Neurophysiology and epileptogenesisCKJ23.ppt

Neurophysiology and epileptogenesis 2021 Prof Corné Kros – [email protected] Sussex Neuroscience School of Life Sciences, University of Sussex 1. 2. 3. 4. A physiologist’s view of epilepsy Ion channels and epilepsy: channelopathies The electroencephalogram (EEG) Origin and spread of focal and g...

Neurophysiology and epileptogenesis 2021 Prof Corné Kros – [email protected] Sussex Neuroscience School of Life Sciences, University of Sussex 1. 2. 3. 4. A physiologist’s view of epilepsy Ion channels and epilepsy: channelopathies The electroencephalogram (EEG) Origin and spread of focal and generalized seizures **1. A physiologist’s view of epilepsy • Epileptogenesis – the process by which parts of a normal brain are converted to a hyperexcitable brain • Epileptic seizure – physiological definitions: • an explosion of synchronous activity by lots of neurons at once that has a tendency to spread throughout the cerebral cortex causing an ‘electrical brain-storm’ • a brief change in behaviour caused by the synchronous and rhythmic firing of action potentials by populations of neurons in the CNS ** But why is the brain prone to seizure activity? • action potentials are regenerative events relying on positive feedback: inherently unstable • a single neuron can fire a train (or trains) of action potentials spontaneously, without any external stimulation (intrinsic excitability) • thus, a network of excitatory neurons connected together in convergent and divergent pathways is potentially explosive: Stimulation of any one cell can lead to a chain reaction due to the progressive spread of activity over a large area • to avoid this ‘explosion’, the brain requires at least as much inhibition as excitation, by means of inhibitory synapses From Pocock & Richards Epilepsy represents a hyperexcitation or a failure of inhibitory regulation, either focally (e.g. motor cortex, temporal cortex) or generally (whole cortex at once) From Carpenter 2. Ion channels and epilepsy: channelopathies • 1. Na+ channel inactivation too slow in excitatory neurons • e.g., generalized epilepsy with febrile seizures plus (GEFS+) • point mutation in part of Na+ channel (β subunit)  abnormally slow inactivation • action potential repolarization impaired • 2. Reduced number of functional Na+ channels in inhibitory neurons • e.g., generalized epilepsy with febrile seizures plus (GEFS+) •missense mutations or truncated protein results in reduction or loss of Na+ channel function • action potential generation impaired • 3. Reduced number of functional K+ channels in excitatory neurons • e.g., benign familial neonatal convulsions • defect in KCNQ2 or KCNQ3 K+ channel subunit  impaired activation Variety of ion channels implicated in genetic • 1. Ion channel families epilepsy contributing to epilepsy when mutated: • Voltage-gated ion channels: • Na+ channels, K+ channels and Ca2+ channels; hyperpolarization-activated cyclic nucleotide-gated channels (HCN1) • Ligand-gated ion channels: • GABA receptors (inhibitory), glutamate receptors (NMDA; excitatory) and acetylcholine receptors (modulatory) • 2. Considerations for developing targeted drug therapies: • no simple match between type of epilepsy and specific mutations • which ion channel is mutated? Oyrer JL, Malevic S et al (2018) Ion channels in genetic epilepsy: from genes and • is the mutation mechanisms to gain-ofdisease-targeted therapies. Pharmacological Reviews 70:142-173. **3. The electroencephalogram (EEG) • rather like an ECG, recording with an array of Origin: cerebral cortex Origin: feedback between cerebral cortex and thalamus Origin: hippocampus Origin: brainstem electrodes attached to the scalp gives information about the electrical activity of very large numbers of neurons in the cerebral cortex: EEG records summed activity of apical dendrites of pyramidal neurons in cerebral cortex • paradoxically, the largest potentials are recorded when the brain is at rest • when left alone and without sensory inputs the various neural networks feedback upon themselves, leading to rhythmic oscillations when aroused, neuronal activity becomes • the hyperexcitation of seizure leads again desynchronized to synchronous activity on the EEG • EEG can help with determining the localization of a seizure From Pocock & Richards **4. Origin and spread of focal and generalized seizures • Focal (partial) seizures originate within a small group of about 1000 neurons: the seizure focus (temporal lobe seizures, focal motor convulsions) • synchronized ‘paroxysmal depolarizing shift’ (PDS, 20 to 40 mV, lasting 50 to 200 ms) overcomes inhibition • increased extracellular K+ due to neuronal damage or reduced uptake by the astrocytes as well as glutamate release from neurons or astrocytes contribute to PDS • during the PDS trains of action potentials occur • hippocampal neurons have similar responses under normal conditions, making the hippocampus more prone to seizures than the neocortex • Focal seizures may spread to other brain regions along the normal neuronal pathways and may also show secondary generalization if the activity spreads to the thalamus (tonic clonic seizure) • Primary generalized seizures reach the cerebral cortex via normal neuronal pathways from the thalamus (e.g. tonic clonic seizure; absence; juvenile myoclonic epilepsy) • pathways originate in the brainstem and are normally involved in regulating the sleep/wake cycle and arousal of the cerebral cortex From Kandel