Extrasynaptic GABA and glutamate receptors in epilepsy.
Epilepsy is a neurological disorder in which normal brain function is disrupted as a consequence of intensive and synchronous burst activity from neuron assemblies. Epilepsies result from long-lasting plastic changes in the brain affecting neurotransmitter release, the properties of receptors and channels, synaptic reorganization and astrocyte activity. There is considerable evidence for alterations in glutamatergic and GABAergic synaptic transmission in the origin of the paroxysmal depolarization shifts that initiate epileptic activity. However, recent studies on non-synaptic transmission, receptor mobility and glia-neuron signaling pathways suggest that extrasynaptic GABA and glutamate receptors may play an important role in seizure initiation, maintenance and arrest. Extracellular aminoacids such as glutamate, aspartate, glycine and GABA seem to communicate neurons and glial cells acting primarily on extrasynaptic receptors. Synaptic and extrasynaptic glutamate and GABA receptors have been show to play different roles in neuronal excitability. NMDA and GABAA receptors expressed in a single neuron can be differentially regulated based on subcellular localization, and it has been proposed that distinct regulation of synaptic versus extrasynaptic receptors provides a mechanism for receptor adaptation in response to a variety of stimuli. Furthermore, glutamate and GABA receptors are highly mobile, and the number and composition of extrasynaptic receptors can be modulated by several factors. This review addresses recent advances in our understanding of the role of extrasynaptic receptors in epilepsy, suggesting that extrasynaptic receptors and their mechanisms of regulation are expected to be important pharmacological targets.
Sierra-Paredes
Germán
G
Neuroscience Division, Department of Biochemistry and Molecular Biology, School of Medicine, University of Santiago, San Francisco 1, 15782 Santiago de Compostela, Spain. bngersp@usc.es
Sierra-Marcuño
Germán
G
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use*; D004827:Epilepsy / Q000188:drug therapy* / Q000503:physiopathology*; D006801:Humans; D008024:Ligands; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018079:Receptors, GABA / Q000187:drug effects* / Q000502:physiology*; D017470:Receptors, Glutamate / Q000187:drug effects* / Q000502:physiology*; D012640:Seizures / Q000503:physiopathology; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects
D000927:Anticonvulsants; D008024:Ligands; D018079:Receptors, GABA; D017470:Receptors, Glutamate