Nicotinic receptor modulation of neurotransmitter release in the cerebellum

Nicotinic ACh receptors (nAChRs) are formed by pentameric combinations of alpha and beta subunits, differentially expressed throughout the central nervous system (CNS), where they have been shown to play a role in the modulation of neurotransmitter release. nAChRs are also important during neuronal differentiation, regulating gene expression and contributing to neuronal pathfinding. The cerebellum, which is involved in the maintenance of balance and orientation as well as refinement of motor action, in motor memory and in some aspects of cognition, undergoes a significant process of development and maturation of its neuronal networks during the first three postnatal weeks in the rat. Autoradiographic as well as in situ hybridization and immunocytochemical studies have shown that several nicotinic receptor binding sites and subunits are expressed in the rat cerebellum from embryonic stage through to adulthood, with the highest expression levels seen during the development of the cerebellar cortex. A diffuse cholinergic afferent projection to all lobules of the cerebellar cortex has been described, with the uvulanodulus, flocculus and lobules I and II of the anterior vermis regions receiving a particularly dense projection. Low levels of nAChR subunit transcripts and immunoreactivity, particularly during adulthood, and the scattered distribution of immunoreactivity between neurons in the cerebellar cortex, can explain the difficulty in assessing electrophysiologically the presence of functional nAChRs in the cerebellar cortex and some contradictory results reported in the early-published papers. In recent years, several groups have shown that also in the cerebellum different nAChR subtypes modulate release of glutamate and GABA at different synapses. The possible role of these mechanisms in synaptic consolidation during development, as well as on plasticity phenomena and network activity at mature synapses, are discussed.