Striatal cholinergic dysfunction as a unifying theme in the pathophysiology of dystonia. (April 2015)

• Record Type: Journal Article
• Authors: Eskow Jaunarajs, K.L.; Bonsi, P.; Chesselet, M.F.; Standaert, D.G.; Pisani, A.
• Is Part Of: Progress in neurobiology. Volume 127/128(2015:Apr.)
• Page Start: 91
• Page End: 107
• Publication Date: 2015-04
• Subjects: GPi globus pallidus internus -- STN subthalamic nucleus -- MSN medium spiny neurons -- SNpr substantia nigra pars reticulata -- CM/Pf centromedian/parafascicular complex -- vGluT vesicular glutamate transporter -- TAN tonically active neurons -- DTI diffusion tensor imaging -- FS fast-spiking -- PLTS persistent and low-threshold spike -- ChI cholinergic interneurons -- ChAT choline acetyltransferase -- AHP afterhyperpolarization -- SK small-conductance calcium-activated potassium channels -- GPe globus pallidus externus -- DARPP-32 dopamine- and cAMP-regulated phosphoprotein Mr 32 kDa -- DBS deep brain stimulation -- IP3 inositol trisphosphatase -- DAG diacyl-glycerol -- PKC protein kinase C -- PKA protein kinase A -- LTP long-term potentiation -- STDP spike-timing-dependent plasticity -- LTD long-term depression -- SD synaptic depotentiation -- MS medial septal nucleus -- nBM nucleus basalis of Meynert -- DB diagonal band of Broca -- PPT pedunculopontine tegmental nucleus -- LDT laterodorsal tegmental nucleus; Dystonia -- Striatum -- Basal ganglia -- Acetylcholine interneurons -- Dopamine -- Animal models; Neurobiology -- Periodicals; Neurology -- Periodicals; Neurology -- Periodicals; Neurobiologie -- Périodiques; 612.8
• DOI: 10.1016/j.pneurobio.2015.02.002
• Languages: English
• ISSNs: 0301-0082

Abstract

Highlights: Cholinergic interneurons (ChIs) play a central role in striatal function. Impairment of ChIs produces dystonic movements. ChIs are paradoxically excited by dopamine D2 receptor agonism. Deficits in striatal synaptic plasticity are improved by muscarinic antagonists. ChI alterations may be a common endophenotype useful for investigations in dystonia. Abstract: Dystonia is a movement disorder of both genetic and non-genetic causes, which typically results in twisted posturing due to abnormal muscle contraction. Evidence from dystonia patients and animal models of dystonia indicate a crucial role for the striatal cholinergic system in the pathophysiology of dystonia. In this review, we focus on striatal circuitry and the centrality of the acetylcholine system in the function of the basal ganglia in the control of voluntary movement and ultimately clinical manifestation of movement disorders. We consider the impact of cholinergic interneurons (ChIs) on dopamine–acetylcholine interactions and examine new evidence for impairment of ChIs in dysfunction of the motor systems producing dystonic movements, particularly in animal models. We have observed paradoxical excitation of ChIs in the presence of dopamine D2 receptor agonists and impairment of striatal synaptic plasticity in a mouse model of DYT1 dystonia, which are improved by administration of recently developed M1 receptor antagonists. These findings have been confirmed across multiple animal models of DYT1 dystonia and may represent a common endophenotype by which to investigate dystonia induced by other types of genetic and non-genetic causes and to investigate the potential effectiveness of pharmacotherapeutics and other strategies to improve dystonia.