The role of neuroligin-3 and neuroligin-4 in synaptic transmission, long-term synaptic plasticity and excitation/inhibition balance in dentate granule cells

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The dentate gyrus of the hippocampus is important for learning and memory. Efficient processing of information in the dentate network requires a fine balance of excitation and inhibition. This balance is controlled by molecular players at excitatory and inhibitory synapses. Therefore, in this project proposal, we focus on neuroligins (NLs). Neuroligins form a group of synaptic proteins, which play a critical role in balancing excitation and inhibition, as has been shown by our previous work on NL1 and NL2. NL3 and NL4 are clinically the most important neuroligins since gene mutations in NL3 and NL4 have been associated with autism spectrum disorders. Dysbalance between excitation and inhibition is thought to be the central mechanism underlying the pathogenesis of autism. However the regulation of the excitation-inhibition balance by NL3 and NL4 is poorly understood. Therefore, in this project proposal we focus on NL3- and NL4-dependent mechanisms for fine-tuning of excitatory and inhibitory synaptic transmission. Our main questions are: How do NL3 and NL4 influence the functional properties of dentate granule cells and their major excitatory input synapses? Does the loss of NL3 or NL4 in granule cells lead to impairments of their excitability or synaptic input properties and synaptic plasticity? How do NL3 and NL4 influence the in vivo network activity in the dentate gyrus circuitry? What are the effects of NL3 or NL4 deletion on network inhibition? What are the effects of altered NL3 or NL4 expression on excitation/inhibition balance selectively in dentate granule cells? Do NL3 or NL4 participate in maintaining normal output of dentate granule cells?This project pursues a novel experimental approach to uncover the role of NL3 and NL4 in the dentate gyrus of live animals. Specifically, the project proposes to use electrophysiological recordings in combination with neurohistological methods to unravel, at a cellular and network level, the functional impact of NL3 and NL4 loss in granule cells of the dentate gyrus. We will use conditional, cell-type specific knockout of NL3 to investigate the effects of selective deletion of NL3 in dentate granule cells. We aim to study the role of NL3 and NL4 in the dentate gyrus (1) in vivo, by using extracellular field potential recordings in the intact dentate gyrus circuitry of live animals, (2) ex vivo and in vitro, by using intracellular patch-clamp recordings and performing immunohistological analyses. The combination of genetic, functional and morphological methods will allow us to test the hypotheses concerning NL3 and NL4 effects on the balance of inhibition and excitation within the dentate gyrus.