Background Although dystonia represents a major source of motor disability in Huntington’s Disease (HD), its pathophysiology remains unknown. Because recent animal studies indicate that loss of PARV+ striatal interneurons can cause dystonia, we investigated if loss of PARV+ striatal interneurons occurs during human HD progression, and thus might contribute to dystonia in HD. Methods We used immunolabeling to detect PARV+ interneurons in fixed sections, and corrected for disease-related striatal atrophy by expressing PARV+ interneuron counts in ratio to interneurons co-containing somatostatin and neuropeptide Y (whose numbers are unaffected in HD). Results At all symptomatic HD grades, PARV+ interneurons were reduced to less than 26% of normal abundance in rostral caudate. In putamen rostral to the level of globus pallidus, loss of PARV+ interneurons was more gradual, not dropping off to less than 20% of control until grade 2. Loss of PARV+ interneurons was even more gradual in motor putamen at globus pallidus levels, with no loss at grade 1, and steady grade-wise decline thereafter. Conclusions A large decrease in striatal PARV+ interneurons occurs in HD with advancing disease grade, with regional variation in the loss per grade. Given the findings of animal studies and the grade-wise loss of PARV+ striatal interneurons in motor striatum in parallel with the grade-wise appearance and worsening of dystonia, our results raise the possibility that loss of PARV+ striatal interneurons is a contributor to dystonia in HD.

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Recent evidence has shown that the activity of cAMP responsive element-binding protein (CREB) and of CREB-binding protein (CBP) is decreased in Huntington's disease (HD) [Steffan et al. (2000)Proc. Natl Acad. Sci. USA, 97, 6763-6768; Gines et al. (2003)Hum. Mol. Genet., 12, 497-508; Rouaux et al. (2004) Biochem. Pharmacol., 68, 1157-1164; Sugars et al. (2004)J. Biol. Chem., 279, 4988-4999]. Such decrease is thought to reflect the impaired energy metabolism observed in a HD mouse model, where a decline in striatum cAMP levels has been observed [Gines et al. (2003)Hum. Mol. Genet., 12, 497-508]. Increased levels of CREB have also been demonstrated to exert neuroprotective functions [Lonze & Ginty (2002)Neuron, 35, 605-623; Lonze et al. (2002)Neuron, 34, 371-385]. Our study aimed to investigate the distribution of CREB in the neuronal subpopulations of the striatum in normal rats compared to the HD model of quinolinic acid lesion. Twenty-five Wistar rats were administered quinolinic acid 100 mm into the right striatum, and killed after 24 h, 48 h, 1 week, 2 weeks, and six weeks, respectively. The contralateral striata were used as controls. Dual-label immunofluorescence was employed using antibodies against phosphorylated CREB and each of the different neuronal subpopulations markers. Our results show that activated CREB levels decrease progressively in projection neurons and parvalbumin (PARV) and calretinin (CALR) interneurons, whereas such levels remain stable in cholinergic and somatostatin interneurons. Thus, we speculate that the ability of cholinergic interneurons to maintain their levels of CREB after excitotoxic lesions is one of the factors determining their protection in Huntington's disease.

Transient receptor potential channels (TRPC) are plasma membrane, non-selective cationic channels and have been proposed as candidates involved in the regulation of cellular Ca2+ influx. The expression, at mRNA level, of several TRPCs has been demonstrated recently in dopaminergic neurons of the substantia nigra (SN). The aim of the present study was to characterize the expression of TRPC1, at a protein level, in the substantia nigra neurons and non-excitable cells of Wistar rats. Single-label immunohistochemistry and double-label immunofluorescence were used to study the expression of TRPC1 among substantia nigra dopamine neurons and cellular processes using antibodies against tyrosine hydroxylase (TH), substance P (SP), enkephalin, synaptophysin, vesicular glutamate transporter-2 (Vglut-2), microtubule associated protein-2 and metabotropic glutamate receptor 1 (mGluR1). Moreover, the ultrastructural localization of TRPC1 was investigated by means of electron microscopy. A set of dual label experiments was also performed to investigate the presence of TRPC1 among glial cells. Our results showed that TRPC1 is localized mainly in dendritic processes of dopamine neurons, whereas a relatively small percentage of neuronal somata display a light TRPC1 immunoreactivity. Such results were confirmed by our electron microscopy observations. Our study demonstrates, for the first time, a coexpression of TRPC1 and mGluR1 receptors in dendrites of the substantia nigra dopaminergic neurons. Such observation reinforces the concept of an involvement of TRPC1 in mGluR1-mediated excitatory inputs in rat dopamine neurons.