Synaptic transmission and plasticity in cerebellar nuclear neuronsPublic Deposited
Synapses in the central nervous system vary widely in how they transmit and store information. The properties of short-term and long-term plasticity, in particular, seem to be specific for each class of synapse studied. The types of plasticity expressed at a particular synapse determine how it processes, transmits and possibly stores information. Understanding how synaptic responses are regulated over time reveals how a synapse contributes to the neural circuit. Purkinje cell synapses are specialized for high-frequency transmission through incorporation of multiple release sites per bouton opposed to multiple postsynaptic densities. Postsynaptic densities are not isolated by intervening GABA transporters, raising the possibility that GABA released at one site can diffuse out and active postsynaptic GABAA receptors at multiple postsynaptic densities. We tested this hypothesis by recording GABAA mediated currents elicited by rapid application of GABA to outside-out patches pulled from dissociated cerebellar nuclear neurons. We used measurements of kinetic parameters, including receptor activation, deactivation, desensitization and recovery rates, and receptor affinity to constrain a computer model of GABAA receptor gating. When we drove this model with simulated concentration transients of GABA at various distances from the site of release, we found that distant GABAA receptors in nuclear neurons are able to open and contribute to the IPSC rather then desensitize. Spillover-mediated activation of GABA receptors allows a maximal response from each release event while minimizing desensitization of postsynaptic receptors. Behavioral and computational studies have predicted that plasticity of mossy fiber synapses in the cerebellar nuclei participate in cerebellar learning. We tested this by applying patterns of stimulation to nuclear neurons in the slice preparation that mimic in vivo firing patterns during cerebellar learning. We found that high-frequency mossy fiber stimulation immediately preceding a postsynaptic hyperpolarization and ensuing rebound firing induces potentiation of mossy fiber synapses. We hypothesize that the mechanism of induction includes a synapse-specific "priming" signal, likely initiated by activation of calcineurin by calcium influx through NMDA receptors, and a global "triggering" signal, activated by changes in intracellular calcium during the hyperpolarization and rebound firing.