Characterisation of GABAergic neurotransmission within basal ganglia circuit in R6/1 Huntington's disease mouse model
Defended on February 21, 2014
GABAergic neurotransmission is widely distributed in the CNS and is the major inhibitory neurotransmission in the brain. Two important components of the basal ganglia, Caudate Putamen (CPu) and Globus Pallidus (GP), are almost exclusively made of GABAergic neurons. Basal ganglia plays an important role in control of movement, the abnormal GABAergic neurotransmission in CPu and GP may be linked to movement deficits observed in Huntington disease (HD). This disease is caused by a mutation in the huntingtin gene leading to dysfunctions of medium spiny neurons (MSNs) in the CPu.
Using molecular methods, state-of-the-art imaging techniques combined with stereology and electrophysiology we have investigated the change of GABAergic neurotransmission during HD progression in a R6/1 HD mouse model to assess the disease progression in presymptomatic (2 months) and symptomatic (6 months) animals.
We used Western blotting to investigate the expression levels of proteins which are involved in GABAergic neurotransmission. These protein markers included presynaptic markers, GABAAreceptor subunits, and anchor or scaffold proteins. Our results showed alterations of these markers in the GP and/or CPu. In R6/1 mice, α1 subunit was significantly increased in the CPu of symptomatic mice and decreased in the GP at both presymptomatic and symptomatic ages; GABAAR α5 and δ subunits were dramatically increased and decreased, respectively, in the CPu at 6 months; expression of proteins involved in the formation of GABAergic synapses were all decreased in the GP at both ages.
These results indicated a developmental dysfunction of GABAergic neurotransmission in basal ganglia circuit of R6/1 mouse model. In the CPu, we used fluorescent immunohistochemistry to show that α1 subunit is expressed in PV neurons as well in a group of unidentified neurons of WT mice. In R6/1 mice, at 6 months, this specific α1 expression is dramatically decreased which might lead to enhanced inhibition of striatal MSNs. In the GP, we show a decrease of both sIPSCs (spontaneous inhibitory post-synaptic currents) and mIPSCs (miniature inhibitory post-synaptic currents) showing that GABAergic dysfunctions developed before the onset of motor symptoms.
We also combined confocal microscopy, mosaic scanning and stereology to show a reduction of total number of GABAergic synapses in the GP of R6/1 model at 6 months and an alteration of GABAergic synapses on PV positive neurons. All the data demonstrate an alteration of GABAergic neurotransmission in the basal ganglia of presymptomatic R6/1 mice and a reduced GABAergic inhibition in the GP of R6/1 mice which could result in the disinhibition of basal ganglia output nuclei and decreased motor activity.
- Kerry MURPHY
Professor, University of Science, Milton Keynes, UK
- Marco SASSOE
Professor, Univerita di Torino, Italy
- Jocelyne CABOCHE
Directeur de Recherche, Université Pierre et Marie Curie, Paris
- Philippe DE DEURWAERDERE
Professeur, Université Bordeaux
- Nicolas MALLET
Chargé de Recherche, Bordeaux
- Maurice GARRET
Directeur de Recherche, Bordeaux
Directeur de recherche – PhD
Institut de Neurosciences cognitives et intégratives d’Aquitaine
Université de Bordeaux
Team : Coordination and Plasticity of Spinal Generators