A novel mechanism for timing of neuronal activity

Derek Garden, Marlies Oostland, Ian Duguid, Matt Nolan and colleagues have published a study demonstrating a novel mechanism for timing of neuronal activity. The study suggests new directions for research into mechanisms for cognitive deficits in psychiatric disorders.

The study focusses on a relatively under-explored brain area called the inferior olive. Neurons in this area are a key coordinator of activity in the cerebellum, forming a system that is well studied for its role in movement and that is also thought to have important cognitive functions. The inferior olive can be thought of as a conductor of an orchestra, training and instructing the neurons in the cerebellum to perform in a coordinated way appropriate for behaviours that are being carried out. The study addresses how signals from other brain areas control the timing of outputs from the inferior olive.

A first set of experiments use ex-vivo approaches to show that deletion of a gene called HCN1, or pharmacological block of the protein encoded by the gene, impairs mechanisms that would usually ensure precise timing of the output signals from the inferior olive. Further ex-vivo experiments reveal novel roles for the ion channel encoded by the HCN1 gene and give new insights into exactly how timing of outputs from the inferior olive is controlled. In particular, the experiments show that actions of HCN1 channels are in part mediated by electrical connections between neurons in the inferior olive. This provides a novel mechanism for integrative local with global signals in a neural circuit. A final set of experiments tests the contribution of this mechanism to neural signalling in behaving animals. They show that deletion of HCN1 affects the timing of outputs from the inferior olive, which is consistent with predictions made from the ex-vivo experiments.

We know that altered functioning of the cerebellum contributes to autism spectrum disorders. The present study opens up new approaches for figuring out roles played by computations within the inferior olive and its outputs to the cerebellum.

The study was funded by the following organisations: Medical Research Council, the Wellcome Trust, and the BBSRC.

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