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Séminaire - Arnaud RuizBi-directional modulation of synaptic integration in small diameter neocortical dendrites

Abstract :

The neuronal distribution of voltage-gated K+ channels and their contribution to dendritic integration is paramount to the fine-tuning of cortical excitability. 

Here, I will present recent evidence that A-type K+ channels act as powerful brake on membrane depolarisation caused by highly synchronised excitatory synapses formed onto pyramidal neurones. I will also show that these channels regulate dendritic integration in synergy with other cationic conductances such as NMDA receptors and Na+ channels. In brief, we recorded from mouse layer 3 pyramidal neurones held in current-clamp at 32˚ C. Cells were filled biocytin for post-hoc analysis of the dendritic tree and with a fluorescent dye (Alexa 594) for 2-photon laser-scanning imaging of basal dendrites and apical obliques. In a typical experiment, focal uncaging of caged-glutamate was performed in control condition at individual spines and at a combined number of neighbouring spines (2-8).
The resulting depolarisation was recorded at the soma. The potassium channel blockers 4-aminopyridine, barium, and phrixotoxin-2; a sodium channel blocker (TTX) and the NMDA receptor antagonist D-AP5 were bath-applied to examine the relative contribution of individual conductances to summed glutamate-evoked responses. A computational model based on the detailed anatomy of a layer 3 pyramidal neuron embedded with an A-type K+ conductance was used to evaluate the range of channel densities and cellular properties that might explain the effect of pharmacological manipulations.

We found that NMDA receptors conferred a large degree of super-linear summation of input at distal dendritic locations. Na+ channels had a preferential influence at proximal sites and elicited dendritic spikes in basal dendrites. We also found that Kv1.4, Kv4.2, Kv4.3 subunits contributed to A-type K+ currents in basal and apical oblique dendrites and that their density did not follow a steep gradient. Finally, we demonstrated that A-type K+ channels reduced the amplitude and duration of summed excitatory synaptic inputs.

Thus, A-type K+ channels, NMDA receptors and Na+ channels exert opposite and dynamic regulation of signal integration in small diameter dendrites. Such findings bolster our mechanistic understanding of information transfer in larger scale neocortical networks.

Publications PubMed


UCL School of Pharmacy Research Innovation Committee
Departmental Seminar Series Coordinator

Research interests
Excitability of cortical circuits in health and disease: This research aims at understanding how presynaptic receptors and ion channels regulate information flow and synaptic plasticity in the normal brain and in mice models of inherited channelopathies.

Zinc and inhibition: Zinc is extremely abundant at some excitatory terminals in the forebrain where it modulates glutamate receptors and transporters. However, how it affects inhibitory circuits and interneurone function in cortices remains poorly researched. Latest developments in zinc research can be found on the website of the International Society for Zinc Biology.

Information processing in dendrites: We study layer 2/3 cortical pyramids with multi-photon imaging and laser-guided glutamate uncaging at nearby dendritic spines. Central to this research is the role of dendritic K+ channels in shaping the integration of glutamatergic events evoked at single synaptic sites. The data generated will be integrated in a large scale model of cortical function as part of the Human Brain Project initiative.

Drug discovery: Developing selective glutamate receptor ligands offers great therapeutic potential to interact with brain circuits. In collaboration with Dr Steve Hilton we have synthesised and discovered a new family of molecules that could act as nootropic drugs to treat memory related disorders.