The role of hippocampal long-term depression in novel spatial exploration

The exploration and encoding of a novel environment is a fundamental learning process that occurs on a short time scale, and is a useful model for studying how the hippocampus encodes and represents complex and arbitrary associations, as is required for episodic memory. Novelty exploration has been demonstrated to promote long-term depression (LTD) induction in area CA1 of the hippocampus, but it is unclear what role this LTD plays as the novel space becomes familiarized and encoded in the hippocampus. In order to determine whether de novo LTD occurs during novelty exploration, we utilized multi-array electrophysiological recording in freely moving rats and demonstrated an AMPA receptor endocytosis-dependent LTD in CA1 in the absence of a paired LTD induction protocol. To determine what role this LTD played in forming spatial representations, we recorded the spiking activity of multiple single units in hippocampal CA1 using multi-tetrode electrophysiological recordings to observe the development of place field firing in a novel environment, and the effect of LTD blockade using an inhibitor of AMPAR endocytosis. Place fields formed in the presence of LTD blockade, however the maintenance of place field firing location between the novel environmental exposure and re-exposure one day later was impaired by inhibition of LTD. To investigate the dynamics of place field formation over the first several minutes of exposure, hippocampal neurons were recorded during exposure to a novel linear environment. While fields developed and stabilized over several minutes in control rats, we found that LTD blockade produced a rapid establishment of stable place fields after a single lap, suggesting the dynamics of field formation are altered with LTD blockade. To test the role of this LTD in novel spatial learning, the effect of LTD blockade on contextual fear was assessed using a modification of inhibitory avoidance training that separated the acquisition of contextual information from the pairing with an aversive stimulus. This demonstrated that LTD is required on the first exposure to a novel context. These results place the activity dependent weakening of synapses as a central process in the rapid acquisition of novel spatial information in the hippocampus.Medicine, Faculty ofGraduat