Local circuit neurons in the striatum regulate neural and behavioral responses to dopaminergic stimulation

Abstract

Interneurons are critical for shaping neuronal circuit activity in many parts of the central nervous system. To study interneuron function in the basal ganglia, we tested and characterized an NK-1 receptor-based method for targeted ablation of specific classes of interneuron in the striatum. Our findings demonstrate that the neurotoxin SP-PE35, a substance P-Pseudomonas exotoxin conjugate, selectively targets striatal cholinergic and nitric oxide synthase͞somatostatinergic interneurons when injected locally into the striatum. The effects of this selective cell targeting encompassed alterations in both behavioral and neural responses to dopaminergic stimulation, including altered patterns of early-gene response in striosomes and matrix. We conclude that NK-1-bearing local circuit neurons of the striatum regulate the differential responses of striatal projection neurons to dopamine-mediated signaling.T he striosome and matrix compartments of the striatum are vividly demarcated by their differential expression of neurotransmitter-related compounds ranging from second messengers to neurotransmitters, neuropeptides, and their receptors (1, 2). The different connections of striosomes and matrix suggest that they participate differentially in limbic-based (striosome) and sensorimotor͞associative (matrix) forebrain circuits (3-6). No behavioral or electrophysiological assays have yet identified specific functions for these compartments, but indirect assays with intracranial self-stimulation (7), early-gene activity (8), and metabolic activity (9) suggest different neural operations for striosome-based and matrix-based circuits.How such differential functional activity is brought about in the two compartments is not known, but much interest is focused on the possibility that striatal interneurons differentially regulate activity in the striosomes and surrounding matrix (10-13). Two classes of interneuron have been implicated in such differential regulation: the cholinergic interneurons and the interneurons coexpressing nitric oxide synthase (NOS), somatostatin, and neuropeptide Y (NOS neurons). Both have been implicated in striatal plasticity, including the induction of long-term depression and long-term potentiation (14). Both lie mainly in the matrix and tend to lie at striosome-matrix borders (15-17).These two classes of striatal interneuron both express high levels of NK-1 receptor, the tachykinin receptor at which substance P (SP) acts (18). This differential NK-1 expression pattern suggested the possibility of using a toxin-induced ablation technique to destroy these interneurons selectively (19,20). We implemented this technology by injecting a neuronal toxin that in other systems selectively destroys neurons bearing SP (NK-1) receptors. ¶ SP-PE35 is a site-specific conjugate between a Nterminally derivatized SP peptide and an N-terminally truncated Pseudomonas exotoxin (PE35). SP-PE35 does not contain the native binding domain of the exotoxin (present on the amino end), but it does contain its endosome-release an...

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