CAREER: Optical approaches to Synaptic Learning Rules

Princeton University, Princeton NJ

Investigators

Abstract

Synaptic learning rules describe the relationship between neural activity patterns and the resulting changes in synaptic strength. Such persistent modifications of synaptic strength are widely believed to underlie functional changes such as learning in the central nervous system. Increases and decreases in synaptic strength - long-term potentiation (LTP) and long-term depression (LTD) - are present in a wide variety of excitatory synapses and have been the focus of thirty years of intensive research. In recent years, whether an activity pattern induces LTP or LTD has been shown to depend on the exact timing of single presynaptic and postsynaptic action potentials. But in the most general case, the rules for how activity is mapped to plasticity are not well understood. A key issue in the study of LTP and LTD is the lack of a unifying model that explains synaptic plasticity in terms of individual plasticity events. Work in this proposal will identify separable components of bidirectional plasticity. The investigators will then measure the activity dependent properties of these components, and use these properties to account for the original rules observed in the entire synaptic ensemble. The model system to be used is the mammalian hippocampal Schaffer collateral-CA1 synapse, which has NMDA-type and metabotropic glutamate receptors that evoke postsynaptic dendritic calcium signals. Calcium is an intermediate bottleneck in synaptic plasticity, and this fact will be used to divide the project into separate questions: How is activity mapped to calcium? How is calcium mapped to plasticity? These questions will be pursued in three stages. First, bidirectional plasticity will be separated into component mechanisms of potentiation and depression/depotentiation. Second, rules will be measured by which activity is transformed into synaptic plasticity and to dendritic calcium signals, which are known to be necessary and sufficient to induce both potentiation and depression. Third, calcium signals will be identified that are optimally tuned to evoke potentiation or depression, and used to create a general model predicting plasticity for arbitrary patterns of synaptic activity. Taken together, these experiments will test the idea that calcium signals can be used to predict the type and amount of plasticity resulting from an arbitrary pattern of synaptic neural activity. Experimental tools include patch clamp recording, multiphoton laser scanning microscopy, and focal photolysis of caged neurotransmitters and second messengers. Particular use will be made of an instrument for uncaging at many sites at once (up to 100,000 locations per second). The proposed experiments may help provide a general framework for learning rules not only at hippocampal synapses, but in the rest of the vertebrate central nervous system. This work will support the continued development of the institutions program in neurobiology through course development and graduate and postdoctoral training. Further, the work should result in continued development of experimental tools useful to the scientific community.