Abstracts

In certain neurons, stimulation of muscarinergic receptors attenuates a repolarizing potassium current, the M-current. This leads to increase in action-potential firing frequencies and neuronal electrical activity. M-currents are mediated by voltage-gated potassium channels of the KCNQ family. Mutations in the genes coding for KCNQ2 and KCNQ3 subunits are associated with inherited forms of generalized epilepsy and myokymia. In order to investigate the physiological role of M-channels in neurons of the central nervous system of mice, we have generated transgenic mouse lines, which specifically express dominant-negative KCNQ2 subunits in brain. This strategy was chosen to avoid lethal phenotypes associated with a general loss of KCNQ2 gene function. Also, the expected assembly of dominant-negative KCNQ2 subunits with wild-type KCNQ2 and/or KCNQ3 subunits was supposed to inactivate M-currents mediated by respective homo- or heteromultimeric KCNQ channels. CA1 neurons in acute slice preparations of mutant brains, which expressed the dominant negative KCNQ2 transgene, showed attenuated M-current amplitudes, reduced mAHP amplitude, increased excitability, and altered subthreshold resonance behavior. Mutant mice exhibit behavioural hyperactivity and spontaneous epileptic seizures. Here, we show that suppression of M-currents during postnatal development induced progressive morphological changes in hippocampus, which were most pronounced in the CA1 field and dentate gyrus (DG). Both structures are known to express KCNQ2/3 subunits. The changes included loss of neurons and degeneration of mossy fibres. Electron microscopy revealed the presence of inclusion bodies in CA1 and DG neurons as early as in seven-days-old mice. Postnatal suppression of transgene expression during the first two weeks of life prevented the neurodegenerative alterations. These data indicate that M-channel activity plays an important role in the developing brain of newborn and adolescent mice. (Supported by German Genome Research Net)