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
Lisa Gunaydin, Postdoctoral Fellow
Giao Hang, Postdoctoral Fellow
Arnaud Lalive D'Epinay, Postdoctoral Fellow
Moses Lee, Postdoctoral Fellow
Alexandra Nelson, Postdoctoral Fellow
Scott Owen, Postdoctoral Fellow
Phil Parker, Graduate Student
Tom Roseberry, Graduate Student
Delanie Schulte, Research Associate
Wall NR, De La Parra M, Callaway EM, Kreitzer AC (2013). Differential innervation of direct- and indirect-pathway striatal projection neurons. Neuron 79:347-60.
Kravitz AV, Tye LD, Kreitzer AC (2012). Distinct roles for direct and indirect pathway striatal neurons in reinforcement. Nature Neuroscience 15: 816–818.
Lerner TN, Kreitzer AC (2012). RGS4 is required for dopaminergic control of striatal LTD and susceptibility to parkinsonian motor deficits. Neuron 73:347-359.
Gittis AH, Hang GB, LaDow ES, Shoenfeld LM, Atallah BV, Finkbeiner S, Kreitzer AC (2011). Rapid target-specific remodeling of fast-spiking inhibitory circuits after loss of dopamine. Neuron 71:858-868.
Kravitz AV, Freeze BS, Parker PRL, Kay K, Thwin MT, Deisseroth K, Kreitzer AC (2010). Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Nature 466:622-626.
Anatol Kreitzer , Ph.D.
UCSF MC 1230
Gladstone Institute of Neurological Disease
1650 Owens Street, Room 307
San Francisco, CA 94158