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Epilepsy
| Question | Answer |
|---|---|
| Thalamocortical circuit - disruption causes epilepsy (related to GABAb) | oscillations between thalamus and cortex determine the level of consciousness and perception: Burst mode (sleep, low-f, synchronised); Tonic mode (awake, high-f, asynchronous) |
| Corticothalamic network and spike-wave generation 1 (EEG) | 1)the thalamocortical relay neurons receive afferent sensory excitatory input and subsequently activate the cortical pyramidal neurons and adjacent GABA interneurons |
| Corticothalamic network and spike-wave generation 2 | 2)this is further spread to adjacent cortical neurons, generating a burst of activity and propagate back to the thalamus, acitivating nucleus reticularis thalami GABAergic neurons and local thalamic GABAerigc interneurons |
| Corticothalamic network and spike-wave generation 3 | 3)The hyperpolerising effects may activate low-threshold ch., generating slow waves which will then trigger the activation of the circuit |
| Systems involved | 1)Glutamatergic transmission 2)GABAerigc transmission 3)Voltage-gated channels (Na, Ca and KCNQ) |
| Causes of epilepsy | Dysfunction to ion channel and receptor trafficking Mutation of transmembrane channels (V and L-gated) are the underlying cause of many forms of human epilepsy Loss of function in inhibitory neurotransmission or gain """, leading to disinhibition |
| Definition of epilepsy | long-term neurological disorder characterised by epileptic seizures |
| Neuronal excitability | depends on the movement of ions ion channels are heterooligmeric proteins specially adapted to regulate trans membrane ion fluxes that respond to ligand binding/ voltage changes |
| Ca channels | membrane excitability due to voltage-activated Ca currents P/Q type plays a dominant role in synaptic transmission *T currents can sustain rhythmic burst of firing in thalamocortical relay neurons, essential for synchronisation during absense seizures |
| Absence seizure | Large part of T-C circuit becomes synchronised due to prolonged GABAB-R activation |
| Mutation of GABAa-R have been linked to three types of idiopathic epilepsies | 1)childhood absence epilepsy 2)abnormal dominant epilepsy with febrile seizures plus (ADEFS+) 3)juvenile myoclonic epilepsy |
| Mutation in GABAa-R subunit gens have been associated with idiopathic generalised epilepsy syndromes | mutation include mis-sense, nonsense, and frameshift mutations in coding or non-coding genes |
| Mis-sense | in general, cause trafficking and/or gating defects |
| Premature translation-termination codon (PTC) | generated by nonsense, deletion or frameshift mutation produce truncated protein, often causes server disease than mis-sense |
| Nonsense mediated decay | PTC-generating mutant subunits are subject to NMD |
| ERAD | mutants that escape NMD often are trafficking, misfold and misrouted - endoplasmic reticulum associated degradation |
| Gamma2 Q351X | Mis-sense, produce no functional Cl ch. due to intracellular retention |
| Gamma2 K289M | Mis-sense at linker of M2 and M3, tonic-chronic and febrile seizures, causes significant reduction in the amplitude of GABAa current and shortening of the receptor open time |
| Delta E177A | Mis-sense, activated of the peak current under saturated doses of GABA without changing the binding affinity, decreased open time and reduced cellular expression |
| Anticonvulsants | Carbamazepine (Na Ca) Valproate (Ca and GABA-T) Lamotrigine (Glu) Vigabatrin (GABA-T) Benzodiazepines and Barbiturates |
Created by:
JonLai
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