Neuroscience Graduate Program at UCSF
Synaptic Plasticity and Circuit Function in the Basal Ganglia
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 learning, selection, and initiation of appropriate actions. Individuals suffering from movement disorders such as Parkinson’s Disease (PD) or dystonia have profound difficulties performing appropriate movements, yet the cellular and synaptic basis of these disorders is not well understood. A thorough understanding 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.
To address the functional properties of basal ganglia motor circuits, my laboratory applies a variety of experimental approaches. We perform whole-cell patch-clamp electrophysiology in brain slices, which allows us to record and analyze the properties of synaptic currents from individual neurons. We utilize in vivo single-unit recordings in awake behaving mice. Both in vitro and in vivo experiments take advantage of recently-developed optogenetic techniques to identify and selectively stimulate different cell types. In vivo recording/optogenetic experiments are integrated with sophisticated behavioral monitoring techniques, allowing a detailed picture of neural activity in specified cell types in vivo during behavior.
A major focus of the laboratory is the striatum, which forms the input nucleus of the basal ganglia. 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 have 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. More recently, we have characterized the functional role of the direct and indirect pathways in behaving animals, using optogenetic methods. Current studies are aimed at elucidating additional pathway-specific mechanisms of neuromodulation and synaptic plasticity in the striatum and their role in basal ganglia circuit function and motor control.
Mechanisms and function of synaptic plasticity in basal ganglia circuits
Synaptic plasticity and dendritic integration of thalamostriatal and corticostriatal inputs
The role of tonic and phasic dopamine signaling in the striatum
The role of striatal microcircuits in striatal function and dysfunction
Regulation of basal ganglia output nuclei by direct and indirect pathway activity
The pathophysiology of Parkinson’s disease and dystoniaThe role of direct and indirect pathways in motor learning
Ben Freeze, MSTP Graduate Student
Aryn Gittis, Postdoctoral Fellow
Nora Hammack, Research Associate
Giao Hang, Postdoctoral Fellow
Robyn Javier, Graduate Student
Lex Kravitz, Postdoctoral Fellow
Talia Lerner, Graduate Student
Alexandra Nelson, Postdoctoral Fellow
Phil Parker, Graduate Student
Lynne Tye, Graduate Student
Kravitz AV, Freeze BS, Parker PRL, Kay K, Thwin MT, Deisseroth K, Kreitzer AC. Regulation of parkinsonian motor behaviors by optogenetic control of basal ganglia circuitry. Nature 466:622-626, 2010
Gittis AH, Nelson AB, Thwin AT, Palop JJ, Kreitzer AC. Distinct roles of GABAergic interneurons in the regulation of striatal output pathways. Journal of Neuroscience 30(6):2223-2234, 2010
Lerner TN, Horne EA, Stella N, Kreitzer AC. Striatal endocannabinoid signaling mediates psychomotor activation by adenosine A2A antagonists. Journal of Neuroscience 30(6):2160-2164, 2010
Kreitzer AC, Malenka RC. Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson’s disease models. Nature 445:643-647, 2007
Kreitzer AC, Malenka RC. Dopamine modulation of state-dependent endocannabinoid release and LTD in the striatum. Journal of Neuroscience 25(45):10537-10545, 2005.
Kreitzer AC, Carter AG, Regehr WG. Inhibition of interneuron firing extends the spread of endocannabinoid signaling in the cerebellum. Neuron 34:787-796, 2002.
Kreitzer AC, Regehr WG. Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells. Neuron 29:717-727, 2001.
Kreitzer AC, Gee KR, Archer EA, Regehr WG. Monitoring presynaptic calcium dynamics in projection fibers by in vivo loading of a novel calcium indicator. Neuron 27:25-32, 2000.
Anatol Kreitzer , Ph.D.
UCSF MC 1230
Gladstone Institute of Neurological Disease
1650 Owens Street, Room 307
San Francisco, CA 94158