Abstracts

Rationale: Hippocampal corticotropin-releasing hormone (CRH) neurons are a recently identified and sparsely characterized type of inhibitory interneuron. While previous studies demonstrated a critical role for CRH interneurons in stress-mediated effects in the hippocampus, they largely focused on the release of the excitatory neuropeptide CRH rather than the inhibitory neurotransmitter GABA. Recent work from our lab has demonstrated that CRH interneurons in stratum pyramidale of area CA1 form GABAergic synapses on CA3 principal cells. This unique anatomic and synaptic connectivity makes CRH interneurons well-suited to exert a strong influence over the excitability of the hippocampal network. Considering their role in stress signaling, CRH interneurons are therefore a highly attractive candidate for regulating the effects of stress on hippocampal excitability and seizure susceptibility. Using a transgenic mouse line to selectively manipulate CRH interneurons, we examined the effects of CRH interneuron activation in the hippocampus on neuronal excitability and susceptibility to seizures.Methods: To assess postsynaptic currents elicited by selective CRH interneuron activation, we performed whole-cell patch clamp while simultaneously activating hippocampal CRH neurons in acute brain slices from mice expressing Channelrhodopsin in CRH neurons (ChR-Crh). To examine the effects of CRH interneuron activation on hippocampal excitability, we applied field potential recordings from the mossy fiber-CA3 synapse in conjunction with optogenetics in ChR-Crh brain slices. The impact of selective optogenetic stimulation of CRH interneurons on seizure susceptibility was assessed using in vivo EEG recordings of kainic acid-induced seizures in ChR-Crh mice.Results: Optogenetic stimulation of CRH neuron projections gives rise to inhibitory postsynaptic currents in CA3 principal cells. Preliminary results suggest that at the network level, selective activation of CRH neurons causes an excitatory shift in the input-output curve at the mossy fiber-CA3 pathway, and alters susceptibility to acute seizures induced with kainic acid (20 mg/kg i.p.).Conclusions: We observed alterations in seizure susceptibility following optogenetic stimulation of CRH interneurons, suggesting that these neurons are capable of modulating hippocampal excitability. Consistent with the ability of CRH interneurons to modulate hippocampal function, we observe an excitatory shift in input-output curves at the mossy fiber-CA3 pathway following optogenetic stimulation of these interneurons. Given the excitatory and inhibitory effects of these neurons mediated by CRH and GABA signaling, respectively, these neurons may be able to bi-directionally modulate hippocampal activity under different conditions. A.H. was supported by the Dean’s Fellowship from the Sackler School of Graduate Biomedical Sciences at Tufts University School of Medicine. J.M. was supported by NS073574 and a Research Grant from the Epilepsy Foundation.