A Characterization of the Morphology, Function, and Evolution of Purkinje Cells with Multiple Primary Dendrites

Canonically, each Purkinje cell (PC) in the adult cerebellum receives only one climbing fiber (CF) from the inferior olive. Underlying current theories of cerebellar function is the notion that the equally unusual singularity of the CF input and numerousness of excitatory parallel fiber (PF) inputs renders PC dendrites into a single computational compartment. In this thesis, I outline my use of several anatomical and physiological methods both in vitro and in vivo to determine that PC morphology is diverse and impacts CF-PC connectivity and dendritic signaling in the mouse cerebellum. I also describe my expanded anatomical findings that PC morphology varies substantially across cerebellar regions and across species, with a focus on the primate lineage in relation to humans. First, I demonstrate that PCs with multiple primary dendrites can receive non-canonical CF multi-innervation in mice, rejecting a textbook dogma of cerebellar physiology that has existed since the 1960's. This may be a specific phenomenon permitting CF-PF receptive field matching for PCs with separated primary dendrite compartments. This is further supported by a second set of findings that 'enhanced' CF-PC signaling is not always beneficial and can be pathological in some disease states. Third, my analysis of human PCs, remarkably uncharacterized since their original illustration at the end of the 19th century, reveals that they exceed allometric constraint in their expanded size, compartmentalization, and spine structure. Finally, I have found that PC morphology is surprisingly diverse across species such that the cerebellum—classically considered a conserved and stereotypical brain region—may be a brain area for which evolutionary adaptation is detectable at the level of cellular morphology and physiology. Morphological variation is better predicted by phylogeny than allometry, adding further support for the hypothesis that PC morphology dictates function and that PC demographics may thus be recruited depending on a regional or species-specific functional need.