At many excitatory synapses in the brain the strength of synaptic transmission is not fixed but instead can be regulated by patterns of synaptic stimulation. These long lasting changes in synaptic strength, known as long-term potentiation (LTP) and long-term depression (LTD), have a crucial role in the storage of new information during memory formation and are a prominent feature of synaptic transmission in brain regions that have an important role in learning and memory, such as the hippocampus. Although it is not yet clear how physiological patterns of synaptic activity might induce LTP and LTD in vivo, a number of studies indicate that the induction of LTP and LTD is critically dependent on the precise timing and order of single pre- and postsynaptic action potentials, a phenomenon known as spike timing-dependent plasticity or STDP.
STDP not only represents a physiologically realistic basis for understanding how LTP and LTD can be induced by normal patterns of neuronal activity but also provides a computationally powerful formulation for how these forms of synaptic plasticity might be involved in complex computational tasks such as coincidence detection and sequence learning. Importantly, STDP has been primarily studied in the immature brain and recent studies suggest that the properties of STDP are very different in the adult hippocampus. Thus, the functional role of STDP in the adult hippocampus is unclear. In this project a combination of electrophysiological, pharmacological, and modeling approaches will be used to study three fundamental aspects of STDP at excitatory synapses in the adult hippocampus. First, studies of cells in the highly interconnected neuronal network found in the hippocampal CA3 region will be used to determine whether STDP has a crucial role in allowing interconnected cells to form networks that avoid runaway excitation or epileptic-like activity. Second, studies in the hippocampal CA1 region, where cells are not highly interconnected but instead form simple feed-forward networks, will be used to investigate whether STDP exists in a latent or hidden form at synapses in feed-forward networks. Finally, experiments will be done to examine whether modulatory neurotransmitters known to have an important role in learning and memory can modulate the induction of STDP in the hippocampus. Together, the results of these experiments will provide key information regarding how STDP may be involved in hippocampal information processing and hippocampal-dependent forms of learning in the adult brain. Moreover, the project will provide a unique opportunity for the multidisciplinary training of both undergraduate and graduate students in a highly interactive project using a combination of cellular neurophysiological and computational approaches.
