Abstract
It is believed that the rewarding actions of drugs are mediated by dysregulation of the mesolimbic dopaminergic system leading to increased levels of dopamine in the nucleus accumbens (nAc). It is widely recognized that GABAergic transmission is critical for neuronal inhibition within nAc. However, it is currently unknown if medium spiny neurons (MSNs) also receive inhibition by means of glycinergic synaptic inputs. We used a combination of proteomic and electrophysiology studies to characterize the presence of glycinergic input into MSNs from nAc demonstrating the presence of glycine transmission into nAc. In D1 MSNs, we found low frequency glycinergic miniature inhibitory postsynaptic currents (mIPSCs) which were blocked by 1 μM strychnine (STN), insensitive to low (10, 50 mM) and high (100 mM) ethanol (EtOH) concentrations, but sensitive to 30 μM propofol. Optogenetic experiments confirmed the existence of STN-sensitive glycinergic IPSCs and suggest a contribution of GABA and glycine neurotransmitters to the IPSCs in nAc. The study reveals the presence of glycinergic transmission in a non-spinal region and opens the possibility of a novel mechanism for the regulation of the reward pathway.
Highlights
IntroductionPrevious studies with Glycine receptors (GlyRs) mutant mice strains (spastic, oscillator and spasmodic) having mutations in the GlyR α1 subunit (spasmodic and oscillator) or β subunit (spastic) demonstrated the inhibitory role of glycinergic phasic currents in sensorial processing (Buckwalter et al, 1994; Mülhardt et al, 1994; Ryan et al, 1994)
After blocking AMPA, NMDA- and GABAA-mediated neurotransmissions, we performed patch clamp recordings in D1 medium spiny neurons (MSNs) and we examined the effects of 30 μM propofol, a glycinergic modulator (Moraga-Cid et al, 2011), on spontaneous Glycine receptors (GlyRs)-mediated miniature inhibitory postsynaptic currents (mIPSCs) (Figure 5) and electrically-evoked glycine IPSCs
This conclusion is based on the presence of GlyT2, a presynaptic glycine transporter and the β GlyR subunit, which is well known to anchor, together with gephyrin, the GlyR to the postsynaptic region (Weltzien et al, 2012; Zeilhofer et al, 2005)
Summary
Previous studies with GlyR mutant mice strains (spastic, oscillator and spasmodic) having mutations in the GlyR α1 subunit (spasmodic and oscillator) or β subunit (spastic) demonstrated the inhibitory role of glycinergic phasic currents in sensorial processing (Buckwalter et al, 1994; Mülhardt et al, 1994; Ryan et al, 1994). These mice show an increased muscular tone, and show a strong hyperekplexic phenotype with altered motor neuronal transmission due to an impairment of the glycinergic inhibitory mechanism, similar to some epileptogenic human diseases (Koch et al, 1996). The dysregulation of glycinergic transmission can lead to several neurological pathologies.
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