Recent Advances in the Neurochemistry of Epilepsy
Recent Advances in the Neurochemistry of Epilepsy
Epilepsy is a common neurological disorder, affecting 1–2% of the population worldwide, and is characterised by recurrent spontaneous seizures. Seizures are brief behavioural changes caused by the abnormally synchronous and rhythmic firing of neuronal assemblies in the brain, which may either involve specific systems of the brain or start in a restricted area and spread to involve multiple cortical and subcortical circuits. Epilepsies may result from long-lasting plastic changes in the brain affecting neurotransmitter release and transport, the properties of receptors and channels, regulation of gene expression, synaptic re-organisation and astrocyte activity. There is considerable evidence of ion channel alterations being the origin of the paroxysmal depolarisation shifts that initiate epileptic activity; however, recent studies on synaptic and non-synaptic transmission, the ion channels interactome, intracellular signalling pathways and glia–neuron signalling suggest that many neurochemical pathways play an important role in seizure initiation, maintenance and arrest. This article addresses some recent advances in our understanding of the neurochemical basis of the seizures that are suggesting new targets for antiepileptic therapy.
Epilepsy is a common neurological disorder, affecting 1–2% of the population worldwide, and is characterised by recurrent spontaneous seizures. Seizures are brief behavioural changes caused by the abnormally synchronous and rhythmic firing of neuronal assemblies in the brain, which may either involve specific systems of the brain or start in a restricted area and spread to involve multiple cortical and subcortical circuits. Epilepsies may result from long-lasting plastic changes in the brain affecting neurotransmitter release and transport, the properties of receptors and channels, regulation of gene expression, synaptic re-organisation and astrocyte activity. There is considerable evidence of ion channel alterations being the origin of the paroxysmal depolarisation shifts that initiate epileptic activity; however, recent studies on synaptic and non-synaptic transmission, the ion channels interactome, intracellular signalling pathways and glia–neuron signalling suggest that many neurochemical pathways play an important role in seizure initiation, maintenance and arrest. This article addresses some recent advances in our understanding of the neurochemical basis of the seizures that are suggesting new targets for antiepileptic therapy.
Ion Channels Interactome
Changes in ionic currents that flow through sodium, potassium, chloride and calcium channels have been proposed to be involved in epileptogenesis.1,2 The blockade of γ-aminobutyric acid (GABA) and glycine-mediated inhibitory neurotransmission or the potentiation of excitatory neurotransmission can induce generalised phasic activity resembling paroxysmal depolarisation shifts. Similar effects are seen with epileptogenic agents that act on the intrinsic mechanisms underlying membrane excitability, such as increasing sodium or calcium depolarising currents or reducing hyperpolarising potassium currents. In addition, the majority of current antiepileptic drugs are thought to modify excitatory and inhibitory neurotransmission through effects on voltage-gated ion channels, GABAA receptors and glutamate-mediated excitatory neurotransmission.3,4
However, as structure–function analyses in both physiological and pathophysiological conditions have shown potentially epileptogenic changes in the structure of ion channels in only a minority of human epilepsies,1 much recent research has focused on a variety of intracellular proteins that somehow interact with ion channels and receptors.
Anchoring Proteins
Many proteins are involved in the anchoring and trafficking of ion channels. A large group of these proteins are found in post-synaptic densities, including spectrin, actin, calpain, calcineurin, contactin, PSD-95, SAP-90, gephyrin, acidic calponin, Homer and several protein kinases. The expression of many of these molecules changes in epileptic tissue and in diverse experimental models of epilepsy.3
Studies performed on in vitro preparations and in cell cultures showed that glutamate receptors are anchored in the dendritic spines by an actin cytoskeleton. The mechanism for receptor redistribution involves calcium-mediated actin depolymerisation, and is related to rapid dendritic spine plasticity. This receptor redistribution has been shown to participate in pathological processes leading to epileptogenesis.5 When perfused in conscious, freely moving animals, the actin-disrupting agents latrunculin A and jasplakinolide modify neuronal excitability and lead to epileptic seizures.6
The permanent decrease in the seizure threshold observed after latrunculin A microperfusion6 is more likely to be related to morphological changes in the number or shape of dendritic spines, or a permanent re-organisation in the location of glutamate receptors or other proteins within the post-synaptic density that are highly dependent on F-actin for their localisation, such as CaMKII, spectrin, myosin V, α-adducin, neurabin, neurabinII/spinophilin, cortactin and many others. The major functions of those actin-associated component proteins of the post-synaptic membrane appear to be signal transduction and modification of the microfilament arrays in response to synaptic activation, events thought to mediate long-term synaptic plasticity.
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