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Insulin Reduces Neuronal Excitability by Turning on GABA(A) Channels that Generate Tonic Current

Jin, Zhe; Jin, Yang; Kumar-Mendu, Suresh; Degerman, Eva LU ; Groop, Leif LU and Birnir, Bryndis (2011) In PLoS ONE 6(1).
Abstract
Insulin signaling to the brain is important not only for metabolic homeostasis but also for higher brain functions such as cognition. GABA (c-aminobutyric acid) decreases neuronal excitability by activating GABA(A) channels that generate phasic and tonic currents. The level of tonic inhibition in neurons varies. In the hippocampus, interneurons and dentate gyrus granule cells normally have significant tonic currents under basal conditions in contrast to the CA1 pyramidal neurons where it is minimal. Here we show in acute rat hippocamal slices that insulin (1 nM) "turns on" new extrasynaptic GABA(A) channels in CA1 pyramidal neurons resulting in decreased frequency of action potential firing. The channels are activated by more than million... (More)
Insulin signaling to the brain is important not only for metabolic homeostasis but also for higher brain functions such as cognition. GABA (c-aminobutyric acid) decreases neuronal excitability by activating GABA(A) channels that generate phasic and tonic currents. The level of tonic inhibition in neurons varies. In the hippocampus, interneurons and dentate gyrus granule cells normally have significant tonic currents under basal conditions in contrast to the CA1 pyramidal neurons where it is minimal. Here we show in acute rat hippocamal slices that insulin (1 nM) "turns on" new extrasynaptic GABA(A) channels in CA1 pyramidal neurons resulting in decreased frequency of action potential firing. The channels are activated by more than million times lower GABA concentrations than synaptic channels, generate tonic currents and show outward rectification. The single-channel current amplitude is related to the GABA concentration resulting in a single-channel GABA affinity (EC50) in intact CA1 neurons of 17 pM with the maximal current amplitude reached with 1 nM GABA. They are inhibited by GABA(A) antagonists but have novel pharmacology as the benzodiazepine flumazenil and zolpidem are inverse agonists. The results show that tonic rather than synaptic conductances regulate basal neuronal excitability when significant tonic conductance is expressed and demonstrate an unexpected hormonal control of the inhibitory channel subtypes and excitability of hippocampal neurons. The insulin-induced new channels provide a specific target for rescuing cognition in health and disease. (Less)
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organization
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type
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publication status
published
subject
in
PLoS ONE
volume
6
issue
1
publisher
Public Library of Science
external identifiers
  • wos:000286516500036
  • scopus:79251552543
ISSN
1932-6203
DOI
10.1371/journal.pone.0016188
language
English
LU publication?
yes
id
6034ce8e-10dd-4f4e-b38b-4804d908f607 (old id 1868869)
date added to LUP
2011-04-04 13:11:35
date last changed
2017-09-17 06:56:50
@article{6034ce8e-10dd-4f4e-b38b-4804d908f607,
  abstract     = {Insulin signaling to the brain is important not only for metabolic homeostasis but also for higher brain functions such as cognition. GABA (c-aminobutyric acid) decreases neuronal excitability by activating GABA(A) channels that generate phasic and tonic currents. The level of tonic inhibition in neurons varies. In the hippocampus, interneurons and dentate gyrus granule cells normally have significant tonic currents under basal conditions in contrast to the CA1 pyramidal neurons where it is minimal. Here we show in acute rat hippocamal slices that insulin (1 nM) "turns on" new extrasynaptic GABA(A) channels in CA1 pyramidal neurons resulting in decreased frequency of action potential firing. The channels are activated by more than million times lower GABA concentrations than synaptic channels, generate tonic currents and show outward rectification. The single-channel current amplitude is related to the GABA concentration resulting in a single-channel GABA affinity (EC50) in intact CA1 neurons of 17 pM with the maximal current amplitude reached with 1 nM GABA. They are inhibited by GABA(A) antagonists but have novel pharmacology as the benzodiazepine flumazenil and zolpidem are inverse agonists. The results show that tonic rather than synaptic conductances regulate basal neuronal excitability when significant tonic conductance is expressed and demonstrate an unexpected hormonal control of the inhibitory channel subtypes and excitability of hippocampal neurons. The insulin-induced new channels provide a specific target for rescuing cognition in health and disease.},
  author       = {Jin, Zhe and Jin, Yang and Kumar-Mendu, Suresh and Degerman, Eva and Groop, Leif and Birnir, Bryndis},
  issn         = {1932-6203},
  language     = {eng},
  number       = {1},
  publisher    = {Public Library of Science},
  series       = {PLoS ONE},
  title        = {Insulin Reduces Neuronal Excitability by Turning on GABA(A) Channels that Generate Tonic Current},
  url          = {http://dx.doi.org/10.1371/journal.pone.0016188},
  volume       = {6},
  year         = {2011},
}