Anatol Kreitzer, Ph.D.
Assistant Investigator
Gladstone Institute of Neurological Disease
Assistant Professor of Physiology and Neurology
University of California, San Francisco
Email: akreitzer@gladstone.ucsf.edu
Telephone: 415-734-2507
Fax: 415-355-0824

Areas of Investigation
The research in our laboratory is focused on understanding the mechanisms of cellular and synaptic plasticity within neural circuits of the basal ganglia that control motor planning, learning, and movement. Our long-term goal is to understand how plasticity in these circuits shapes motor behavior and how neurological disorders such as Parkinson’s disease (PD) and Huntington’s disease (HD) affect synaptic, cellular, and circuit function in the basal ganglia.

Significance
The control of movement is among the most fundamental functions of the nervous system. The basal ganglia, and the striatum in particular, play a critical role in the selection and learning of appropriate actions. Individuals suffering from movement disorders such as PD or HD have profound difficulties performing appropriate movements, yet the cellular and synaptic basis of these disorders is not well understood. A thorough knowledge of the mechanisms underlying circuit function in the basal ganglia, both in health and disease, will provide a framework that can be used to develop novel treatments for neurological disorders.

Approaches
To address the functional properties of basal ganglia motor circuits, our laboratory applies a variety of experimental approaches. We use whole-cell patch-clamp electrophysiology in brain slices, which allows us to record and analyze the properties of synaptic currents from individual neurons. Optical imaging provides a technique to monitor activity in larger populations of neurons and within microcircuits. Transgenic animals expressing biological indicators in specific subpopulations of neurons allow for the in vitro and in vivo identification and modification of basal ganglia circuit function. Additionally, we use genetic and pharmacological animal models of human disease, as well as a battery of behavioral testing procedures.

Contributions
The striatum forms the input nucleus of the basal ganglia, and striatal projection neurons target either the substantia nigra pars reticulata (direct pathway) or the lateral globus pallidus (indirect pathway). Imbalances between neural activity in these two circuits have been proposed to underlie the profound motor deficits observed in PD and HD. We described important differences in the cellular and synaptic properties of striatal medium spiny neurons in these pathways, including the selective expression of a form of long-term synaptic depression (LTD) mediated by endocannabinoid signalling and regulated by dopamine at indirect pathway synapses. In animal models of PD, this LTD was absent but could be rescued by an inhibitor of endocannabinoid degradation. This inhibitor could also enhance the rescue of locomotor deficits in PD models, suggesting that modulation of the endocannabinoid system could provide a novel therapeutic target for the treatment of basal ganglia disorders.

Questions Addressed in Ongoing Studies

• What are the physiological roles of the anatomical compartmentalization of the striatum and basal ganglia?
• How can we selectively modulate different basal ganglia circuits in vitro and in vivo?
• How do striatal microcircuits function in information transfer through the basal ganglia?
• What is the functional role of dopamine signaling and what signaling pathways lie downstream of dopamine receptor activation?
• How can we restore basal ganglia circuit function in the absence of dopamine, such as during PD?
• What are the physiological causes of striatal cell death in HD?
• Can we design novel strategies for reducing or eliminating neuronal death in HD?

Recent Publications

 
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