Information flow through the cerebellar cortex is highly regulated to ensure tight control over out-going motor commands. One of the key players in regulating the tone of information flow into the cerebellar cortex is the Golgi cell (GoC), an inhibitory interneuron residing the granule cell layer of the cerebellar cortex. This tight control over motor commands is necessary to prevent movement related pathologies like the many spinocerebellar ataxias. One way information flow is regulated is through the specificity of connections between neurons and information flow through synapses. However, extrasynaptic transmission does take place in many brain regions and can be involved in several pathological states such as Alzheimer's disease. Our lab recently showed that glutamate, the primary excitatory neurotransmitter, can spill out of the climbing fiber (CF) - Purkinje cell (PC) synapse to activate glutamate receptors on interneurons in the molecular layer of the cerebellum without a synapse present. Many studies suggest that this extrasynaptic transmission provides another layer of flexibility to information encoding in the brain. Similar to findings in the molecular layr of the cerebellum, we have found that CF released glutamate also spills over to Golgi cells. The consequences of glutamate spillover to GoCs are still unknown. To determine the effect of CF glutamate spillover to GoCs and its effects on input processing, we will 1) define the molecular mechanisms of CF glutamate spillover and their effects on GoC output and 2) determine how CF spillover modulates the processing of inputs to the cerebellar cortex. These goals will be accomplished using several diverse techniques including electrophysiology and optogenetics under the expert supervision of the sponsor and collaborators. The aforementioned work will provide insight into the role of GoCs in gating information flow into the cerebellar cortex. Our ability to study extrasynaptic signaling under healthy conditions will allow us to further our understanding of extrasynaptic signaling as it relates to pathology. This work will not only benefi our understanding of healthy cerebellar processing, but also enhance our understanding of disease states in which the cerebellum plays a role. Training plan for the PI consists of participation in journal clubs, formal lab meetings, speaking at seminar opportunities, formal and informal technical and ethical scientific training, regular meetings with the mentor, and presentations at national scientific forums.
The cerebellum is a brain region that is critical for coordinated movement. The experiments proposed here will investigate an unusual form of synaptic connectivity within the cerebellar cortex that results from neurotransmitter spillover in the absence of anatomically defined synapses. The results of these experiments will help to expand understanding of spillover neurotransmission and elucidate how the cerebellar cortex processes sensory information to enable coordination of movement.
| Nietz, Angela K; Vaden, Jada H; Coddington, Luke T et al. (2017) Non-synaptic signaling from cerebellar climbing fibers modulates Golgi cell activity. Elife 6: |
