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 |