Mechanisms of mesial temporal lobe epilepsy

Epilepsy is a disorder of the brain which causes recurring ?brain storms? or seizures, where very large numbers of neurons become excessively active. The seizures are the most prominent symptom, but the underlying changes in brain structure and function lead to other, more subtle, problems that can prove difficult for people with epilepsy. One of the more common kinds of epilepsy is known as temporal lobe epilepsy (TLE) after the part of the brain that starts the seizures. It can be difficult to treat because many patients with TLE do not respond to the drugs normally used to control seizures, and because parts of the brain may become damaged as a result of the repeated epileptic seizures. Experimental models are used to help develop better treatments for many conditions, including epilepsy. Here we will use a model of TLE produced by injecting a tiny amount of tetanus toxin (which is similar to Botox) into the part of the rat?s brain equivalent to that responsible for TLE in humans. We will find out: why the inhibitory systems that normally control brain activity fail even though the inhibitory cells are still present in the epileptic focus; how the wiring of the nerve cells changes; and what are the mechanisms that eventually stop seizures even though inhibition and wiring do not return to normal. These insights will provide new leads in the search for improved treatments.

Mesial temporal lobe epilepsy (TLE) is one of the most common epilepsies in adults. It often presents problems, including resistance to antiepileptic medication. Tetanus toxin injected into the rat hippocampus provides a model of TLE, characterised by brief spontaneous recurrent seizures, both partial and secondarily generalized. It differs from several other common models of TLE in not starting with status epilepticus, and not being associated with early structural lesions. Clinical TLE does not normally start with status epilepticus and a substantial proportion of cases do not have hippocampal sclerosis, so that tetanus toxin significantly extends the repertoire of experimental models of TLE. We have shown that the epileptic tissue experiences a transient reduction of GABA release, which is followed by a prolonged period of functionally impaired synaptic inhibition. Rats normally gain remission from seizures ~2 months after injection, but surprisingly the impaired inhibition persists, suggesting that remission is an active process. Here we propose to identify the cellular mechanisms of the epileptic focus and of the later remission. We will focus on the CA3 region because our in vivo recordings found that seizures start here. Methods will include electrophysiology in vitro, pharmacology, immunohistochemistry and an innovative molecular approach to labelling monosynaptically connected neurons. The main questions to be answered during the active seizing phase are (1) what causes impairment of inhibition when interneurons are present and can be made to release GABA normally when stimulated directly, and (2) do CA3 pyramidal cell axons sprout like those of granule cells and CA1 pyramidal cells and what impact do they have on recurrent excitation. The main questions to be answered during remission are whether changes in synaptic transmission and intrinsic properties identified previously in CA1 occur in CA3 and if so whether they are sufficient to prevent epileptic activity. Answering these questions will identify (a) the cellular mechanisms of the development of the active epileptic focus and (b) how they are overcome during seizure remission.