Inhibitory regulation of hippocampal CA3 neuron activity, learning, and memory

PROJECT SUMMARY/ABSTRACT Inhibitory GABAergic neurons comprise only about 15% of all neurons in the brain yet their activity is critical for all aspects of brain function and GABA neuron dysfunction is implicated in many neurological disorders and mental illnesses. In particular, inhibition likely plays a unique and important role in hippocampal area CA3. In the CA3 region, DG neurons synapse onto CA3 pyramidal neurons via giant excitatory mossy fiber terminals and CA3 neurons make many recurrent connections. Thus, the potential for runaway excitation in CA3 is high. Feed-forward inhibition from DG to CA3 is thought to be critical allow specific excitatory inputs to generate meaningful activity patterns. Despite the likely importance of inhibition in hippocampal area CA3, few studies have directly examined how GABA neuron activity controls CA3 pyramidal neuron activity. We identified a group of dendrite-targeting GABA neurons that commonly express the synaptogenic protein Kirrel3. Kirrel3 protein is necessary to form MF filopodia synapses, a special type of excitatory synapse that connects DG neurons to GABA neurons and mediates feed- forward inhibition to CA3. Because Kirrel3 must be expressed in both the pre- and post-synaptic neuron to make a synapse, it strongly suggests Kirrel3-expressingn GABA neurons are direct targets of MF filopodia and the study of K3-GABA neurons will shed light on the precise function of MF filopodia-mediated inhibition in CA3. We will test this in three aims spanning ultrastructural analysis to large-scale functional cell imaging to behavior. Throughout, we will examine the selectivity of this group of dendrite-targeting GABA neurons by comparing their function to soma- targeting neurons that do not express Kirrel3. Regardless of outcome, our results are expected advance our understanding of GABA neuron activity in learning and memory and could provide a new framework for studying GABA neurons that share synaptic connectivity genes.