Project 3An injury to the nervous system induces chronic changes in synaptic activity. Experimentally producedchanges in synaptic activity have been shown to induce compensatory changes in synaptic strength. Thismodulation has been termed homeostatic since the changes are in the direction that maintains networkactivity at its normal level. Most studies of homeostatic modulation have used manipulations that up- ordown-regulate presynaptic and postsynaptic activity in parallel. After an injury the situation is likely to bemore complex. Partial denervation of a cell may reduce postsynaptic activity but have little, or no, effect onthe level of activity of its remaining inputs. The result will be chronic mismatches in pre-and postsynapticactivity. In this situation it is unclear what the 'homeostatic response' would be. In the most popular versionof the homeostatic hypothesis the postsynaptic cell is the key element. The postsynaptic cell is proposed tosense a change in its activity and react by increasing its own responsiveness to all its inputs. However,recent results in the literature, and our own studies, suggest a different view. We believe that both thepre-and the postsynaptic elements are important in the response to a chronic change in activity. In our model,changes in activity of the presynaptic and postsynaptic cells trigger distinct sets of changes in synapticproperties. Our model can better account for previously published findings following chronic mismatches ofpre- and postsynaptic activity than can the current homeostatic model. In this proposal, we will use themammalian neuromuscular junction and will independently alter pre-and postsynaptic activity to determinewhich model can better predict changes in synaptic strength triggered by altered activity. Understandinginjury-induced plasticity of synaptic strength is an essential step in the search for therapeutic strategies.Only when we understand how the nervous system responds to injury will we be able to harness thesemechanisms to promote more extensive recovery.
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