Insulin decreases epileptiform activity in rat layer 5/6 prefrontal cortex in vitro

Area of Science:

• Neuroscience
• Neuroendocrinology
• Molecular Biology

Background:

• Insulin signaling in the brain is crucial for neuronal function and implicated in neurological disorders like Alzheimer's and Parkinson's disease.
• Hyperglycemia and insulin resistance are linked to seizure activity and brain injury, highlighting the importance of brain insulin regulation.
• Previous research demonstrated insulin's role in increasing inhibitory GABA_A-mediated tonic currents in the prefrontal cortex (PFC).

Purpose of the Study:

• To investigate the effect of insulin on seizure-like activity (SLEs) in the prefrontal cortex (PFC).
• To elucidate the underlying signaling pathways and specific GABA_A receptor subtypes involved in insulin's modulatory effects on neuronal excitability.

Main Methods:

• Utilized local field potential recordings and calcium imaging in PFC slices.
• Induced seizure-like events (SLEs) using magnesium-free artificial cerebrospinal fluid (ACSF) with 4-aminopyridine (4-AP).
• Administered insulin, PI3K/Akt pathway inhibitors, gaboxadol (THIP), and L-655,708 to assess effects on SLEs and neuronal synchrony.

Main Results:

• Insulin significantly decreased the frequency, amplitude, and duration of 4-AP-induced SLEs in PFC slices.
• Insulin reduced the synchronized activity of PFC neurons.
• These effects were mediated by the PI3K/Akt pathway, mimicked by gaboxadol, and partially blocked by an α5 subunit-selective GABA_A receptor inverse agonist.

Conclusions:

• Insulin reduces neuronal excitability in the PFC by enhancing GABAergic tonic currents, likely via PI3K/Akt signaling and GABA_A receptors.
• These findings suggest a neuroprotective role for insulin and highlight its potential as a therapeutic agent for conditions involving neuronal hyperexcitability.