Exploiting the Other Inhibitory Ion: KCNQ Potassium Channels and Regulation of Excitability in Developing and Mature Brain
Authors: Cooper Edward C. 
Published: July 2006

Epileptiform Activity Induced by Pharmacologic Reduction of M-Current in the Developing Hippocampus In Vitro

Pena F, Alavez-Perez N

Epilepsia 2006;47(1):47–54

Purpose

Benign familial neonatal convulsions (BFNCs), an inheritable epilepsy that occurs in neonates but not in adults, is caused by hypofunctional mutations in genes codifying for the M-type K+ current. In an attempt to develop an in vitro model of this disease, we tested whether blocking M-current with linopirdine induces epileptiform activity in brain slices from animals of different ages.

Methods

Horizontal hippocampus–entorhinal cortex slices were obtained from neonatal (1–2 weeks after birth) and adult (8–9 weeks after birth) rats. Extracellular field recordings of the CA1 region were performed. After recording control conditions, linopirdine was added to the bath, and field activity was recorded continuously for 3 hours. A drug 4-aminopyridine, commonly used to induce epileptiform activity in vitro, was used as a control for our experimental conditions.

Results

Bath perfusion of linopirdine induced epileptiform activity only in slices from neonatal rats. Epileptiform activity consisted of interictal-like and ictal-like activity. In slices from adult rats, linopirdine induced erratic interictal-like activity. In contrast, 4-aminopyridine was able to induce epileptiform activity in slices from both neonatal and adult rats.

Conclusions

We demonstrated that blockade of Mcurrent in vitro produces epileptiform activity with a developmental pattern similar to that observed in BNFCs. This could be an in vitro model that can be used to study the cellular mechanisms of epileptogenesis and the developmental features of BFNCs, as well as to develop some therapeutic strategies. Conditional Transgenic Suppression of M Channels in Mouse Brain Reveals Functions in Neuronal Excitability, Resonance and Behavior Peters HC, Hu H, Pongs O, Storm JF, Isbrandt D Nat Neurosci 2005;8(1):51–60 In humans, mutations in the KCNQ2 or KCNQ3 potassium-channel genes are associated with an inherited epilepsy syndrome. We have studied the contribution of KCNQ/M-channels to the control of neuronal excitability by using transgenic mice that conditionally express dominant-negative KCNQ2 subunits in brain. We show that suppression of the neuronal M current in mice is associated with spontaneous seizures, behavioral hyperactivity and morphological changes in the hippocampus. Restriction of transgene expression to defined developmental periods revealed that M-channel activity is critical to the development of normal hippocampal morphology during the first postnatal weeks. Suppression of the M current after this critical period resulted in mice with signs of increased neuronal excitability and deficits in hippocampus-dependent spatial memory. M-current-deficient hippocampal CA1 pyramidal neurons showed increased excitability, reduced spike-frequency adaptation, attenuated medium afterhyperpolarization and reduced intrinsic subthreshold theta resonance. M channels are thus critical determinants of cellular and neuronal network excitability, postnatal brain development and cognitive performance.