The brain is a complicated place and one small mutation could set things on fire. Epilepsy is an excellent example. There is no single gene that is the source of epilepsy. Rather, epilepsy can develop from any number of mutations that affect the various processes in the brain. But what happens when you have multiple mutations for known epilepsy genes? Recent research shows two mutations that actually compliment each other to restore normal function.

More details after the jump.

Ion Channels

Epilepsy is characterized by uncontrolled or abnormal neuronal activity. In a network where your behavior is dependent on the behavior of your neighbors, anything out of the ordinary could disrupt normal activity. This small disruption then cascades through the entire network, causing a seizure. Ion channels are often implicated as sources of epileptic seizures. They are good candidates because network behavior is largely regulated by synaptic firing, which is in turn regulated by voltage potentials on individual neurons. Ion channels modulate these voltage potentials to keep things running smoothly.

The lab looked at two epileptic genes, Kcna1 and Cacna1a. Both are linked to epilepsy and show similar distribution in the brain. More importantly, both localize to presynaptic terminals and have opposing affects on polarization. Kcna1 encodes a protein involved in K+ pores and acts to polarize the cell, inhibiting action potentials. Mutations in Kcna1 remove the inhibitory affect and lead to hyperexcitability, causing the neuron to fire frequently. Abnormally frequent firing can disrupt nearby neurons and lead to a seizure.

Conversely, Cacna1a encodes a protein that forms Ca²⁺ pores and helps depolarize cells, stimulating action potentials. Mutations in Cacna1a leads to overly inhibited neurons, resulting in fewer action potentials. Seizures are not just caused by overly frequent firing. They can also be caused by a lack of firing, as in the case of Cacna1a.

Complementation

Mutations in either of these genes can cause seizures, although through entirely different mechanisms. The research team hypothesized that combining mutations together in the same presynaptic terminal could restore normal function. The over excitability of Kcna1 theoretically could recover the under excitability of Cacna1a and vice versa.

The lab discovered that mice expressing both mutations lived considerably longer than those with single mutations. Only 10% of mice lacking Kcna1 lived to ten weeks. When mice lacked Kcna1 and expressed a mutated form of Cacna1a, their 10-week life expectancy jumped to 87%. These mice were also healthier, experiencing 80% fewer seizures than their singly-mutated littermates.

The lab was able to reproduce these reductions in seizure by injecting a drug called 4-aminopyridine. This drug is a synthetic potassium channel blocker, effectively mimicking the effects of a mutated or missing Kcna1 gene. The results of this drug decreased seizure activity for several hours after injection, further supporting the complementation hypothesis.

Lastly, the lab looked at network excitability of the brain itself. Singly mutated mice showed abnormal burst rates and discharge times. Doubly mutated mice still showed abnormalities but they were diminished and closer to wildtype mice. The incomplete recovery of wildtype activity was attributed to only partial overlap between the localization of Kcna1 and Cacna1a in the brain.

These results clearly support the idea that these two mutations, while lethal on their own, compliment eachother when they are found in the same organism. The hyperactivity of one helps recover the overinhibition of the other.

References

Edward, G., Jing, Q., Jong, Y., Jeffrey, N. (2007). Masking epilepsy by combining two epilepsy genes. Nature Neuroscience. DOI: 10.1038/nn1999