Developmental regulation of K+ M-current in brain

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DESCRIPTION (provided by applicant): The M-current (IM) is a voltage-dependent K+ current that is important in regulating neuronal excitability. M-channels have slow opening and closing kinetics and do not deactivate. They are partially open in the range of the resting membrane potential and open further upon depolarization. Thus they act as a "clamp" to keep a neuron below its threshold for firing, and profoundly influence the response of a neuron to synaptic input. KCNQ subtypes of K+ channels have been shown to underlie IM; in the brain KCNQ2/KCNQ3 and KCNQ3/KCNQ5 heterotetramers appear to make up native M-channels. Interestingly, mutations in KCNQ subunits have been shown to underlie several human genetic diseases. Mutations in KCNQ2 and KCNQ3 subunits resulting in dysfunctional channels are linked to a congenital epilepsy, benign familial neonatal convulsions (BFNC). This epilepsy is characterized by generalized seizures that appear shortly after birth and spontaneously remit weeks to months later. However a higher incidence of adult epilepsy is seen in these patients. This suggests that IM may be especially critical in immature brain. Our major hypothesis is as follows. In normal human brain a critical level of IM is reached prior to an increase in cortical excitability that appears shortly after birth. This important inhibitory mechanism prevents seizure generation. However, when one of the channels is mutated, as in BFNC, a mismatch appears between expression of appropriate current density and the increase in cortical excitability. This corresponds to the onset of seizures in this disease. Eventually, the "safety threshold" is reached by the mutated channels, but it is developmentally delayed compared to normal channels. Once this safety level is reached, seizures remit. We have designed an integrative approach that it allows us to directly relate developmental changes in subunit expression patterns, IM levels, and IM contribution to both normal and epileptic brain function. The project described in this application should clarify the pathophysiology of this disease and provide insight into the function of IM, that is an important inhibitory regulator in immature brain.