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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.

journal_name

Neuroscience

journal_title

Neuroscience

authors

Rothe T,Deliano M,Wójtowicz AM,Dvorzhak A,Harnack D,Paul S,Vagner T,Melnick I,Stark H,Grantyn R

doi

10.1016/j.neuroscience.2015.10.039

subject

Has Abstract

pub_date

2015-12-17 00:00:00

pages

519-38

eissn

0306-4522

issn

1873-7544

pii

S0306-4522(15)00958-6

journal_volume

311

pub_type

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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.