title: Age-dependent modulation of hippocampal excitability by KCNQ-channels.
abstract: Recently, mutations of KCNQ2 or KCNQ3, members of the KCNQ-related K(+)-channel (KCNQ-channel) family, were identified as cause of benign familial neonatal convulsions (BFNC). However, the exact pathogenic mechanisms of age-dependent development and spontaneous remission of BFNC remain to be elucidated. To clarify the age-dependent etiology of BFNC, we determined age-dependent functional switching of KCNQ-channels, GABAergic- and glutamatergic-transmission in rat hippocampus. The effects of inhibitors of KCNQ-channel, GABA- and glutamate-receptors on propagation of neuronal-excitability and neurotransmitter release were determined by 64-channel multielectrode-dish (MED64), whole-cell recording, in vitro release technique and in vivo microdialysis biosensor, using rat hippocampus from day of birth (P0) to postnatal-day 56 (P56). Inhibition of KCNQ-channels enhanced depolarization-induced glutamate and GABA releases during P0-P7, but not during P14-P28. Inhibition of KCNQ-channels magnified neuronal-excitability propagation from P0 to P14: maximal at P3, but this effect disappeared by P28. GABA(A)-receptor inhibition surprisingly reduced neuronal-excitability propagation during P0-P3, but not at P7. AMPA/glutamate-receptors inhibition reduced propagation of neuronal-excitability throughout the study period. KCNQ-channels inhibition shortened spike-frequency adaptation, but this stimulation was more predominant during P<7 than P>14. During the first week of life, KCNQ-channels performed as a predominant inhibitory system, whereas after this period GABAergic-transmission switched from excitatory to inhibitory function. Contrary, glutamatergic-transmission has acquired as excitatory function from P0. These findings suggest that the pathogenic mechanisms of age-dependent development and spontaneous remission of BFNC are, at least partially, associated with the interaction between age-dependent reduction of inhibitory KCNQ-channel activity and age-dependent functional switching of the GABAergic-system from excitatory to inhibitory action in neonatal CNS.
authors.affiliation: Department of Neuropsychiatry, Hirosaki University, 036-8562, Hirosaki, Japan. okadamot@cc.hirosaki-u.ac.jp
authors.forename: Motohiro
authors.initials: M
authors.lastname: Okada
authors.forename: Gang
authors.initials: G
authors.lastname: Zhu
authors.forename: Shinichi
authors.initials: S
authors.lastname: Hirose
authors.forename: Ken Ichi
authors.initials: KI
authors.lastname: Ito
authors.forename: Takuya
authors.initials: T
authors.lastname: Murakami
authors.forename: Makoto
authors.initials: M
authors.lastname: Wakui
authors.forename: Sunao
authors.initials: S
authors.lastname: Kaneko
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D015374:Biosensing Techniques; D013181:Cortical Spreading Depression / Q000502:physiology; D020936:Epilepsy, Benign Neonatal / Q000235:genetics*; D018698:Glutamic Acid / Q000502:physiology; D006624:Hippocampus / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D017551:Microdialysis; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018377:Neurotransmitter Agents / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology; D015221:Potassium Channels / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D012075:Remission, Spontaneous; D009435:Synaptic Transmission; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D018377:Neurotransmitter Agents; D015221:Potassium Channels; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D011188:Potassium