The basal ganglia is an essential component of the central circuitry controlling voluntary movement as well as sensorimotor integration, motor and non-motor learning, and a number of higher cognitive functions. The major input structure of the basal ganglia is the striatum, comprised mostly of medium sized GABAergic spiny projection neurons (MSNs) that make up about 95% of striatal neurons in the rodent. The remaining neurons consist of cholinergic interneurons and 3 types of GABAergic interneurons. The GABAergic interneurons play a crucial role in striatal function by participating in a powerful feedforward inhibitory circuit that affects spike timing in the spiny neurons. Dopamine (DA), originating in the substantia nigra, has long been recognized to play an essential role in striatal function, and it is the degeneration of the nigrostriatal DAergic pathway that is the cause of Parkinson's disease, a progressive and incurable disorder that affects between 1 and 1.5 million Americans. In addition to the cell types listed above, a population of striatal neurons has been recognized that expresses tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of DA. In primates essentially all of these neurons also express the DA transporter (DAT) suggesting strongly that they are DAergic. These neurons also express glutamate decarboxylase, the enzyme responsible for the synthesis of GABA and a common marker for GABAergic neurons. The numbers of these neurons increases several-fold following DA denervation, and some of these neurons have been shown to express L-amino acid decarboxylase (AADC) and the vesicular monoamine transporter (VMAT). These neurons could represent a heretofore-unappreciated source of striatal DA and a potentially useful source of compensation for DA loss in idiopathic Parkinson's disease as well as a potential target for novel therapeutic approaches to the treatment of the disease. These striatal TH+ neurons represent novel components of the intrastriatal circuitry about which little or nothing is known, since they have never been recorded from, but only studied with immunocytochemistry. We used striatal slices from mice genetically engineered to express enhanced green fluorescent protein (EGFP) under the control of the TH promoter to obtain visually guided recording from these neurons in brain slices. We have identified 4 electrophysiologically distinct subtypes and provide preliminary data on their efferent and afferent synaptic connectivity. Using these mice, both untreated and after unilateral dopaminergic denervation and/or L-DOPA replacement therapy, we will describe the basic electrophysiological properties of striatal DA neurons, their afferent and efferent connectivity, compensatory changes in DA depletion animal models of PD, and their role in striatal DA and GABAergic neurotransmission. In addition, these mice afford a novel way to study the electrophysiological and anatomical properties of uncharacterized populations of striatal interneurons that have been difficult or impossible to study previously in any systematic way.

Public Health Relevance

Parkinson's disease (PD) is the most common neurological disorder, affecting nearly 15% of people over the age of 65 and over 50% of people over the age of 85. This translates to approximately 1.5 million Americans. The disease is progressive and incurable. PD is caused by a loss of dopamine input to the neostriatum, a brain structure that controls voluntary movement. In this project we will characterize electrophysiologically, neurochemically and neuroanatomically novel dopamine-like neurons in the striatum that have the potential to serve as the focal point for novel therapeutic approaches to ameliorating the symptoms of the PD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034865-14
Application #
8289646
Study Section
Sensorimotor Integration Study Section (SMI)
Program Officer
Sutherland, Margaret L
Project Start
1997-02-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
14
Fiscal Year
2012
Total Cost
$331,209
Indirect Cost
$116,834
Name
Rutgers University
Department
None
Type
Organized Research Units
DUNS #
130029205
City
Newark
State
NJ
Country
United States
Zip Code
07102
√únal, Bengi; Shah, Fulva; Kothari, Janish et al. (2015) Anatomical and electrophysiological changes in striatal TH interneurons after loss of the nigrostriatal dopaminergic pathway. Brain Struct Funct 220:331-49
English, Daniel F; Ibanez-Sandoval, Osvaldo; Stark, Eran et al. (2012) GABAergic circuits mediate the reinforcement-related signals of striatal cholinergic interneurons. Nat Neurosci 15:123-30
Brazhnik, Elena; Shah, Fulva; Tepper, James M (2008) GABAergic afferents activate both GABAA and GABAB receptors in mouse substantia nigra dopaminergic neurons in vivo. J Neurosci 28:10386-98
Tepper, James M; Wilson, Charles J; Koos, Tibor (2008) Feedforward and feedback inhibition in neostriatal GABAergic spiny neurons. Brain Res Rev 58:272-81
Duque, Alvaro; Tepper, James M; Detari, Laszlo et al. (2007) Morphological characterization of electrophysiologically and immunohistochemically identified basal forebrain cholinergic and neuropeptide Y-containing neurons. Brain Struct Funct 212:55-73
Lee, Christian R; Tepper, James M (2007) A calcium-activated nonselective cation conductance underlies the plateau potential in rat substantia nigra GABAergic neurons. J Neurosci 27:6531-41
Tepper, James M; Lee, Christian R (2007) GABAergic control of substantia nigra dopaminergic neurons. Prog Brain Res 160:189-208
Tepper, J M; Abercrombie, E D; Bolam, J P (2007) Basal ganglia macrocircuits. Prog Brain Res 160:3-7
Lee, Christian R; Tepper, James M (2007) Morphological and physiological properties of parvalbumin- and calretinin-containing gamma-aminobutyric acidergic neurons in the substantia nigra. J Comp Neurol 500:958-72
Tepper, James M; Koos, Tibor; Wilson, Charles J (2004) GABAergic microcircuits in the neostriatum. Trends Neurosci 27:662-9

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