The Origin of Physiological Local mGluR1 Supralinear Ca Signals in Cerebellar Purkinje Neurons.

In mouse cerebellar Purkinje neurons (PNs), the climbing fiber (CF) input provides a signal to parallel fiber (PF) synapses, triggering PF synaptic plasticity. This signal is given by supralinear Ca transients, associated with the CF synaptic potential and colocalized with the PF Ca influx, occurring only when PF activity precedes the CF input. Here, we unravel the biophysical determinants of supralinear Ca signals associated with paired PF-CF synaptic activity. We used membrane potential () and Ca imaging to investigate the local CF-associated Ca influx following a train of PF synaptic potentials in two cases: (1) when the dendritic is hyperpolarized below the resting , and (2) when the dendritic is at rest. We found that supralinear Ca signals are mediated by type-1 metabotropic glutamate receptors (mGluR1s) when the CF input is delayed by 100-150 ms from the first PF input in both cases. When the dendrite is hyperpolarized only, however, mGluR1s boost neighboring T-type channels, providing a mechanism for local coincident detection of PF-CF activity. The resulting Ca elevation is locally amplified by saturation of endogenous Ca buffers produced by the PF-associated Ca influx via the mGluR1-mediated nonselective cation conductance. In contrast, when the dendritic is at rest, mGluR1s increase dendritic excitability by inactivating A-type K channels, but this phenomenon is not restricted to the activated PF synapses. Thus, is likely a crucial parameter in determining PF synaptic plasticity, and the occurrence of hyperpolarization episodes is expected to play an important role in motor learning. In Purkinje neurons, parallel fiber synaptic plasticity, determined by coincident activation of the climbing fiber input, underlies cerebellar learning. We unravel the biophysical mechanisms allowing the CF input to produce a local Ca signal exclusively at the sites of activated parallel fibers. We show that when the membrane potential is hyperpolarized with respect to the resting membrane potential, type-1 metabotropic glutamate receptors locally enhance Ca influx mediated by T-type Ca channels, and that this signal is amplified by saturation of endogenous buffer also mediated by the same receptors. The combination of these two mechanisms is therefore capable of producing a Ca signal at the activated parallel fiber sites, suggesting a role of Purkinje neuron membrane potential in cerebellar learning.