Neurons process information in a highly nonlinear manner, generating oscillations, bursting, and resonance, enhancing responsiveness at preferential frequencies. It has been proposed that slow repolarizing currents could be responsible for both oscillation/burst termination and for high-pass filtering that causes resonance (Hutcheon and Yarom, 2000). However, different mechanisms, including electrotonic effects (Mainen and Sejinowski, 1996), the expression of resurgent currents (Raman and Bean, 1997), and network feedback, may also be important. In this study we report theta-frequency (3-12 Hz) bursting and resonance in rat cerebellar granule cells and show that these neurons express a previously unidentified slow repolarizing K ϩ current (I K-slow ). Our experimental and modeling results indicate that I K-slow was necessary for both bursting and resonance. A persistent (and potentially a resurgent) Na ϩ current exerted complex amplifying actions on bursting and resonance, whereas electrotonic effects were excluded by the compact structure of the granule cell. Theta-frequency bursting and resonance in granule cells may play an important role in determining synchronization, rhythmicity, and learning in the cerebellum.

Synaptic activity can induce persistent modifications in the way a neuron reacts to subsequent inputs by changing either synaptic efficacy or intrinsic excitability. After high-frequency synaptic stimulation, long-term potentiation (LTP) of synaptic efficacy is commonly observed at hippocampal synapses (Bliss and Collingridge, 1993), and potentiation of intrinsic excitability has recently been reported in cerebellar deep nuclear neurons (Aizenmann and Linden, 2000). However, the potential coexistence of these two aspects of plasticity remained unclear. In this paper we have investigated the effect of high-frequency stimulation on synaptic transmission and intrinsic excitability at the mossy fiber-granule cell relay of the cerebellum. High-frequency stimulation, in addition to increasing synaptic conductance (D'Angelo et al., 1999), increased granule cell input resistance and decreased spike threshold. These changes depended on postsynaptic depolarization and NMDA receptor activation and were prevented by inhibitory synaptic activity. Potentiation of intrinsic excitability was induced by relatively weaker inputs than potentiation of synaptic efficacy, whereas with stronger inputs the two aspect of potentiation combined to enhance EPSPs and spike generation. Potentiation of intrinsic excitability may extend the computational capability of the cerebellar mossy fiber-granule cell relay.

During development of neuronal circuits, presynaptic and postsynaptic functions are adjusted in concert, to optimize interneuronal signaling. We have investigated whether activation of glutamate receptors affects presynaptic function during synapse formation, when constitutive synaptic vesicle recycling is downregulated. Using primary cultures of hippocampal neurons as a model system, we have found that chronic exposure to both NMDA and non-NMDA glutamate receptor blockers during synaptogenesis produces an increase in miniature EPSC (mEPSC) frequency, with no significant changes in mEPSC amplitude or in the number of synapses. Enhanced synaptic vesicle recycling, selectively in glutamatergic nerve terminals, was confirmed by the increased uptake of antibodies directed against the lumenal domain of synaptotagmin. No increased uptake was detected in neuronal cultures grown in the chronic presence of TTX, speaking against an indirect effect caused by decreased electrical activity. Enhanced mEPSC frequency correlated with a reduction of synaptophysin-synaptobrevinvesicle-associated membrane protein 2 (VAMP2) complexes detectable by immunoprecipitation. Intracellular perfusion with a peptide that inhibits the binding of synaptophysin to synaptobrevin-VAMP2 induced a remarkable increase of mEPSC frequency in control but not in glutamate receptor blockertreated neurons. These findings suggest that activation of glutamate receptors plays a role in the downregulation of the basal rate of synaptic vesicle recycling that accompanies synapse formation. They also suggest that one of the mechanisms through which this downregulation is achieved is an increased interaction of synaptophysin with synaptobrevin-VAMP2.