dorsomorphin and deguelin

Leptin is produced in the adipocytes and plays a pivotal role in regulation of energy balance by controlling appetite and metabolism. Leptin receptors are widely distributed in the brain, especially in the hypothalamus, hippocampus, and neocortex. The insular cortex (IC) processes gustatory and visceral information, which functionally correlate to feeding behavior. However, it is still an open issue whether and how leptin modulates IC neural activities. Our paired whole-cell patch-clamp recordings using IC slice preparations demonstrated that unitary inhibitory postsynaptic currents (uIPSCs) but not uEPSCs were potentiated by leptin in the connections between pyramidal (PNs) and fast-spiking neurons (FSNs). The leptin-induced increase in uIPSC amplitude was accompanied by a decrease in paired-pulse ratio. Under application of inhibitors of JAK2-PI3K but not MAPK pathway, leptin did not change uIPSC amplitude. Variance-mean analysis revealed that leptin increased the release probability but not the quantal size and the number of release site. These electrophysiological findings suggest that the leptin-induced uIPSC increase is mediated by activation of JAK2-PI3K pathway in presynaptic FSNs. An in vivo optical imaging revealed that leptin application decreased excitatory propagation in IC induced by electrical stimulation of IC. These leptin-induced effects were not observed under the low energy states: low glucose concentration (2.5 mM) in vitro and one-day-fasting condition in vivo. However, leptin enhanced uIPSCs under application of low glucose with an AMPK inhibitor. These results suggest that leptin suppresses IC excitation by facilitating GABA release in FSN→PN connections, which may not occur under a hunger state.

Topics: AMP-Activated Protein Kinase Kinases; Animals; Cerebral Cortex; Chromones; Cortical Excitability; Electric Stimulation; Flavonoids; GABAergic Neurons; Glucose; Inhibitory Postsynaptic Potentials; Janus Kinase 2; Leptin; Mitogen-Activated Protein Kinase Kinases; Morpholines; Patch-Clamp Techniques; Phosphoinositide-3 Kinase Inhibitors; Primary Cell Culture; Protein Kinases; Proto-Oncogene Proteins c-akt; Pyramidal Cells; Pyrazoles; Pyrimidines; Rats; Rats, Transgenic; Rotenone; Signal Transduction; Synaptic Transmission; Wortmannin