Plasticity of the developing glutamate synapse in the hippocampus

Abstract

Synapses are highly plastic, i.e. they have the ability to change their signaling strength both in the short- and long-term (e.g. long-term potentiation - LTP) in response to specific patterns of activity. In the developing brain synaptic plasticity promotes activity-dependent development, whereas in the mature brain synaptic plasticity forms the basis for learning and memory. Although both development and learning involve organization and reorganization of synaptic circuits, the extent to which the plasticity behind these two phenomena uses the same mechanisms is unknown. The glutamate synapse which represents > 90 % of the brain synapses signals mainly via postsynaptic AMPA and NMDA receptors. In the developing brain, sparse synaptic activation can make the synapse lose its AMPA signaling capacity, i.e. make it AMPA silent, while LTP can reinstall the AMPA signaling (unsilencing). The aim of this study was to investigate the possible role of the AMPA silent synapse, and its unsilencing, in developmental and mature synaptic plasticity. Electrophysiological recordings of synaptic transmission in the CA1 region and in the dentate gyrus of acute hippocampal slices were used for these studies. A new and unexpected finding was that AMPA unsilencing can also be induced by not activating the AMPA silent synapse for tens of minutes. Together with previous findings this suggests a model in which the glutamate synapse is born with a single AMPA labile module, i.e. the synapse cycles between an AMPA silent state, induced by sparse synaptic activity, and an AMPA signaling state, induced by the absence of synaptic activity. The results further suggest that AMPA silencing is a prerequisite for developmental LTP to occur. In other words, developmental LTP does not potentiate synaptic transmission but rather stabilizes the AMPA labile module. It can, however, transiently potentiate the synapse by the addition of a labile AMPA module to an existing synapse with a single stable AMPA module. After this initial period of synaptic stabilization there is an increase in synaptic connectivity between pre- and postsynaptic neurons. It is proposed that this increased connectivity can be explained, at least partly, by the addition of stable AMPA modules to existing synapses promoted by mature LTP. This thesis thus proposes that, using the same principle mechanism, namely the addition of stable AMPA modules, developmental LTP promotes initial synaptic stabilization while mature LTP promotes synaptic growth.