Regulation of inhibitory synapse function by Neuroligin 2 membrane dynamics, trafficking and phosphorylation

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Nerve cells communicate with each other via specialised cell-cell contact sites called synapses. On the presynaptic side the input neuron releases neurotransmitters that activate specialised neurotransmitter receptors located on the receiving neuron at the postsynaptic side. Synapses can have either an excitatory (activating) or an inhibitory (inactivating) role in brain signalling. For the brain to function well, it is important that synapses are formed correctly, i.e. the pre- and postsynaptic side are precisely apposed to each other, and that brain activity is properly regulated. If synapses do not wire correctly during development or go wrong later in life this can lead to devastating neuropsychiatric and neurodegenerative brain disorders like Schizophrenia, autism and Alzheimer's disease, respectively. The protein family of Neuroligins play a key role in synapse formation and maintenance. They are positioned in the membrane of the postsynaptic side and, by binding the protein Neurexin at the presynaptic side, bridge the synaptic cleft. Neuroligin-2 (NL2) is specifically located at the inhibitory synapse, where it induces clustering of the protein gephyrin to form a scaffold. The main inhibitory neurotransmitter receptor of our central nervous system, the GABA-A receptor, is then stabilised at the synapse by gephyrin and LHFPL4. Synapses can change their strength in response to changes in neural activity, an important property for key brain functions such as learning and memory, and for maintaining the balance between excitation and inhibition. The strength of the response at a synapse can be regulated by altering the size of the scaffold and the number of attached neurotransmitter receptors. Through its role in stabilising the synapse, NL2 is likely to be a key regulator of the number of GABA-A receptors in the postsynaptic membrane, and thus of inhibitory synapse strength and information processing in the brain. Little is known, however, about the molecular mechanisms that control NL2 number at the synapse, or its dynamic movement into and out of the synapse.We have initial data suggesting that brain activity causes a change in the amount of NL2 on the cell surface, through its release from the synapse and uptake into the cell (a process called endocytosis). We have also identified a number of novel proteins that interact with NL2 and may be involved with either its stabilisation at the synapse, or regulating whether NL2 taken into the cell is recycled to the synapse or sent for destruction. It is, however, still unknown how brain activity affects these processes, and reciprocally how alterations of NL2 number at the synapse affects its strength. Our research is therefore aimed at answering the following related questions:- Under what physiologically relevant conditions is the stability of NL2 at the synapse altered?- How do the various binding partners of NL2 regulate its stability at the synapse, as well as its endocytosis, recycling and degradation?- How do changes in the amount of NL2 at the synapse affect the strength of the inhibitory synapse?Ultimately, by gaining molecular insight into how inhibitory synapses are formed and regulated, we will better understand how wiring in the brain is controlled. In addition, since synaptic dysfunction is implicated in many neurodegenerative and neuropsychiatric diseases, our proposed work may also lead to an improved understanding of diseases such as epilepsy, stroke, Alzheimer's disease, Huntington's disease and schizophrenia, and may suggest targets for therapeutic intervention. A detailed understanding of the processes that we study for NL2, will also have implications for other Neuroligins, synaptic membrane proteins, and membrane proteins in non-neuronal cells. Thus, our research may contribute to understanding basic cell biological principles as well as specifically how connections in the brain are formed and maintained.