Neuronal input-output computation and mechanisms of cognition in health and disease

Tony Kelly

I am fascinated by the beautiful structures of neurones. They have expansive dendrites that receive the majority of synaptic inputs but rather than passively transmit the signal to the soma, dendrites perform complex computations that determine the appropriate output of the neurone and the micro-network. We investigate these intricate dendritic structures and their unique morphological and biophysical features in regard to physiological function (see Thome & Kelly et al. 2014) and contribution to pathologies such as epilepsy (Royeck et al 2015, Kelly & Beck 2017). We are currently part of the Forschergruppe (FOR2715) investigating epileptogenesis in genetic epilepsies.

Genetic Epilepsies

With the recent advent of deep sequencing there has been an exponential increase in the number of genes discovered that contribute to epilepsy. These epilepsies with a genetic contribution can be especially sever and particularly affect children, with 30% of childhood epilepsies having a genetic component. The genetic contribution varies from the rare mongenic forms where a single mutation is causally related to an epilepsy (eg. SCN2A in EE); to the common genetic generalised epilepsies where the exact network of genetic factors resulting in predisposition remains unknown.

Although new candidate genes are being discovered that result in epilepsy, we still do not know how mutations in specific proteins result in the coordinated hyper-excitability of large populations of neurones, which charaterise seizures. For instance, although the gene mutation is present from before birth, seizures may only be observed years later. This latency suggests that the gene mutation acts on developmental processes in circuit maturation to result in epileptogenesis. We are pursuing how neuronal circuits are altered during development in models of genetic epilepsies.

Currently we are focusing on how excitatory and inhibitory pathways are integrated in the hippocampus, which is suggested to be one of the firsts brain regions to exhibit aberrant oscillatory activity in the SCN2A model of genetic epilepsy.
First we are interested in the circuit mechanisms responsible for the initiation and propagation of aberrant activity within and out of the hippocampus.
Secondly, we are interested in how this altered circuitry results in deficits in hippocampal function such as spatial coding.
To interrogate behaviourally-relevant circuits at the dendritic, neuronal and network level in both health and disease we use two photon imaging and glutamate uncaging in vitro and in vivo Ca2+ imaging and optogenetics in awake behaving animals.