Increased basal synaptic inhibition of hippocampal area CA1 pyramidal neurons by an antiepileptic drug that enhances I(H).
The hyperpolarization-activated cation current (I(H)) regulates the electrical activity of many excitable cells, but its precise function varies across cell types. The antiepileptic drug lamotrigine (LTG) was recently shown to enhance I(H) in hippocampal CA1 pyramidal neurons, showing a potential anticonvulsant mechanism, as I(H) can dampen dendrito-somatic propagation of excitatory postsynaptic potentials in these cells. However, I(H) is also expressed in many hippocampal interneurons that provide synaptic inhibition to CA1 pyramidal neurons, and thus, I(H) modulation may indirectly regulate the inhibitory control of principal cells by direct modulation of interneuron activity. Whether I(H) in hippocampal interneurons is sensitive to modulation by LTG, and the manner by which this may affect the synaptic inhibition of pyramidal cells has not been investigated. In this study, we examined the effects of LTG on I(H) and spontaneous firing of area CA1 stratum oriens interneurons, as well as on spontaneous inhibitory postsynaptic currents in CA1 pyramidal neurons in immature rat brain slices. LTG (100 microM) significantly increased I(H) in the majority of interneurons, and depolarized interneurons from rest, promoting spontaneous firing. LTG also caused an increase in the frequency of spontaneous (but not miniature) IPSCs in pyramidal neurons without significantly altering amplitudes or rise and decay times. These data indicate that I(H) in CA1 interneurons can be increased by LTG, similarly to I(H) in pyramidal neurons, that I(H) enhancement increases interneuron excitability, and that these effects are associated with increased basal synaptic inhibition of CA1 pyramidal neurons.
Peng
Bi-Wen
BW
Department of Physiology, School of Medicine, Wuhan University, Wuhan, Hubei, China. pengbiwen@whu.edu.cn
Justice
Jason A
JA
Zhang
Kun
K
He
Xiao-Hua
XH
Sanchez
Russell M
RM
D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology*; D001703:Biophysics / Q000379:methods; D056547:CA1 Region, Hippocampal / Q000166:cytology*; D019256:Cadmium Chloride / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004558:Electric Stimulation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects*; D007395:Interneurons / Q000187:drug effects; D000077213:Lamotrigine; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000379:methods; D026902:Potassium Channel Blockers / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D019789:Tetraethylammonium / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D018691:Excitatory Amino Acid Antagonists; D026902:Potassium Channel Blockers; D011810:Quinoxalines; D014227:Triazines; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D019789:Tetraethylammonium; C056639:2-amino-5-phosphopentanoic acid; D015761:4-Aminopyridine; C013411:biocytin; D014633:Valine; D019256:Cadmium Chloride; D008239:Lysine; D000077213:Lamotrigine