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Interplay between glucose and leptin signalling determines the strength of GABAergic synapses at POMC neurons.

Lee DK, Jeong JH, Chun SK, Chua S, Jo YH - Nat Commun (2015)

Bottom Line: Thus, understanding how POMC neurons integrate these two signal molecules at the synaptic level is important.Inhibition of AMPK activity in presynaptic terminals decreases GABA release at 10 mM glucose.However, postsynaptic TRPC channel opening by the PI3K-PLC signalling pathway in POMC neurons enhances spontaneous GABA release via activation of presynaptic MC3/4 and mGlu receptors at 2.5 mM glucose.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine of Yeshiva University, 1300 Morris Park Avenue, Bronx, New York 10461, USA.

ABSTRACT
Regulation of GABAergic inhibitory inputs and alterations in POMC neuron activity by nutrients and adiposity signals regulate energy and glucose homeostasis. Thus, understanding how POMC neurons integrate these two signal molecules at the synaptic level is important. Here we show that leptin's action on GABA release to POMC neurons is influenced by glucose levels. Leptin stimulates the JAK2-PI3K pathway in both presynaptic GABAergic terminals and postsynaptic POMC neurons. Inhibition of AMPK activity in presynaptic terminals decreases GABA release at 10 mM glucose. However, postsynaptic TRPC channel opening by the PI3K-PLC signalling pathway in POMC neurons enhances spontaneous GABA release via activation of presynaptic MC3/4 and mGlu receptors at 2.5 mM glucose. High-fat feeding blunts AMPK-dependent presynaptic inhibition, whereas PLC-mediated GABAergic feedback inhibition remains responsive to leptin. Our data indicate that the interplay between glucose and leptin signalling in glutamatergic POMC neurons is critical for determining the strength of inhibitory tone towards POMC neurons.

No MeSH data available.


Related in: MedlinePlus

TRPC channels mediate leptin’s stimulatory effectA) Representative recording samples showing mIPSCs recorded from POMC neurons in the presence of the TRPC channel blocker 2-APB. Leptin no longer modulated mIPSCs under these conditions. HP = −70mV.B) Sample traces showing mIPSCs recorded from POMC neurons following treatment with leptin in the absence of extracellular calcium. Leptin still reduced mIPSC frequency without extracellular calcium.C) Representative recording samples showing mIPSCs recorded from POMC neurons in the presence of the PLC inhibitor U73122. Pharmacological blockade of PLC signaling abolished leptin's stimulatory effect. Under these conditions, leptin remained effective in reducing GABA release. Scale bar: 100 pA, 10 s.D) Summary plot showing leptin's effect on mIPSC frequency following blockade of TRPC channel signaling (2-APB: n = 9 neurons; 0 calcium: n = 13 neurons; U73122: n = 10 neurons).**p < 0.01, ***p < 0.001 vs. control (paired t-test). All data are shown as mean ± SEM.
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Figure 4: TRPC channels mediate leptin’s stimulatory effectA) Representative recording samples showing mIPSCs recorded from POMC neurons in the presence of the TRPC channel blocker 2-APB. Leptin no longer modulated mIPSCs under these conditions. HP = −70mV.B) Sample traces showing mIPSCs recorded from POMC neurons following treatment with leptin in the absence of extracellular calcium. Leptin still reduced mIPSC frequency without extracellular calcium.C) Representative recording samples showing mIPSCs recorded from POMC neurons in the presence of the PLC inhibitor U73122. Pharmacological blockade of PLC signaling abolished leptin's stimulatory effect. Under these conditions, leptin remained effective in reducing GABA release. Scale bar: 100 pA, 10 s.D) Summary plot showing leptin's effect on mIPSC frequency following blockade of TRPC channel signaling (2-APB: n = 9 neurons; 0 calcium: n = 13 neurons; U73122: n = 10 neurons).**p < 0.01, ***p < 0.001 vs. control (paired t-test). All data are shown as mean ± SEM.

Mentions: It has been reported that calcium entry through TRPC channels triggers dendritic neurotransmitter release in the brain35. We investigated whether leptin-mediated TRPC channel opening induces the release of α-MSH and glutamate from POMC neurons. In the presence of the TRPC channel blocker 2-APB (100 µM), leptin failed to alter mIPSC frequency (Fig. 4A, D and Table 2). As calcium influx through TRPC channels is important for dendritic release, we tested leptin in the absence of external calcium. Under these experimental conditions, most POMC neurons responded to leptin with a decrease in mIPSC frequency. The total mean percent change in mIPSC frequency was 83.6 ± 5.3 % of control (Fig. 4B, D and Table 2). Moreover the intracellular calcium release inhibitor dantrolene completely blocked leptin’s effect (Supplementary Fig. 6).


Interplay between glucose and leptin signalling determines the strength of GABAergic synapses at POMC neurons.

Lee DK, Jeong JH, Chun SK, Chua S, Jo YH - Nat Commun (2015)

TRPC channels mediate leptin’s stimulatory effectA) Representative recording samples showing mIPSCs recorded from POMC neurons in the presence of the TRPC channel blocker 2-APB. Leptin no longer modulated mIPSCs under these conditions. HP = −70mV.B) Sample traces showing mIPSCs recorded from POMC neurons following treatment with leptin in the absence of extracellular calcium. Leptin still reduced mIPSC frequency without extracellular calcium.C) Representative recording samples showing mIPSCs recorded from POMC neurons in the presence of the PLC inhibitor U73122. Pharmacological blockade of PLC signaling abolished leptin's stimulatory effect. Under these conditions, leptin remained effective in reducing GABA release. Scale bar: 100 pA, 10 s.D) Summary plot showing leptin's effect on mIPSC frequency following blockade of TRPC channel signaling (2-APB: n = 9 neurons; 0 calcium: n = 13 neurons; U73122: n = 10 neurons).**p < 0.01, ***p < 0.001 vs. control (paired t-test). All data are shown as mean ± SEM.
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Figure 4: TRPC channels mediate leptin’s stimulatory effectA) Representative recording samples showing mIPSCs recorded from POMC neurons in the presence of the TRPC channel blocker 2-APB. Leptin no longer modulated mIPSCs under these conditions. HP = −70mV.B) Sample traces showing mIPSCs recorded from POMC neurons following treatment with leptin in the absence of extracellular calcium. Leptin still reduced mIPSC frequency without extracellular calcium.C) Representative recording samples showing mIPSCs recorded from POMC neurons in the presence of the PLC inhibitor U73122. Pharmacological blockade of PLC signaling abolished leptin's stimulatory effect. Under these conditions, leptin remained effective in reducing GABA release. Scale bar: 100 pA, 10 s.D) Summary plot showing leptin's effect on mIPSC frequency following blockade of TRPC channel signaling (2-APB: n = 9 neurons; 0 calcium: n = 13 neurons; U73122: n = 10 neurons).**p < 0.01, ***p < 0.001 vs. control (paired t-test). All data are shown as mean ± SEM.
Mentions: It has been reported that calcium entry through TRPC channels triggers dendritic neurotransmitter release in the brain35. We investigated whether leptin-mediated TRPC channel opening induces the release of α-MSH and glutamate from POMC neurons. In the presence of the TRPC channel blocker 2-APB (100 µM), leptin failed to alter mIPSC frequency (Fig. 4A, D and Table 2). As calcium influx through TRPC channels is important for dendritic release, we tested leptin in the absence of external calcium. Under these experimental conditions, most POMC neurons responded to leptin with a decrease in mIPSC frequency. The total mean percent change in mIPSC frequency was 83.6 ± 5.3 % of control (Fig. 4B, D and Table 2). Moreover the intracellular calcium release inhibitor dantrolene completely blocked leptin’s effect (Supplementary Fig. 6).

Bottom Line: Thus, understanding how POMC neurons integrate these two signal molecules at the synaptic level is important.Inhibition of AMPK activity in presynaptic terminals decreases GABA release at 10 mM glucose.However, postsynaptic TRPC channel opening by the PI3K-PLC signalling pathway in POMC neurons enhances spontaneous GABA release via activation of presynaptic MC3/4 and mGlu receptors at 2.5 mM glucose.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine of Yeshiva University, 1300 Morris Park Avenue, Bronx, New York 10461, USA.

ABSTRACT
Regulation of GABAergic inhibitory inputs and alterations in POMC neuron activity by nutrients and adiposity signals regulate energy and glucose homeostasis. Thus, understanding how POMC neurons integrate these two signal molecules at the synaptic level is important. Here we show that leptin's action on GABA release to POMC neurons is influenced by glucose levels. Leptin stimulates the JAK2-PI3K pathway in both presynaptic GABAergic terminals and postsynaptic POMC neurons. Inhibition of AMPK activity in presynaptic terminals decreases GABA release at 10 mM glucose. However, postsynaptic TRPC channel opening by the PI3K-PLC signalling pathway in POMC neurons enhances spontaneous GABA release via activation of presynaptic MC3/4 and mGlu receptors at 2.5 mM glucose. High-fat feeding blunts AMPK-dependent presynaptic inhibition, whereas PLC-mediated GABAergic feedback inhibition remains responsive to leptin. Our data indicate that the interplay between glucose and leptin signalling in glutamatergic POMC neurons is critical for determining the strength of inhibitory tone towards POMC neurons.

No MeSH data available.


Related in: MedlinePlus