In the rat cerebellum, Golgi cells receive serotonin-evoked inputs from Lugaro cells (L-IPSCs), in addition to spontaneous inhibitory inputs (S-IPSCs). In the present study, we analyze the pharmacology of these IPSCs and show that S-IPSCs are purely GABAergic events occurring at basket and stellate cell synapses, whereas L-IPSCs are mediated by GABA and glycine. Corelease of the two transmitters at Lugaro cell synapses is suggested by the fact that both GABA A and glycine receptors open during individual L-IPSCs. Double immunocytochemical stainings demonstrate that GABAergic and glycinergic markers are coexpressed in Lugaro cell axonal varicosities, together with the mixed vesicular inhibitory amino acid transporter. Lugaro cell varicosities are found apposed to glycine receptor (GlyR) clusters that are localized on Golgi cell dendrites and participate in postsynaptic complexes containing GABA A receptors (GABA A Rs) and the anchoring protein gephyrin. GABA A R and GlyR/gephyrin appear to form segregated clusters within individual postsynaptic loci. Basket and stellate cell varicosities do not face GlyR clusters. For the first time the characteristics of GABA and glycine cotransmission are compared with those of GABAergic transmission at identified inhibitory synapses converging onto the same postsynaptic neuron. The ratio of the decay times of L-IPSCs and of S-IPSCs is a constant value among Golgi cells. This indicates that, despite a high cell-to-cell variability of the overall IPSC decay kinetics, postsynaptic Golgi cells coregulate the kinetics of their two main inhibitory inputs. The glycinergic component of L-IPSCs is responsible for their slower decay, suggesting that glycinergic transmission plays a role in tuning the IPSC kinetics in neuronal networks.
Disturbances of the serotoninergic neuromodulation in the cerebellar cortex have been involved in several types of ataxia, but the physiological action of serotonin in this structure remains poorly understood. We report that in slices of the rat cerebellar vermis, serotonin triggers the firing of an inhibitory interneuron presynaptic to Golgi cells. The Lugaro cell, a neglected interneuronal type, satisfies the expected criteria for this input, whereas basket cells, stellate cells, or Golgi cells do not. Lugaro cells are selectively excited by serotonin, and their firing behavior (sustained steady frequency in the 5-15 Hz range) resembles the pattern of occurrence of serotonin-evoked IPSCs in Golgi cells. Immunohistochemical stainings and single cell reconstructions show that Lugaro cell axons form a parasagittal plexus but also extend long transverse branches that run parallel to the parallel fibers and are partly myelinated. Electrophysiological data suggest that these transverse axons participate in synaptic contacts of the Lugaro cells with Golgi cells, and we calculated that in the intact cerebellum a given Lugaro cell contacts Ͼ100 Golgi cells. Serotonin modulation of Lugaro cells may constitute an intracortical switch involved in information patterning at the level of Golgi cells and granule cells populations, and particularly in synchronizations recorded along the transverse axis in vivo.
In the spinal cord, GABA and glycine mediate inhibition at separate or mixed synapses containing glycine and/or GABAA receptors (GlyR and GABAAR, respectively). We have analysed here the sequence of events leading to inhibitory synapse formation during synaptogenesis of embryonic spinal cord neurons between 1 and 11 days in vitro (DIV). We used immunocytochemical methods to detect simultaneously an antigen specific to inhibitory terminals, the vesicular inhibitory amino acid transporter (VIAAT), and one of the following postsynaptic elements: GlyR, GABAAR or gephyrin, the anchoring protein of GlyR, which is also associated with GABAAR. Quantitative analysis revealed that until 5 DIV most gephyrin clusters were not adjacent to VIAAT‐positive profiles, but became associated with them at later stages. In contrast, GlyR and GABAAR clustered predominantly in front of VIAAT‐containing terminals at all stages. However, about 10% of receptor aggregates were detected at nonsynaptic loci. The two receptors colocalized in 66.2 ± 2.5% of the inhibitory postsynaptic domains after 11 DIV, while 30.3 ± 2.6% and 3.4 ± 0.8% of them contained only GlyR and GABAAR, respectively. Interestingly, at 3 DIV GABAAR clustered at a postsynaptic location prior to gephyrin and GlyR; GABAAR could thus be the initiating element in the construction of mixed glycine and GABAergic synapses. The late colocalization of gephyrin with GABAAR, and the demonstration by other groups that, in the absence of gephyrin, postsynaptic GABAAR is not detected, suggest that gephyrin is involved in the stabilization of GABAAR rather than in its initial accumulation at synaptic sites.
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