Distance-dependent synaptic inhibition in hippocampal neuronal networks

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Synaptic interactions between GABAergic inhibitory cells, and glutamatergic excitatory principal cells (PCs) play a fundamental role in processing of information in the brain. Interneuron axons, in particular the ones of parvalbumin (PV)-expressing perisomatic inhibitory interneurons (PIIs), distribute densely over large distances controlling the electrical activity of thousands of target PCs by means of their inhibitory output synapses. They contribute thereby markedly to the processing and storing of information. However, whether IN output signalling in the mature cortex is homogeneously distributed in the network to full-fill the proposed functions, is largely unknown. Our current data indicate that PII-mediated inhibitory output signalling in the dentate gyrus (DG) is not uniformly strong and rapid as previously thought, but highly heterogeneous. Indeed, this heterogeneity is spatially and temporally ordered. We show that the functional properties of perisomatic inhibition depend on the axonal distance between communicating partners, with strong and fast inhibition to close neighbours and weaker and slower inhibition to distant cells. We term this synaptic property distance-dependent inhibitory signalling. In the proposed project we aim to examine (1) whether this form of inhibitory signalling is specific to PIIs or whether it is more generally applicable to other identified interneuron types such as dendrite targeting interneurons by performing quadruple recordings from one presynaptic interneuron and several target cells (principal cells and interneurons). We will focus these investigations on the rodent DG which plays a crucial role as input region of the hippocampus by transcoding the rich multimodal input from the entorhinal cortex into an orthogonalized sparse code for the CA3 area. (2) We aim to examine the cellular and molecular mechanisms underlying interneuron-mediated distance-dependent inhibition by applying a multidisciplinary approach which combines electrophysiological, morphological, immunhistochemical and 2-Photon (2P) imaging techniques in acute hippocampal slice preparations. (3) We will examine whether distance-dependent inhibition is counterbalanced by glutamatergic synaptic excitation. (4) We will test whether distance-dependent inhibition supports processing of information by examining its contribution to the synchronization of fast rhythms in neuronal networks, in particular at gamma (g; 30-100 Hz) frequencies, and the formation of synchronously active cell assemblies by a close interaction between experimental investigations and computational neuronal network analysis. Considering the crucial role of interneurons, in particular PV-PIIs in higher brain function, and their strong relation to cognitive disorders resulting from their malfunction, we believe that this work will markedly contribute to a better understanding of interneurons and synaptic non-uniformity in cortical information processing.