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Altered Brain Expression Of A Specific Voltage-Gated Ion Channel In An Animal Model Of Cortical Dysplasia

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Altered Brain Expression Of A Specific Voltage-Gated Ion Channel In An Animal Model Of Cortical Dysplasia

A study published in Scientific Reports from the laboratory of Dr. Anne Anderson, epileptologist at Texas Children’s Hospital and principal investigator in the Gordon and Mary Cain Pediatric Neurology Research Foundation Laboratories shows that mice with cortical dysplasia have an altered expression of a specific subunit of a voltage-gated ion channel in the hippocampus, a region of the brain critical for memory formation.

Cortical dysplasia is a developmental disability that occurs when the top layer of the brain does not form properly. Abnormal brain development is among the most common causes of early-life intractable epilepsy that is characterized by severe and recurrent seizures that cannot be controlled with conventional anti-epileptic drugs (e.g. carbamazepine). Brain surgery is often the only option for these patients. In fact, cortical dysplasia is the first and third most common cause of epilepsy-related surgery in children and adults respectively.

In some cases, cortical dysplasia results from genetic mutations that cause constitutive activation of the PI3K (phosphoinositide 3-kinase)-Akt-mechanistic target of the rapamycin (mTOR) signaling pathway. One of the main biological functions of the mTOR pathway is to regulate the synthesis of new proteins. When this pathway is permanently turned on, as in the case of cortical dysplasia patients, it leads to excessive growth of the neurons in the cortical layers of the brain.

Previous studies showed that treating mouse models of cortical dysplasia with rapamycin, an mTOR inhibitor, could suppress the excess growth of neurons and also, dramatically reduce the frequency of seizures.

However, it was not clear how mTOR dysregulation in the hippocampal cortical neurons led to intractable seizures. Identifying the key molecular player is crucial for researchers to understand the pathogenesis of cortical dysplasia and to develop a targeted therapy against it.

In this study, researchers found that hyper-activation of PI3K-Akt-mTOR signaling in a mouse model of cortical dysplasia was accompanied by an age-dependent increased expression of a specific subunit of a voltage-gated potassium channel protein (Kv1.1) in the hippocampus.

Voltage-gated potassium channels are tetramers of four proteins that form channels on the outer membrane of neurons through which potassium ions are diffused in and out, depending on voltage changes in the neuron’s membrane potential.

In the hippocampus, the Kv1 subfamily of potassium channel consists of four integral subunits, α subunit, Kv1.1, Kv1.2, and Kv1.4 that together regulate many critical neuronal functions. Dysfunction in Kv1 channel subunits has been linked to hyper-excitability of neurons and epilepsy. In the study, researchers did not observe any change in the expression of α subunit, Kv1.2, and Kv1.4 subunits.

Interestingly, early and late-stage inhibition of mTOR signaling with rapamycin normalized the Kv1.1 protein levels in the mouse models of cortical dysplasia. This clearly shows that the increased expression of Kv1.1 protein in the hippocampus was a result of the hyper-activation of mTOR pathway in these mice and suggests a role for the mTOR pathway in regulating Kv1 channel expression in the mouse models of cortical dysplasia.

Thus, this study provides the experimental framework to dissect the connection between hyper-activation of mTOR signaling in the hippocampus and uncontrollable seizures observed in cortical dysplasia patients.