Abstract #11

Presenter

Madison Gray is a PGY4 in Neuropathology at the University of Western Ontario.

Authors

Madison T. Gray^{1, 2}, Julie L. Lefebvre²

1. Present address: Department of Pathology and Laboratory Medicine, Western University, London, Ontario
2. Neuroscience and Mental Health, Hospital for Sick Children, Toronto, Ontario
   Department of Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto, Ontario

CanMEDS:
Medical Expert (the integrating role), Scholar

Cadherin-23 is essential for the normal organisation of cerebellar mossy fibre synapses

Abstract

To understand the physiological basis of neurological disease, one must first identify which neurons are connected and how they form those connections. Here, we identify a novel cell adhesion molecule signature in Golgi cells, an inhibitory interneuron in the granular layer of the cerebellar cortex. Golgi cells receive excitatory input from both precerebellar mossy fibres and cerebellar granule cells, while providing inhibition to those same granule cells in a feedback loop. We show that both Golgi cells and their mossy fibre partners express cadherin 23 (Cdh23) – a pattern conserved in evolution.

Using explant cultures in vitro and ectopic viral expression in vivo, we demonstrate that Cdh23 is sufficient to induce the formation of synapses by mossy fibres. The known in vivo roles of Cdh23 depend on binding protocadherin 15 (Pcdh15) in trans. However, here we show that Pcdh15 is not expressed in mossy fibre neurons, Golgi cells, or their cerebellar targets. A Cdh23 mutant incapable of binding Pcdh15 nonetheless induces mossy fibre synapses in vitro and in vivo, confirming that the synaptic organiser function of Cdh23 is independent of Pcdh15 binding.

Finally, analysis of a Cdh23-null mouse reveals that Cdh23 is not necessary for anatomical synapse formation but mossy fibres. However, loss of Cdh23 results in enlarged, sparse mossy fibre terminals suggesting a role for Cdh23 in mossy fibre bouton development.