Glutamatergic Modulation of Cerebellar Interneuron Activity Is Mediated by an Enhancement of GABA Release and Requires Protein Kinase A/RIM1α Signaling

Information processing in the CNS is controlled by the activity of neuronal networks composed of principal neurons and interneurons. Activity-dependent modification of synaptic transmission onto principal neurons is well studied, but little is known about the modulation of inhibitory transmission between interneurons. However, synaptic plasticity at this level has clear implications for the generation of synchronized activity. We investigated the molecular mechanism(s) and functional consequences of an activity-induced lasting increase in GABA release that occurs between inhibitory interneurons (stellate cells) in the cerebellum. Using whole-cell recording and cerebellar slices, we found that stimulation of glutamatergic inputs (parallel fibers) with a physiological-like pattern of activity triggered a lasting increase in GABA release from stellate cells. This activity also potentiated inhibitory transmission between synaptically connected interneurons. Extracellular recording revealed that the enhanced inhibitory transmission reduced the firing frequency and altered the pattern of action potential activity in stellate cells. The induction of the sustained increase in GABA release required activation of NMDA receptors. Using pharmacological and genetic approaches, we found that presynaptic cAMP/PKA (protein kinase A) signaling and RIM1 alpha, an active zone protein, is the critical pathway that is required for the lasting enhancement of GABA release. Thus, a common mechanism can underlie presynaptic plasticity of both excitatory and inhibitory transmission. This activity-dependent regulation of synaptic transmission between inhibitory interneurons may serve as an important mechanism for interneuronal network plasticity.