Nigrostriatal dopamine function

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The basal ganglia is a 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 which make up 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. Recently a novel type of striatal neuron has been recognized in a variety of species including humans. This neuron expresses tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of DA and a reliable marker for DA neurons in the midbrain. 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 in all species following experimental DA denervation, and some of them 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. However, virtually nothing is known about the electrophysiological properties of these neurons, as there are no published reports of recordings from them. Similarly, there are no data on their efferent or afferent synaptic connectivity, or even whether they release DA and/or GABA. The use of striatal slices from mice genetically engineered to express green fluorescent protein (EGFP) under the control of the TH promotor allows visually guided recording from these neurons in vitro. 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 novel populations of striatal interneurons that have been very difficult or impossible to study previously.