E/I balance in neural circuits is an essential component of homeostatic synaptic plasticity, which is thought to restrain cortical network activity to operate at optimal levels by weakening synaptic efficacy after heightened activity and increasing it after low levels of activation [
29]. A disturbed E/I balance, particularly in neocortical circuits, has been proposed and observed in ASD individuals and in animal models [
7,
30,
31].
In neurodevelopmental disorders, failure in neuronal differentiation [
32], defects in neurotransmitter release, and their postsynaptic receptors [
33‐
35] have been linked to altered E/I balance. In neocortical circuits, interactions between Gamma-aminobutyric acidergic (GABAergic) interneurons and glutamatergic pyramidal neurons that form the corticocortical, callosal, and subcortical connections have been targeted by numerous studies seeking to unveil the circuit defects in disorders with cognitive symptoms. GABAergic neurons are a small population of neocortical residents, but they control inhibition of the most populous excitatory cortical neurons. Defects in differentiation of GABAergic interneurons, GABAergic synaptic transmission, and postsynaptic receptors have been the usual suspects in altered excitability and homeostatic plasticity of neural circuits.
Met receptor tyrosine kinase is a cell surface receptor activated by hepatocyte growth factor (HGF). For obvious reasons, Met and HGF signaling have been extensively studied in the liver. Met is structurally related to the insulin receptor tyrosine kinase and Met signaling is essential in regulation of insulin response by hepatocytes [
36]. In fact, a potential therapeutic role for HGF treatment for insulin resistance in type 2 diabetes has been suggested [
36]. A more recent study on cell cocultures and in knockout mice brings conclusive evidence for Met regulation of insulin sensitivity [
37]. While both Met and HGF are expressed in a spatiotemporal specificity in the brain (reviewed in [
1]), there are no studies examining any link between Met signaling and insulin sensitivity in neocortical excitatory neurons and how lack of it might affect GABAergic synaptic transmission.
In the primary somatosensory cortex of mice, with inactive autism-associated Met receptor tyrosine kinase, we found that increased excitation is due to decreased postsynaptic inhibition mediated via the GABA
A receptors [
6]. Altered GABA
A receptor function can directly affect the E/I balance. In transgenic mice lacking the β3 subunit of the GABA
A receptor (Gabrb3), seizure susceptibility, hypersensitivity, hyperactivity, learning, and memory deficits have been reported [
38,
39]. In fragile X mouse models too, decreased GABA
A receptor expression has been observed [
40‐
42]. A potential strategy to ameliorate decreased GABA
A receptor function is to increase receptor sensitivity. In cultured hippocampal neuron, application of insulin increased GABA
A receptor-mediated response [
43,
44]. We confirmed this response in thalamocortical slices taken from WT mice [
6]. However, in thalamocortical slices from
Met-Emx1 mice, insulin application did not change GABA
A receptor-mediated response, suggesting that there might be insulin resistance in neocortical neurons that lack Met function [
6]. In the present study, we show that insulin resistance of GABA
A receptor-mediated response in
Met-Emx1 mice can be altered by insulin sensitization. We find that application of PIO, a common insulin sensitizer used in diabetes therapy, can significantly alter the GABA
A receptor response and restore E/I balance to levels of normalcy. At the present time, we do not know how Met deficiency in excitatory cortical neurons alters receptor desensitization or the intracellular signaling pathways involving insulin receptors. Further studies are needed to investigate these mechanisms in a cell type-specific manner to determine whether Met signaling through insulin receptors occurs in similar ways between the neocortical excitatory neurons and hepatocytes.