Received for publication March 9, 2007.
Revised April 4, 2007.
Accepted for publication April 4, 2007.

Nigrostriatal damage preferentially decreases a subpopulation of 62* nAChRs in mouse, monkey and Parkinson’s disease striatum

Abstract

Parkinson's disease is a neurodegenerative movement disorder characterized by a loss of substantia nigra dopamine neurons, and corresponding declines in molecular components present on striatal dopaminergic nerve terminals. These include the 62* nicotinic receptors (nAChRs), which are localized exclusively on dopamine terminals in striatum (*denotes the presence of possible additional subunits). Here, we used a novel -conotoxin MII (-CtxMII) analog E11A to further investigate 62* nAChR subtypes in mouse, monkey and human striatum. Receptor competition studies with ¹²⁵I--CtxMII showed that E11A inhibition curves were biphasic, suggesting the presence of two distinct 62* nAChR subtypes. These include a very high (fM) and a high (pM) affinity site, with ~40% of the sites in the very high affinity form. Interestingly, only the high affinity form was detected in 4 nAChR null mutant mice. Since ¹²⁵I--CtxMII binds primarily to 642*3* and 62*3* nAChR subtypes in mouse striatum, these data suggest that the population lost in the 4 knockout mice was the 62*3* subtype. We next investigated the effect of nigrostriatal lesioning on these two striatal 62*populations in two animal models and in Parkinson's disease. There was a preferential loss of the very high affinity subtype in striatum of MPTP-treated mice, MPTP-treated monkeys and Parkinson's disease cases. These data suggest that dopaminergic terminals expressing the 642*3* population are selectively vulnerable to nigrostriatal damage. This latter nAChR subtype, identified with -CtxMII E11A, may therefore provide a unique marker for dopaminergic terminals particularly sensitive to nigrostriatal degeneration in Parkinson's disease.

Key words: Nicotinic cholinergic, Receptor binding studies, Knockout, Excitotoxicity, neurodegeneration

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