In article <6tsmjt$rgh at dfw-ixnews7.ix.netcom.com> F. Frank LeFever,
flefever at ix.netcom.com writes:
>Well....Where to begin? "Crossing the synapse ineffectively"? Well,
>no; one might say TOO effectively--or more to the point, there is an
>imbalance between excitatory synapses (e.g. NMDA glutaminergic) and
>inhibitory ones (e.g. GABA). Crudely, think of a runaway engine with
>no governor, no brakes, etc.
I'm no expert, but Mr. LeFever is right. An imbalance between excitation
(both NMDA and non-NMDA) and GABAergic inhibition within a circuit is
probably at the root of a lot of seizure disorders. There are a lot of
ways that such an imbalance might develop. Injury, heredity, fever, etc.
A lot of the time, "epilepsy" which is a term that describes a continuing
_tendency_ to experience seizures rather than just having a seizure, can
be traced back to a single seizure event. For example, say a person is in
a car accident and sustains a head injury. That injury might cause a
seizure (perhaps right then, perhaps later). Since the person doesn't
have epilepsy at the time, they and their families aren't aware that the
seizure is going to occur, and therefore don't take various precautions.
When the seizure occurs, the person isn't in a hospital, and doesn't have
access to antiepileptic drugs, etc. So this initial seizure may be very
severe and last for a long time (i.e., the person may be in "status
epilepticus" for tens of minutes before it subsides or can be treated).
Seizures can result from damage, but more importantly they also cause
damage themselves. So this initial severe seizure can set up a "chain
reaction" of biochemical and physiological events that will predispose
the person to experience further seizures later in life. Some of these
changes might involve the expression of new neuronal genes that favor
increased excitability, or the suppression of genes that favor inhibition
(see a recent J. Neuroscience paper by Kapur and Macdonald). Some of the
changes seem to involve an actual outgrowth of excitatory axons, so that
the density of excitatory synapses is greatly increased ("sprouting").
Why does the brain respond like this to an injury? It would seem that a
rational brain would do exactly the opposite. I suppose its because the
brain didn't really evolve to cope with head trauma, but rather to be a
very flexible, very plastic organ that accomodates itself to make the
best of new input. In the healthy brain, there are all sorts of
mechanisms for _increasing_ the strength of excitatory connections in
response to various events. For example, there's a thing called Long Term
Potentiation (LTP), where a strong stimulus causes the excitatory
synapses to get stronger, and to stay stronger for a really long time.
There's also a bunch of mechanisms for downregulating inhibition during
strong stimuli (autoinhibition of GABA release via GABA-B receptors,
postsynaptic GABA-A receptor desensitization, downregulation of GABA
receptor density, etc.). So the brain appears to be poised and ready to
rev itself up at the drop of a hat. Given that, it's no surprise that
epilepsy is such an insidious problem.
Cheers,
Matt Jones
The Vollum Institute
Portland, OR