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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 Huntington’s Disease (HD) 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. Optical imaging and optical stimulation provide techniques to monitor activity in larger populations of neurons and within microcircuits. We also utilize transgenic animals designed to allow 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.
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. 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 transmission and plasticity at thalamostriatal synapses
Mechanisms of phasic and tonic dopamine signaling in the striatum
The role of striatal microcircuits in synaptic integration and basal ganglia circuit function
Striatal neurophysiology of Huntington’s disease
Striatal neurophysiology of Parkinson’s disease
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. Neurotransmission: emerging roles of endocannabinoids. Current Biology 15:R549-551, 2005
Foster KF, Kreitzer AC, Regehr WG. Interaction of postsynaptic receptor saturation with presynaptic mechanisms produces a reliable synapse. Neuron 36:1115-1126, 2002.
Kreitzer AC, Regehr WG. Retrograde signaling by endocannabinoids. Current Opinions in Neurobiology 12:324-330, 2002.
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. Cerebellar depolarization-induced suppression of inhibition is mediated by endogenous cannabinoids. Journal of Neuroscience RC174:1-5, 2001.
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.
Kreitzer AC, Regehr WG. Modulation of transmission during trains at a cerebellar synapse. Journal of Neuroscience 20:1348-1357, 2000.
Dittman JS, Kreitzer AC, Regehr WG. Interplay between facilitation, depression, and residual calcium at three presynaptic terminals. Journal of Neuroscience 20:1374-1385, 2000.
Anatol Kreitzer , Ph.D.
Phone
415-734-2507
Mailing Address
Gladstone Institute of Neurological Disease
1650 Owens St., Room 307
San Francisco, CA 94158
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