Class Notes (838,386)
Canada (510,872)
Pharmacology (260)
PCL102H1 (157)

24. Epilepsy 3. Neurophysiological - Neurochemical Substrates.doc

8 Pages
Unlock Document

Mac Burnham

E PILEPSY 3 – E PILEPTIC D ISCHARGE (electrophysiology/neurochemistry) During seizure activity, 90% of the cells in any part of the brain are firing, and they’re all firing together. If you ask what transmitters are elevated during seizure discharge, the answer is: all of them. What is Epileptic Discharge? • Still poorly understood – next lecture will consider in detail • Historically, it has been described at a number of different levels: 1) Behavioural: The Clinical Seizure • Observation of clinical seizures led to Hughling Jackson’s famous formulation: “an occasional, an excessive and a disorderly discharge (not useful work) of nervous tissue’’ (idea: hyperexcitation) 2) Metabolic Studies • Reinforced the idea of excessive discharge: o blood flow ↑, 2 use ↑, glucose use ↑  The hemisphere where partial seizures occur is often hypometabolic (decreased activity) in between seizures. This suggests that maybe the brain is trying to stop seizure activity by an excess of inhibitory control on the side with seizure focus.  Focus of seizure is old term for epileptogenic zone o seizure activity may kill neurons – this is certainly true if the seizure activity is extended into status epilepticus  Many types of status (absence, complex-partial, tonic-clonic which is the most dangerous and needs to be treated at a hospital if longer than 5 minutes) Seizures often arise in the temporal lobe (which is the most common place in the brain where they arise). This is because the temporal lobes contains the limbic structures, which have the lowest seizure threshold in the brain. A lot of people will have temporal lobe epilepsy and the typical seizures will be simple partial seizures of temporal lobe origin followed by complex-partial seizures (a lot of the complex partial seizures come from the temporal lobe). 3) Gross Electrographic Studies –EEG • 1920-30s Berger (Germany), Jasper (Montreal), Gibbs (Chicago) • revealed discharge types: polyspike (tonic-clonic), spike wave – also interictal spikes o Some people, particularly those with epilepsy arising in the temporal lobes, will show abnormalities between attacks (interical spikes [IISs] or interical discharges [IIDs]). These are probably short fragmentary seizures and the brain is controlling them. Some studies have demonstrated that the person may have a lapse of consciousness each time this occurs. These IIDs are much more visible in sleepy individuals and often patients are asked to come in sleep depreived. • Saw synchrony of spike and wave or polyspikes all over the neocortex. Saw the onset of the seizure, which appeared to start all over the neocortex at the same time. Recall this is what lead to Penfield and Jasper’s centrencephalic approach – the discharge must be starting in a central structure and one which projected to the whole neocortex. • great diagnostic tool – especially for non-convulsive seizures 4) Single Cell Studies 1960s Extracellular: what is seen are action potentials, usually from the soma • revealed bursts of action potentials during EEG “spikes” (“burst response”), with silences in between • revealed synchronous discharge in many neurons (all over the neocortex). I.e., synchronous bursts and silence Intracellular: • revealed that the burst response occurs together with something that looks like a giant EPSP - called the paroxysmal depolarization shift (PDS) or paroxysmal depolarization event (PDE) o The EPSPs are generally going to be recorded from the large neurons (glutamatergic) and this is therefore excitatory activity o The GABAergic neurons are also firing very rapidly, and they may be what’s helping to impose the hyperpolarization between the spikes • PDS: Considered the hallmark of epilepsy – they could find them in all sorts of animal models and slices o absence seizures? Probably seen here too. They find a burst of firing during the spike (excitatory) and silence during the wave (inhibitory). Are the 3/s spike and wave patterns just a slower version of the PDS? This giant EPSP goes on for too long a time to explain very easily. It is thought to be an EPSP and the result of enormous excitation in the synapse. Not a flaw in the neuron itself. However, the EPSPs caused by sodium tend to be fairly short. The NMDA and AMPA receptors are the two main kinds of receptors activated by glutamate. They often coexist at the same synapse.  Weak stimulation only activates the AMPA receptor, resulting in a slight depolarization of the postsynaptic neuron  When glutamate binds to the NMDA receptor at slightly depolarized or resting membrane voltages, very few ions flow through the channel. This low conductance occurs because the pore of the channel is blocked by Mg 2+ions, which prevents other ions from passing freely through the channel. Under these conditions, the EPSP will be mediated entirely by the AMPA receptors.  Given a stimulus of sufficient strength, AMPA r2+eptors can depolarize the membrane sufficiently to expel the MG from the NMDA channel. The NMDA channel can actively respond to glutamate, admitting not only Na , but large amounts of Ca 2+as well. The calcium acts as an important second messenger, activating several intracellular signaling cascades. 5) Ion Flux: • The PDS is probably caused by calcium influx (too long for sodium) • In the soma and dendrites • Classic explanation: It’s a giant EPSP – mediated by synaptic input o synaptic glutamate triggers AMPA receptors (releasing Na+) which then unblock the NMDA receptors (Na+ and Ca++, longer lasting EPSP)  The NMDA receptors are theoretically blocked during normal synaptic traffic and are unblocked by voltage shifts. The AMPA receptors make a voltage shift in the positive direction causing the
More Less

Related notes for PCL102H1

Log In


Join OneClass

Access over 10 million pages of study
documents for 1.3 million courses.

Sign up

Join to view


By registering, I agree to the Terms and Privacy Policies
Already have an account?
Just a few more details

So we can recommend you notes for your school.

Reset Password

Please enter below the email address you registered with and we will send you a link to reset your password.

Add your courses

Get notes from the top students in your class.