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Analysis of spontaneous and cortically evoked activity of striatal medium spiny neurons during the occurrence of L-DOPA-induced dyskinesias

Grant number: 18/24428-3
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): February 01, 2019
Effective date (End): April 10, 2020
Field of knowledge:Biological Sciences - Pharmacology - Neuropsychopharmacology
Principal researcher:Fernando Eduardo Padovan Neto
Grantee:Carlos Henrique Zanello Talarico
Home Institution: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (FFCLRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:17/00003-0 - Role of neuronal nitric oxide synthase and phosphodiesterase 10A in striatal medium spiny neuron activity during L-Dopa-induced dyskinesia, AP.JP
Associated scholarship(s):19/13519-0 - Impact of local administration of D1 and D2 dopaminergic receptor antagonists on the striatal local field potential (LFP) evoked by cortical stimulation, BE.EP.IC

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects 1% of people over the age of 60. The primary motor symptoms of PD include resting tremor, slowness of movements, rigidity and postural instability. These symptoms result from the degeneration of the dopaminergic cells in the substantia nigra pars compacta (SNc). L-DOPA remains the gold standard treatment for PD. However, with repeated administration, L-DOPA can cause abnormal involuntary movements (e.g. L-DOPA-induced dyskinesia; LID) in 75-80% of PD patients. The striatum receives massive cortical excitatory inputs and is densely innervated by dopaminergic projections. The glutamatergic and dopaminergic information is integrated within the striatal medium spiny neurons (MSNs) and transmitted to the output nuclei of the basal ganglia, the internal portion of the globus pallidus and the substantia nigra pars reticulata (SNr). MSNs can project directly (dMSNs) or indirectly (iMSNs) to the output nuclei of basal ganglia. dMSNs express preferentially D1 dopaminergic receptors as well as the neuropeptides dynorphin and substance P. The iMSNs express mainly D2 dopaminergic receptors and the neuropeptide enkephalin. Models of PD propose that chronic L-DOPA exposure generates a hyperdopaminergia state that contributes to imbalance in the activity of striatal MSNs, generating hyperactivity of dMSNs and hypoactivity of iMSNs. This imbalance between MSN activity during the on-state of L-DOPA treatment would be responsible for the appearance of LID. Unfortunately, direct electrophysiological evidence is lacking. Using in vivo electrophysiological recordings of spontaneous and cortically evoked activity in the 6-hydroxydopamine(OHDA)-lesioned rat model of PD, our study seeks to characterize the physiology of dMSNs and iMSNs during the on-state of L-DOPA treatment in dyskinetic rats. Dissecting these two groups of neurons will be the first step in developing improved PD therapeutics.

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