THE EFFECTS OF NICOTINICS ON THE DEVELOPING CEREBELLUM

Hiroko Shiina

Cerebellar injury or exposure to toxicants during development heightens the risk for neurodevelopmental disorders. Since the cholinergic system is critical in neuronal migration and circuit formation, the rapidly developing cerebellum may be particularly sensitive to perturbation by perinatal exposure to nicotinic compounds, consequently increasing risk for cerebellar-associated neuropathologies. Although the deleterious impacts of smoking while pregnant, such as a reduction in cerebellar size in the offspring, is well-established, the mechanisms by which nicotine affects cerebellar development remain elusive. Chapters in this dissertation characterize how developing cerebellar cortex neurons are affected by the presence of nicotinic compounds acutely, and how chronic developmental exposure results in cerebellar anatomical, physiological and behavioral alterations. I demonstrated in Chapter 2 that migrating and post-migratory granule cells (mig- and GCs), and Purkinje cell (PCs) synaptic dynamics are highly sensitive to nicotine when applied to simulate in utero nicotine exposure. In Chapter 3, I showed that exogenous nicotine also blunts sensitivity of GCs to transient in vivo-like acetylcholine (ACh) release via nicotinic ACh receptor (nAChR) desensitization, and consequently similarly dampens downstream transcerebellar signaling evoked by ACh. Data from Chapters 2 and 3 indicate nicotine usurps endogenous cholinergic signaling in cerebellar cortex, causing a shift from strong pulsatile excitation, to a low grade tonic excitation. Results from Chapter 4 showed that in vivo neonatal nicotine exposure resulted in improved motor learning that persisted to at least adolescence, possibly due to enhanced GC signal throughput consequent to a reduction in GC tonic GABAAR inhibitory current. In Chapter 5, since numerous insecticides that we encounter on a daily basis are nicotine-based, and proximity to agricultural spray sites correlates with the incidence of cerebellar-associated neurodevelopmental disorders, I explored the impacts of a commonly-used neonicotinoid insecticide, imidacloprid on GCs in the developing cerebellum. Data from Chapter 5 demonstrated that imidacloprid affects GABAergic transmission from Golgi cells to GCs similar to nicotine, but less powerfully and more variably. Collectively, the findings in this dissertation suggest that nicotinic compounds hijack endogenous developmental signals, which will likely alter cerebellar development, and thus could account for adverse neurological and behavioral impacts of exposure to nicotinic compounds.

THE EFFECTS OF NICOTINICS ON THE DEVELOPING CEREBELLUM

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