title: Pathological gamma oscillations, impaired dopamine release, synapse loss and reduced dynamic range of unitary glutamatergic synaptic transmission in the striatum of hypokinetic Q175 Huntington mice.
abstract: Huntington's disease (HD) is a severe genetically inherited neurodegenerative disorder. Patients present with three principal phenotypes of motor symptoms: choreatic, hypokinetic-rigid and mixed. The Q175 mouse model of disease offers an opportunity to investigate the cellular basis of the hypokinetic-rigid form of HD. At the age of 1 year homozygote Q175 mice exhibited the following signs of hypokinesia: Reduced frequency of spontaneous movements on a precision balance at daytime (-55%), increased total time spent without movement in an open field (+42%), failures in the execution of unconditioned avoidance reactions (+32%), reduced ability for conditioned avoidance (-96%) and increased reaction times (+65%) in a shuttle box. Local field potential recordings revealed low-frequency gamma oscillations in the striatum as a characteristic feature of HD mice at rest. There was no significant loss of DARPP-32 immunolabeled striatal projection neurons (SPNs) although the level of DARPP-32 immunoreactivity was lower in HD. As a potential cause of hypokinesia, HD mice revealed a strong reduction in striatal KCl-induced dopamine release, accompanied by a decrease in the number of tyrosine hydroxylase-(TH)- and VMAT2-positive synaptic varicosities. The presynaptic TH fluorescence level was also reduced. Patch-clamp experiments were performed in slices from 1-year-old mice to record unitary EPSCs (uEPSCs) of presumed cortical origin in the absence of G-protein-mediated modulation. In HD mice, the maximal amplitudes of uEPSCs amounted to 69% of the WT level which matches the loss of VGluT1+/SYP+ synaptic terminals in immunostained sections. These results identify impairment of cortico-striatal synaptic transmission and dopamine release as a potential basis of hypokinesia in HD.
authors.affiliation: Leibniz Institute for Neurobiology Magdeburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Rothe
authors.affiliation: Leibniz Institute for Neurobiology Magdeburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Deliano
authors.affiliation: Cluster of Excellence NeuroCure, Berlin, Germany.
authors.forename: A M
authors.initials: AM
authors.lastname: Wójtowicz
authors.affiliation: Cluster of Excellence NeuroCure, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Dvorzhak
authors.affiliation: Department of Experimental Neurology, University Medicine Charité, Berlin, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Harnack
authors.affiliation: Cluster of Excellence NeuroCure, Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Paul
authors.affiliation: Cluster of Excellence NeuroCure, Berlin, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Vagner
authors.affiliation: Cluster of Excellence NeuroCure, Berlin, Germany; Bogomoletz Institute of Physiology, Kiev, Ukraine.
authors.forename: I
authors.initials: I
authors.lastname: Melnick
authors.affiliation: Leibniz Institute for Neurobiology Magdeburg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Stark
authors.affiliation: Cluster of Excellence NeuroCure, Berlin, Germany; Department of Experimental Neurology, University Medicine Charité, Berlin, Germany. Electronic address: rosemarie.grantyn@charite.de.
authors.forename: R
authors.initials: R
authors.lastname: Grantyn
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000473:pathology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D065818:Gamma Rhythm / Q000502:physiology*; D006801:Humans; D006816:Huntington Disease / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D013569:Synapses / Q000473:pathology / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology; D046509:Tissue Culture Techniques; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism
chemical_list: D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C497929:Ppp1r1b protein, mouse; C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine
keywords: Huntington’s disease; corticostriatal; dopamine release; gamma oscillations; glutamate release; hypokinesia