Calcium channel-dependent induction of long-term synaptic plasticity at excitatory Golgi cell synapses of cerebellum

Abstract

for Golgi cell morphological reconstruction. Author contribution. FL performed the bulk of electrophysiological experiments and data analysis, TS performed part of the electrophysiological experiments, ST performed microscopy cell reconstruction, LB performed mice genotyping, FP performed part of the data analysis and wrote the paper, ED coordinated the work and wrote the paper. AbstractThe Golgi cells, together with granule cells and mossy fibers, form a neuronal microcircuit regulating information transfer at the cerebellum input stage. Despite theoretical predictions, little was known about long-term synaptic plasticity at Golgi cell synapses. Here we have used wholecell patch-clamp recordings and calcium imaging to investigate long-term synaptic plasticity at excitatory synapses impinging on Golgi cells. In acute mouse cerebellar slices, mossy fiber thetaburst stimulation (TBS) could induce either long-term potentiation (LTP) or long-term depression (LTD) at mossy fiber-Golgi cell and granule cell-Golgi cell synapses. This synaptic plasticity showed a peculiar voltage-dependence, with LTD or LTP being favored when TBS induction occurred at depolarized or hyperpolarized potentials, respectively. LTP required, in addition to NMDA channels, activation of T-type Ca 2+ channels, while LTD required uniquely activation of Ltype Ca 2+ channels. Notably, the voltage-dependence of plasticity at the mossy fiber-Golgi cell synapses was inverted with respect to pure NMDA receptor-dependent plasticity at the neighboring mossy fiber-granule cell synapse, implying that the mossy fiber presynaptic terminal can activate different induction mechanisms depending on the target cell. In aggregate, this result shows that Golgi cells show cell-specific forms of long-term plasticity at their excitatory synapses, that could play a crucial role in sculpting the response patterns of the cerebellar granular layer. Significance statementThis paper shows for the first time a novel form of Ca 2+ channel-dependent synaptic plasticity at the excitatory synapses impinging on cerebellar Golgi cells. This plasticity is bidirectional and inverted with respect to NMDA receptor-dependent paradigms, with LTD and LTP being favored at depolarized and hyperpolarized potentials, respectively. Furthermore, LTP and LTD induction requires differential involvement of T-ype and L-type voltage-gated Ca 2+ channels rather than the NMDA receptors alone. These results, along with recent computational predictions, support the idea that Golgi cell plasticity could play a crucial role in controlling information flow through the granular layer along with cerebellar learning and memory.

Cerebellar Golgi cell models predict dendritic processing and mechanisms of synaptic plasticity

“…Other Ca channels (Cav2.1, Cav1.x) were not introduced but they may conceivably amplify and modify the local response. Recently, dendritic Ca spikes have been measured in Golgi cells [ 40 ] following mossy fiber stimulation and have been related to activation of Cav3.1 and Cav1.x channels and to the induction of long-term synaptic plasticity. The Kca2.2 channels had also fundamental roles: in basal dendrites they caused phase-reset, dumped basal firing frequency and prevented rhythmic low-frequency bursting, while in apical dendrites they limited calcium spike duration.…”