Cerebellar Nicotinic Cholinergic Receptors are Intrinsic to the Cerebellum: Implications for Diverse Functional Roles

Abstract

Although recent studies have delineated the specific nicotinic subtypes present in the mammalian cerebellum, very little is known about their location or function within the cerebellum. This is of increased interest since nicotinic receptors (nAChRs) in the cerebellum have recently been implicated in the pathology of autism spectrum disorders. To begin to better understand the roles of these heteromeric nAChRs in the cerebellar circuitry and their therapeutic potential as targets for drug development, we used various chemical and stereotaxic lesion models in conjunction with slice electrophysiology to examine how specific heteromeric nAChR subtypes may influence the surrounding cerebellar circuitry. Using subunit-specific immunoprecipitation of radiolabeled nAChRs in the cerebella following N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride, p-chloroamphetamine, and pendunculotomy lesions, we show that most, if not all, cerebellar nicotinic receptors are present in cells within the cerebellum itself and not in extracerebellar afferents. Furthermore, we demonstrate that the β4-containing, but not the β2-containing, nAChRs intrinsic to the cerebellum can regulate inhibitory synaptic efficacy at two major classes of cerebellar neurons. These tandem findings suggest that nAChRs may present a potential drug target for disorders involving the cerebellum.

Phenome-wide association study for CYP2A6 alleles: rs113288603 is associated with hearing loss symptoms in elderly smokers

“…Multiple studies have confirmed the role of cerebellum in auditory function 20 , 21 , nicotinic cholinergic receptors are present in this brain region 35 , and hearing loss is one known symptom of cerebellar stroke syndromes 36 . On these bases, our PheWAS results can be explained by the following hypothesis: smokers with rs113288603 * T have increased CYP2A6 expression in cerebellum that results with consequent altered brain exposure to nicotine and some of its metabolites, and thus protects these subjects from the nicotine-induced changes associated with age-related hearing loss.…”

Neuronal nicotinic receptor agonists improve gait and balance in olivocerebellar ataxia

“…Several subtypes of neuronal nicotinic receptors have been reported to be expressed in rat cerebellum including, in decreasing order of abundance, α4β2 > α3β4 > α3β2β4 > α3α4β2 = α4β2β4 (Turner and Kellar, 2005), and recent studies have indicated that most of these receptors are located in cells within the cerebellum including granule cells, Purkinje cells and interneurons, rather than on afferents (Turner et al, 2011). Studies have also indicated the presence of α7 subunits in mostly perisynaptic regions in the granule cell layer, albeit in very low abundance (Caruncho et al, 1997).…”

Genetic background influences the effects of withdrawal from chronic nicotine on learning and high-affinity nicotinic acetylcholine receptor binding in the dorsal and ventral hippocampus

“…Nonspecific binding was determined in the presence of 300 μM nicotine, and specific binding was defined as the difference between total binding and nonspecific binding. Binding data were expressed as fmol/mg tissue (Turner et al 2011a; Turner et al 2011b). …”