La disfunzione del recettore striatale D2 induce un'alterata trasmissione GABAergica in un modello murino di distonia DYT1

DYT1 dystonia is a severe form of inherited generalized dystonia, caused by a deletion in the DYT1 gene encoding the protein torsinA. The physiological function of torsinA is unclear, though it has been proposed to perform chaperone-like functions, assist in protein trafficking, membrane fusion and participate in secretory processing. Alterations in GABAergic signaling have been involved in the pathogenesis of dystonia. I recorded GABA- and glutamate-mediated synaptic currents from striatal neurons obtained from a mouse model of DYT1 dystonia. In medium spiny neurons (MSNs) from mice expressing human mutant torsinA (hMT), we observed a significantly higher frequency, but not amplitude, of GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) and miniature currents (mIPSCs), whereas glutamatergic spontaneous excitatory synaptic potentials (sEPSCs) activity was normal. No alterations were found in mice overexpressing normal human torsinA (hWT). To identify the possible sources of the increased GABAergic tone, I recorded GABAergic Fast-Spiking (FS) interneurons that exert a feed-forward inhibition on MSNs. Both sEPSC and sIPSC recorded from hMT FS interneurons were comparable to hWT and controls.In physiological conditions, dopamine (DA) D2 receptor act presynaptically to reduce striatal GABA release. Notably, application of the D2-like receptor agonist quinpirole failed to reduce the frequency of sIPSCs in MSNs from hMT as compared to hWT and controls. Likewise, the inhibitory effect of quinpirole was lost on evoked IPSCs both in MSNs and FS interneurons from hMT mice. My findings demonstrate a disinhibition of GABAergic synaptic activity, that can be partially attributed to a D2 DA receptor dysregulation. A rise in GABA transmission would result in a profound alteration of striatal output, that might be relevant to the pathogenesis of dystonia.