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Insulin reduces neuronal excitability by turning on GABA(A) channels that generate tonic current.

Jin Z, Jin Y, Kumar-Mendu S, Degerman E, Groop L, Birnir B - PLoS ONE (2011)

Bottom Line: Here we show in acute rat hippocampal 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 single-channel current amplitude is related to the GABA concentration resulting in a single-channel GABA affinity (EC(50)) in intact CA1 neurons of 17 pM with the maximal current amplitude reached with 1 nM GABA.The insulin-induced new channels provide a specific target for rescuing cognition in health and disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Uppsala University, Uppsala, Sweden.

ABSTRACT
Insulin signaling to the brain is important not only for metabolic homeostasis but also for higher brain functions such as cognition. GABA (γ-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 hippocampal 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 (EC(50)) 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.

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Flumazenil and zolpidem increase the excitability of insulin-treated CA1 pyramidal neurons by inhibiting tonic GABAA channels.Current-clamp traces illustrate action potential (AP) firing evoked by a 100 pA current step (500 ms) in ACSF (a) and insulin-incubated neuron (b) before and after application of flumazenil (A, 1 µM) or zolpidem (B, 100 nM). Bar graphs; ACSF (FLU: n = 4; ZOL: n = 4), insulin incubated neurons (FLU: n = 6; ZOL: n = 7). **, P<0.001.
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pone-0016188-g004: Flumazenil and zolpidem increase the excitability of insulin-treated CA1 pyramidal neurons by inhibiting tonic GABAA channels.Current-clamp traces illustrate action potential (AP) firing evoked by a 100 pA current step (500 ms) in ACSF (a) and insulin-incubated neuron (b) before and after application of flumazenil (A, 1 µM) or zolpidem (B, 100 nM). Bar graphs; ACSF (FLU: n = 4; ZOL: n = 4), insulin incubated neurons (FLU: n = 6; ZOL: n = 7). **, P<0.001.

Mentions: GABA-mediated tonic inhibitory conductances have been shown to decrease excitability of neurons by modulating the firing frequency of action potentials [15]. The CA1 pyramidal neurons in slices incubated with insulin had on the average resting membrane potential of −59.2±0.4 mV (n = 10) whereas in control slices it was −57.6±0.4 mV (n = 6) and accordingly, we found that insulin incubation of the slices significantly decreased the action potential firing rate (23.2±1.2 Hz, n = 10) as compared with ACSF control (27.7±1.6 Hz, n = 6). Since flumazenil and zolpidem inhibit the tonic current induced by insulin these drugs can be expected to modulate the firing frequency of the CA1 neurons. Fig. 4A and B show that both 1 µM flumazenil and 100 or 200 nM zolpidem, respectively, significantly increase the action potential firing rate in insulin-treated but not in ACSF control neurons.


Insulin reduces neuronal excitability by turning on GABA(A) channels that generate tonic current.

Jin Z, Jin Y, Kumar-Mendu S, Degerman E, Groop L, Birnir B - PLoS ONE (2011)

Flumazenil and zolpidem increase the excitability of insulin-treated CA1 pyramidal neurons by inhibiting tonic GABAA channels.Current-clamp traces illustrate action potential (AP) firing evoked by a 100 pA current step (500 ms) in ACSF (a) and insulin-incubated neuron (b) before and after application of flumazenil (A, 1 µM) or zolpidem (B, 100 nM). Bar graphs; ACSF (FLU: n = 4; ZOL: n = 4), insulin incubated neurons (FLU: n = 6; ZOL: n = 7). **, P<0.001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3021545&req=5

pone-0016188-g004: Flumazenil and zolpidem increase the excitability of insulin-treated CA1 pyramidal neurons by inhibiting tonic GABAA channels.Current-clamp traces illustrate action potential (AP) firing evoked by a 100 pA current step (500 ms) in ACSF (a) and insulin-incubated neuron (b) before and after application of flumazenil (A, 1 µM) or zolpidem (B, 100 nM). Bar graphs; ACSF (FLU: n = 4; ZOL: n = 4), insulin incubated neurons (FLU: n = 6; ZOL: n = 7). **, P<0.001.
Mentions: GABA-mediated tonic inhibitory conductances have been shown to decrease excitability of neurons by modulating the firing frequency of action potentials [15]. The CA1 pyramidal neurons in slices incubated with insulin had on the average resting membrane potential of −59.2±0.4 mV (n = 10) whereas in control slices it was −57.6±0.4 mV (n = 6) and accordingly, we found that insulin incubation of the slices significantly decreased the action potential firing rate (23.2±1.2 Hz, n = 10) as compared with ACSF control (27.7±1.6 Hz, n = 6). Since flumazenil and zolpidem inhibit the tonic current induced by insulin these drugs can be expected to modulate the firing frequency of the CA1 neurons. Fig. 4A and B show that both 1 µM flumazenil and 100 or 200 nM zolpidem, respectively, significantly increase the action potential firing rate in insulin-treated but not in ACSF control neurons.

Bottom Line: Here we show in acute rat hippocampal 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 single-channel current amplitude is related to the GABA concentration resulting in a single-channel GABA affinity (EC(50)) in intact CA1 neurons of 17 pM with the maximal current amplitude reached with 1 nM GABA.The insulin-induced new channels provide a specific target for rescuing cognition in health and disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Uppsala University, Uppsala, Sweden.

ABSTRACT
Insulin signaling to the brain is important not only for metabolic homeostasis but also for higher brain functions such as cognition. GABA (γ-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 hippocampal 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 (EC(50)) 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.

Show MeSH
Related in: MedlinePlus