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Synchronization of irregular-spiking cortical interneurons

Supervisor: Hugh Robinson

Irregular-spiking (IS) inhibitory interneurons form a mutually electrically-coupled network which is capable of firing action potential in precise synchrony, yet highly irregularly. These intrinsically-generated complex firing patterns are in striking contrast to those of other cortical neurons, and IS neurons exert inhibition both on pyramidal cells and on different classes of inhibitory neuron, as well as on other IS neurons. Their inhibitory output is also subject to strong modulation via CB1 endocannabinoid receptors. Synchrony amongst IS neurons would multiply the effect of their activity on postsynaptic target neurons through convergent projections. Thus, understanding how IS neurons synchronize will be key to understanding their functions in the cortical network. It is speculated that these include gating of periodic network oscillations, and generation of variable firing patterns to drive exploratory behaviour and find solutions to optimization problems. Recently, we showed that irregularity is determined biophysically by an inactivating low-threshold potassium current (Kv4) interacting dynamically with persistent sodium currents in a chaotic manner, with single-channel gating fluctuations also playing a role. Computational modelling of the currents predicts that IS neurons should synchronize with no loss of firing irregularity. This project will use paired whole-cell patch-clamp recording in brain slices, conductance injection (dynamic clamp) and computational modelling to elucidate how IS neurons synchronize with each other. The project would suit a student with a strong physics background, programming experience, and an interest in the biophysical mechanisms of action potential generation in neurons.

Relevant references

Galarreta, M., Erdelyi, F., Szabo, G., and Hestrin, S. (2004). Electrical coupling among irregular-spiking GABAergic interneurons expressing cannabinoid receptors. J. Neurosci. 24, 9770-9778.

Karnani MM, Jackson J, Ayzenshtat I, Tucciarone J, Manoocheri K, Snider WG and Yuste Y (2016) Cooperative subnetworks of molecularly similar interneurons in mouse neocortex. Neuron 90:86-100.

Mendonça PRF, Vargas-Caballero M, Erdélyi F, Szabó G, Paulsen O and Robinson HPC (2016) Stochastic and deterministic dynamics of intrinsically irregular firing in cortical inhibitory interneurons. eLife 2016,5:e16475.

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