequency stimulation these slow-spiking interneurons are synchronized to provide this long-lasting and robust inhibition compared to fast spiking PV interneurons. We mimicked nNOS interneuron recruitment during gamma frequency stimulation using ChR2 to show that GABA_B/GIRK activation provides hyperpolarization and a shunting conductance that reduces EPSP summation.

Conclusions: These results suggest that tonic and phasic GABA_B/GIRK channel activity constitute a strong mechanism to maintain sparse GC spiking. nNOS interneurons display frequency-dependent spike profiles that follow entorhinal rhythm activity to provide strong and long-lasting control of GC burst-firing. Enhancing GABA_B/GIRK signaling in dentate gyrus could be an effective strategy to control seizure activity.

Funding: Please list any funding that was received in support of this abstract.: AES Postdoctoral Research Fellowship (JCG)
NIH NS105438