Regulation Of Mitochondrial K_ATP Channels On Tonic Inhibition Of Cortical Layer 5 Pyramidal Neurons In Developing Rat Brain

ATP-sensitive K+ (KATP) channels couple cell metabolic state to membrane excitability and are enriched both in neurons and glial cells. Activation of neuronal and astrocytic mitochondrial KATP (mitoKATP) channels regulates a variety of neuronal functions. However, less is known about its impact on tonic y-aminobutyric acid (GABA) inhibition ex vivo. This diffusional inhibitory transmission is mediated by extrasynaptic GABA A-type receptors (GABAARs) and activated by ambient GABA, which is involved in regulating neuronal excitability. Here, we found that tonic current, recorded from rat cortical Layer 5 pyramidal cells, was robust in newborns (P2-4) but decreased dramatically by the second postnatal week (P7-8 and P30-34). This neonatal tonic current is partially mediated by the GABAAR a5, and likely the d, subunit. Neither GAT-1 nor GAT-3 played dominant roles in this inhibitory transmission from cortical L5 pyramidal cells with development. Activation of mitoKATP channels with Diazoxide (DIZ) showed an opposite effect on the tonic GABA currents as it potentially decreased the magnitude at P2-4 but increased the magnitude at P7-8 (P<0.001) in the groups of GABA(5μM), control and NO+SNAP+GABA(5μM). However, DIZ significantly enhanced the magnitude of tonic GAB A currents at both P2-4 and P7-11 in NO-711+SNAP-5114 groups. Moreover, DIZ differently increased the magnitude of tonic GABA currents at both P2-4 and P7-11 in groups of THIP and L655708. The results of pharmacological studies, in combination with Western blot analysis and immunofluorescence study suggest that this regulation by DIZ might be partially through neuronal/astrocytic GATs and/or GABAARs. Furthermore, the levels of ambient GABA may also be involved in this DIZ-induced regulation. Taken together, these findings demonstrate that activation of mitoKATP channels can dominate GABAergic transmission in neocortical pyramidal cells with development. Our findings may contribute to a better understanding of the mechanisms for mitoKATP channels as novel targets for neurological disorders in developing brain.