Abstract
Recent studies, have shown that insulin increases extrasynaptic GABAA receptor-mediated currents in the hippocampus, causing alterations of neuronal excitability. The prefrontal cortex (PFC) is another brain area which is involved in cognition functions and expresses insulin receptors. Here, we used electrophysiological, molecular, and immunocytochemical techniques to examine the effect of insulin on the extrasynaptic GABAA receptor-mediated tonic currents in brain slices. We found that insulin (20–500 nM) increases GABAA-mediated tonic currents. Our results suggest that insulin promotes the trafficking of extrasynaptic GABAA receptors from the cytoplasm to the cell membrane. Western blot analysis and immunocytochemistry showed that PFC extrasynaptic GABAA receptors contain α-5 and δ subunits. Insulin effect on tonic currents decreased the firing rate and neuronal excitability in layer 5–6 PFC cells. These effects of insulin were dependent on the activation of the PI3K enzyme, a key mediator of the insulin response within the brain. Taken together, these results suggest that insulin modulation of the GABAA-mediated tonic currents can modify the activity of neural circuits within the PFC. These actions could help to explain the alterations of cognitive processes associated with changes in insulin signaling.
Highlights
GABAA receptors are the main inhibitory ligand-gated ion channels in the adult mammalian central nervous system (CNS)
When the slices were incubated with insulin (20 nM) for 2 h, the application of gabazine produced a clear increase in the shift of the holding current by 38 ± 2.2 pA (25.6 ± 1.8%, n = 7) with respect to the baseline (Figures 1B,C, black circles)
Similar results were observed by using bicuculline or picrotoxin (10 and 40 μM respectively, not shown). These first experiments suggested the presence of GABAA-mediated tonic current and its modulation by insulin in prefrontal cortex (PFC) pyramidal neurons. Since it is well-known that tonic currents depend on the ambient GABA that activates GABAA extrasynaptic receptors (Bright et al, 2007), we wanted to know if the action potentialdependent vesicular release contributed to the ambient GABA in the PFC
Summary
GABAA receptors are the main inhibitory ligand-gated ion channels in the adult mammalian central nervous system (CNS). They are pentamers constituted by different subunits (α1-6, β13, γ1-3, ρ1-3, π, ε, δ, and θ) (McKernan and Whiting, 1996) forming an anion selective pore. GABAA receptors are either located at the synapses (synaptic) or outside the synapses (extrasynaptic) where they mediate phasic and inhibitory tonic currents respectively (Birnir and Korpi, 2007). Synaptic receptors desensitize or inactivate rapidly (Bianchi et al, 2002; Farrant and Nusser, 2005) and mediate transient inhibitory postsynaptic currents (IPSCs) that regulate spike timing (Pouille and Scanziani, 2001). Extrasynaptic GABAA receptors contain α4, α5, α6, or δ subunits (α6βxδ, α4βxδ, and α5βxγ2)
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