Optogenetic Control of Seizures

Principal Investigator: MAJEWSKA, ANNA
Institution Receiving Award: ROCHESTER, UNIVERSITY OF
Program: PRMRP
Proposal Number: PR081302
Award Number: W81XWH-09-1-0480
Funding Mechanism: Translational Research Award: Partnering PI Option
Partnering Awards: PR081302P1
Award Amount: $744,015.00


One percent of the general population has epilepsy, including nearly 3 million people in the United States and 50 million people worldwide. Epilepsy is thought to be caused by an imbalance between the firing of excitatory neurons that drive epileptic activity, and inhibitory neurons that dampen such activity. Epilepsy is currently treated by medications, surgery, and electrical stimulation, which aim to increase inhibitory activity while decreasing excitatory cell firing. None of these approaches is totally effective. Medications are the most common treatment, but approximately 30% of patients continue to have seizures while on medication and most patients are plagued by side effects, which affect their ability to lead a normal life. All the current epilepsy treatments have in common an inability to target specific neurons only during seizure episodes. For instance, medications are relatively "dirty," affecting many neuron types, channels, and locations in the brain. Furthermore, they affect these elements continuously even when the patient is seizure-free. As a result, they may cause severe side-effects by altering normal brain function. Alternatively, electrical stimulation can be restricted to the time of seizure onset but affects all nearby neurons and therefore cannot act specifically on circuit elements that are known to give rise to seizures. New treatments that permit greater control over the activity of specific circuits during epilepsy but that spare normal brain function are sorely needed.

Here we propose an entirely novel approach to treating seizures, which overcomes the limitations of current treatments. This approach relies on using new genetic methods to alter the electrical activity of neurons using light. Recently, light-sensitive proteins called opsins (related to rhodopsin, the retinal pigment that allows us to see), have been isolated from bacteria and algae. These opsins have the ability to inhibit or enhance the electrical activity of cells when they are illuminated. We propose to genetically place these opsins in specific neuron types and affect neuronal activity during seizure episodes using light, without affecting neuron function when seizures are not occurring. We believe that, in the future, this combination of optical and genetic approaches could revolutionize the treatment of seizures. Inhibitory opsins could be targeted to excitatory neurons, while excitatory opsins could be targeted to inhibitory neurons in humans using safe gene therapy approaches. A light source powered by a small power supply could illuminate areas of the brain where seizures are initiated and an electrode near that site, or remotely, could be used to read out brain activity. Abnormal activity patterns that precede seizures or indicate the start of an epileptic event would trigger a circuit that would flood the targeted brain area with light and shut down excitatory activity while enhancing the inhibitory drive, preventing both the initiation and spread of the seizure. The person would not even know that they had just avoided an epileptic episode. This is the vision that we propose to implement in a rodent epilepsy model in preparation for future treatment of human epilepsy.