Information processing by the cerebellar cortex is widely accepted to be critical for the execution of
coordinated movement, and has more recently been shown to play a role in executive control, spatial learning
and memory, and fear responses. Therefore, understanding neurotransmission within the cerebellar cortex is
not only important for understanding the root cause of movement disorders such as ataxias, but also in
disorders involving higher brain functions. Indeed, cerebellar dysfunction has been shown to be related to
schizophrenia and autism.
Molecular layer interneurons (MLIs) shape the output of the cerebellar cortex through feed-forward
inhibition of neighboring Purkinje cells, as well as neighboring MLIs. Feed-forward inhibition is driven by
conventional point-to-point synaptic transmission from parallel fiber axons (PFs), as well as by unconventional
spillover transmission from nearby climbing fiber (CF)-PC synapses. CF spillover onto MLIs has been shown to
be sufficient to drive MLI firing, and thus feed-forward inhibition, and in vivo studies have demonstrated that
CF-MLI transmission can induce potentiation of PF-MLI inputs. However, the subcellular basis for this
unconventional form of neurotransmission has yet to be elucidated.
The experiments in this proposal will employ Ca2+ imaging, electrophysiology, and pharmacology to
determine: 1) the subcellular distribution of receptors activated by glutamate spillover onto MLI dendrites. This
distribution will be determined for glutamate receptors activated by spillover from CF-PC synapses, as well as
spillover resulting from physiologically relevant stimulation of PF-MLI synapses. This pattern of activation will
then be compared to that of synaptic glutamate receptors, which can be isolated pharmacologically from
spillover-activated receptors. 2) The relationship between the spatial extent of CF spillover onto MLIs and CF-
induced plasticity at PF-MLI synapses. Specifically, whether CF-induced plasticity of PF-MLI synapses is
confined to areas that directly receive glutamate spillover from CF-PC synapses will be determined.
Completion of this project will provide insight into an important but sparsely studied form of
transmission that is required to understand information processing within the cerebellar cortex, and will
provide the trainee with extensive training in two-photon imaging, synaptic physiology, and expand the trainees
knowledge of pharmacology. This research will be carried out at a leading biomedical research institution, and
the training plan includes opportunities to present at national and international meetings, regular formal and
informal interactions with the sponsor and co-sponsor, and formal and informal mentoring in the responsible
conduct of research.
