Pierre Sokoloff

Distribution and Regulation of the G Protein- Coupled Receptor Gpr88 in the Striatum: Relevance to Parkinson’s Disease

The human basal ganglia constitutes a functional neural network located at the base of the forebrain. It receives most of its afferent inputs through the striatum, the major nucleus of the basal ganglia accomplishing fast neurotransmitter-mediated operations through somatotopically organized projections to the principal neuron cell type, the striatal GABAergic spiny projection neurons. This spiny projection neurons, which make up 95 % of the neuron population of striatum (Kemp & Powell 1971), receive excitatory glutamatergic inputs from all areas of the cortex and specific thalamic nuclei (Gerfen & Wilson 1996; Bolam et al., 2000; Voorn et al., 2004; Doig et al., 2010), and also modulatory dopaminergic inputs from the substantia nigra pars compacta (Smith & Kieval 2000; Utter. & Basso 2008). Spiny Projection Neurons include two major subpopulations giving rise to the direct striato-nigral pathway, and the indirect striato-pallidal pathway which communicates information to the basal ganglia output structures; the internal segment of the globus pallidus and the substantia nigra pars reticulata (Smith, Y. & Kieval 2000; Gerfen & Wilson 1996). Although the two neuron subpopulations are GABAergic, they differ in a number of properties including the expression of different complements of dopamine, Adenosine, NMDA and acetylcholine receptor subtypes as well as of peptide content; the direct striato-nigral pathway neurons coexpress substance P and dynorphin, whereas the indirect striatopallidal pathway neurons express enkephalin (Gerfen et al., 1990, 1991; Reiner & Anderson 1990; Gerfen & Wilson 1996; Le Moine & Bloch, 1995). Based on the fact that striatal medium-spiny neurons are the major input targets and the major projection neurons of striatum, it is thought that integration of neurotransmission in these neurons is an important determinant of the functional organization of the striatum. Thus, changes in neurotransmission on striatal spiny projection neurons have been involved in the regulation of voluntary movement, behavioral control, cognitive function and reward mechanisms. For instance, massive spiny projection neuron loss and major dopamine

BDNF-Dependent Behavioral Sensitization in Hemiparkinsonian Rats

A diverse role for BDNF (Brain-derived neurotrophic factor) has been inferred from observations that it is anterogradely transported, released upon neuron depolarization and triggers rapid intracellular signals.1’2 Converging evidence implicates the D3 receptor (D3R) in the physiopathology and treatment of various neuropsychiatrie disorders including Parkinson’s disease, 3, 4 schizophrenia, 5, 6 and drug addiction.7, 8 In a rat model of Parkinson’s disease, obtained by unilateral destruction of dopamine neurons by 6- hydroxydopamine (6-OHDA), D3R expression is decreased in the shell part of nucleus accumbens (AccSh) of the denervated side3, by deprivation of BDNF9 synthesized by dopamine neurons. Repeated administration of levodopa triggers D3R overexpression in the denervated striatum3, which is responsible for the development of behavioral sensitization to levodopa. Progressive enhancement of levodopa-induced rotations are blocked by a preferential D3R antagonist3 and induced by a selective partial D3R agonist.8 Here we show that BDNF is also responsible for induction of D3R overexpression in 6- OHDA-lesioned rats, and thereby for behavioral sensitization.