Dynamic Homeostatic Plasticity within Cerebellar Circuitry

University Of Washington, Seattle WA

Investigators

Abstract

The mechanisms that underlie the ability to acquire new knowledge about the external world, to remember it, and to use the information to behave appropriately and adaptively is a long-standing interest of humankind. Experience-dependent plasticity of the synaptic connections between neurons is generally accepted as the cellular mechanism with which a neural circuitry acquires and stores new information, commonly known as learning and memory. This project studies the homeostatic mechanisms that regulate the positive feedback nature of synaptic plasticity, that is, the mechanisms that bound activity levels within an appropriate dynamic range to preserve the ability of plasticity near saturation of activity as well as near absence of activity. How such complex homeostatic tasks are accomplished in the brain is poorly understood. Here, these homeostatic mechanisms are studied in the cerebellum of the mormyrid fish, whose cerebellar circuitry as well as its outputs and inputs are well defined and accessible for detailed examination. Using a combination of electrophysiological, imaging, and pharmacological approaches, the investigators characterize changes in the input/output relationships of cerebellar Purkinje cells during long-term potentiation and long-term depression of synaptic input to these cells, and begin to elucidate the underlying mechanisms. The results will have broad implications for understanding of the neural substrates of learning and memory. The project also involves outreach to Seattle area elementary and middle schools, to teach about behavioral plasticity of electric fish. Synaptic plasticity is generally accepted as the cellular mechanism with which a neural circuitry acquires and stores new information, commonly known as learning and memory. The most studied forms of plasticity include Hebbian long-term potentiation (LTP) and depression (LTD). Hebbian plasticity operates in a positive loop, leading to runaway neuronal activity and requiring additional compensatory processes to stabilize the neural circuitry. Many forms of homeostatic plasticity have been suggested as providing such compensatory role. However, unlike Hebbian synaptic plasticity, the demonstrated forms of homeostatic plasticity require very different time courses to be induced (hours to days versus seconds to minutes). Furthermore, modeling studies suggest that the slow evolution of homeostatic plasticity observed in experiments is insufficient to prevent instabilities of Hebbian plasticity. This project examines rapid, compensatory synaptic processes that could potentially prevent the instabilities associated with the positive feedback nature of Hebbian plasticity. Using dual whole-cell recording in slice reparations of the mormyrid cerebellum, the investigator has found that the strength of a Purkinje cells output synapses onto their target cells is up- and downregulated following LTD and LTP at the same cell’s input synapses, respectively. Here, a combination of in-vitro electrophysiological, imaging, and pharmacological approaches extend these observations to examine the characteristics and mechanisms underlying this bidirectional regulation of a cell’s output transmission following Hebbian plasticity at its input synapses. Establishment of this form of rapid, dynamic homeostatic plasticity and its underlying mechanisms will yield valuable insights into elementary processes of synaptic plasticity. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.