Role of KCNQ2/3 channels in cortical interneurons

We are defining the role of KCNQ2/3 channels in interneuron excitability and their contribution to the Excitation/Inhibition (E/I) balance in the cortex and hippocampus. Previous research on the function of KCNQ channels in vivo nearly exclusively focused on excitatory neurons, but in fact these channels are also expressed by inhibitory interneurons. Insight regarding the function of KCNQ channels in interneurons has become critical as some newly identified epilepsy-associated KCNQ2/3 mutations have a gain-of-function effect on channel activity, and such mutations may lead to seizures through diminished inhibitory neuron activity. For our studies, we have generated new mouse lines in which either Kcnq2 or Kcnq3 is specifically ablated in parvalbumin (PV+) and somatostatin (SST+) positive interneurons, the most numerous interneuron population in the forebrain.

KCNQ channels and brain activity

In collaboration with Dr. LoTurco, University of Connecticut.

We have developed new mice lines to directly study the effect of cell-type specific KCNQ channel ablation on the spatial and temporal patterns of neuronal activity in the young mouse brain. Using our mice, we can optically image calcium activity across the cerebral cortex in vivo in a non-invasive manner. We will use a similar approach to study the effects of different anticonvulsant compounds in vivo and ex vivo. This will allow us to overcome the limitations of standard in vivo approaches, which cannot be used in such young mice. We are particularly interested in compounds that could potentially alleviate KCNQ encephalopathy effects.

The molecular basis of the slow afterhyperpolarization

My previous research has identified many of the molecular components that underlie the slow afterhyperpolarization (sAHP), a critical potassium conductance that acts a brake to limit runaway neuronal activity. Currently we are investigating the mechanism by which the sAHP is gated by calcium and PIP2 using a combination of heterologous expression and mouse genetics. In particular, we are testing the hypotheses that (i) elevated PIP2 levels, the gating entity of the sAHP, shift the voltage-activation of KCNQ2/3 channels to within the operating range of the sAHP, and (ii) different sAHP calcium sensors preferentially elicit sAHPs mediated by distinct KCNQ isoforms, (iii) the role of KCNQ2/3 channels in NE sensitivity of the sAHP.