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Mechanisms of inhibitory transmission at hippocampal synapses


The human brain contains billions of individual cells called neurons which are responsible for controlling all functions from breathing to complex thought. These neurons communicate with each other via the synapse, locations where signals from the presynaptic cell are relayed to the postsynaptic cell. Depending on the type of cell transmitting the signal and the receptors activated on the cell receiving the signal, each instance of communication either relays an excitatory or inhibitory response to increase or decrease the firing of the postsynaptic cell respectively. Each cell receives both excitatory and inhibitory connections from multiple different neurons. Cells that transmit inhibitory signals are much more diverse than the cells that transmit excitatory signals. Adding to this complexity is the vast diversity of proteins expressed at the synapse of inhibitory connections, varying from the composition of the receptors receiving the signal to the presence of multiple transsynaptic adhesion molecules stabilizing and mediating the line of communication. Recent advances have given us the molecular tools in which to probe the function of these proteins overall and with respect to particular connections they may be involved in. Here, I examine the function of two isoforms of the neuroligin family of cell adhesion molecules at inhibitory synapses. I find that one isoform, neuroligin 3, is unable to function at the inhibitory synapse without the presence of the other isoform, neuroligin 2, and that this difference could be attributed to a domain within the extracellular region. I also show that neuroligin 2 can function in both a gephyrin-dependent and gephyrin-independent manner and identify key residues mediating these interactions. I also characterize an autism-associated mutation in the neuroligin 4X isoform and show that it prevents the function of this neuroligin at excitatory synapses by blocking its phosphorylation by PKC. Lastly, I utilize CRISPR/Cas9 technology and optogenetic methods to characterize the function of the different β subunit isoforms of the GABAA receptor in inhibitory transmission. I find that a functional GABAA receptor requires the β subunit and that knockout of the β3 subunit in particular significantly impairs inhibitory transmission coming from PV but not SOM interneurons.

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