Topiramate alters excitatory synaptic transmission in mouse hippocampus.
Antiepileptic drugs may exert neuroprotective effects by decreasing excessive membrane excitability, neurotransmitter release, or postsynaptic Ca2+ entry. To assess these sites of action, we combined fluorescence Ca2+ imaging with extracellular field recording to analyze axonal excitability, evoked presynaptic Ca2+ entry through presynaptic Ca2+ channels, postsynaptic excitatory field potentials (fEPSP), and postsynaptic Ca2+ buildup ([Capost]) at the mouse hippocampal CA3-CA1 synapse exposed to topiramate (TPM). Topiramate had no effect on presynaptic Ca2+ entry, and produced only a minor inhibition of axonal excitability. Topiramate at concentrations up to 100 microM only slightly reduced the amplitude of the evoked fEPSP, but strongly inhibited the [Capost] evoked by repetitive synaptic activation. Postsynaptically, the action of TPM on the fEPSP and [Capost] was not mediated by an inhibition of the NMDA receptor, or by direct modulation of voltage-dependent Ca2+ channels, but reflected reduced somatic or dendritic membrane depolarization by AMPA and kainate receptors. These results are consistent with the known anticonvulsant properties of TPM. In addition, the ability of TPM to reduce postsynaptic Ca2+ buildup may provide a potential mechanism for neuronal protection during paroxysmal firing associated with epileptic seizures.
Qian
Jing
J
Department of Neurology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Noebels
Jeffrey L
JL
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D003952:Diagnostic Imaging / Q000295:instrumentation / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006624:Hippocampus / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors; D000077236:Topiramate; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D000077236:Topiramate; D005632:Fructose; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C056639:2-amino-5-phosphopentanoic acid; D014633:Valine; D002118:Calcium