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Dentate gyrus-CA3 glutamate release/NMDA transmission mediates behavioral despair and antidepressant-like responses to leptin.

Wang X, Zhang D, Lu XY - Mol. Psychiatry (2014)

Bottom Line: A subpopulation of granule neurons that innervated the CA3 region expressed leptin receptors and these cells were not activated by stress.Leptin treatment dampened tail suspension-evoked glutamate release in CA3.On the other hand, intra-CA3 infusion of NMDA blocked the antidepressant-like effect of leptin in reversing behavioral despair in both the tail suspension and forced swim tests, which involved activation of Akt signaling in DG.

View Article: PubMed Central - PubMed

Affiliation: 1] Institute for Metabolic and Neuropsychiatric Disorders, Binzhou Medical University Hospital, Binzhou, China [2] Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.

ABSTRACT
Compelling evidence supports the important role of the glutamatergic system in the pathophysiology of major depression and also as a target for rapid-acting antidepressants. However, the functional role of glutamate release/transmission in behavioral processes related to depression and antidepressant efficacy remains to be elucidated. In this study, glutamate release and behavioral responses to tail suspension, a procedure commonly used for inducing behavioral despair, were simultaneously monitored in real time. The onset of tail suspension stress evoked a rapid increase in glutamate release in hippocampal field CA3, which declined gradually after its offset. Blockade of N-methyl-D-aspartic acid (NMDA) receptors by intra-CA3 infusion of MK-801, a non-competitive NMDA receptor antagonist, reversed behavioral despair. A subpopulation of granule neurons that innervated the CA3 region expressed leptin receptors and these cells were not activated by stress. Leptin treatment dampened tail suspension-evoked glutamate release in CA3. On the other hand, intra-CA3 infusion of NMDA blocked the antidepressant-like effect of leptin in reversing behavioral despair in both the tail suspension and forced swim tests, which involved activation of Akt signaling in DG. Taken together, these results suggest that the DG-CA3 glutamatergic pathway is critical for mediating behavioral despair and antidepressant-like responses to leptin.

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Effect of leptin on tail suspension-evoked glutamate release in CA3. Leptin (1.0 mg/kg) or saline was injected intraperitoneally into the mice 30 min before tail suspension. A. Compositing changes in extracellular glutamate concentrations (μM) converted from current recording at a 1 Hz sampling frequency from 5 saline-treated mice (red open circle) and 4 leptin-treated mice (blue open circle). B. Temporal changes in glutamate concentrations in 1-min bin. C. Rate of change in glutamate concentrations (μM/min). n = 4-5/group. ***P < 0.001 compared to saline-treated controls during 6-min tail suspension. ###P < 0.001 indicating significant overall difference between two treatment groups.
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Figure 4: Effect of leptin on tail suspension-evoked glutamate release in CA3. Leptin (1.0 mg/kg) or saline was injected intraperitoneally into the mice 30 min before tail suspension. A. Compositing changes in extracellular glutamate concentrations (μM) converted from current recording at a 1 Hz sampling frequency from 5 saline-treated mice (red open circle) and 4 leptin-treated mice (blue open circle). B. Temporal changes in glutamate concentrations in 1-min bin. C. Rate of change in glutamate concentrations (μM/min). n = 4-5/group. ***P < 0.001 compared to saline-treated controls during 6-min tail suspension. ###P < 0.001 indicating significant overall difference between two treatment groups.

Mentions: The observation of LepRb granule neurons in DG projecting to CA3 suggests that leptin may modulate glutamate release in CA3 evoked by tail suspension. To test this possibility, mice received an i.p. leptin injection (1.0 mg/kg) 30 min before the TST and changes in extracellular glutamate levels in CA3 were monitored using microelectrode biosensors. There was a significant main effect of leptin treatment on extracellular glutamate concentrations during the 6-min TST (F(1, 49) = 18.883, p < 0.001) and within 32 min after the onset of TST (F(1, 231) = 32.759, p < 0.001). Tail suspension-evoked glutamate release in CA3 was significantly inhibited by leptin treatment (Figure 4). After cessation of tail suspenstion stress, the increased glutamate levels returned to baseline within a shorter period of time in the leptin-treated group in comparison with the vehicle treatment (Figure 4A, B). Leptin-induced inhibition of rate of changes in extracellular glutamate levels occur largely within the first min of tail suspension (Figure 4C).


Dentate gyrus-CA3 glutamate release/NMDA transmission mediates behavioral despair and antidepressant-like responses to leptin.

Wang X, Zhang D, Lu XY - Mol. Psychiatry (2014)

Effect of leptin on tail suspension-evoked glutamate release in CA3. Leptin (1.0 mg/kg) or saline was injected intraperitoneally into the mice 30 min before tail suspension. A. Compositing changes in extracellular glutamate concentrations (μM) converted from current recording at a 1 Hz sampling frequency from 5 saline-treated mice (red open circle) and 4 leptin-treated mice (blue open circle). B. Temporal changes in glutamate concentrations in 1-min bin. C. Rate of change in glutamate concentrations (μM/min). n = 4-5/group. ***P < 0.001 compared to saline-treated controls during 6-min tail suspension. ###P < 0.001 indicating significant overall difference between two treatment groups.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4362753&req=5

Figure 4: Effect of leptin on tail suspension-evoked glutamate release in CA3. Leptin (1.0 mg/kg) or saline was injected intraperitoneally into the mice 30 min before tail suspension. A. Compositing changes in extracellular glutamate concentrations (μM) converted from current recording at a 1 Hz sampling frequency from 5 saline-treated mice (red open circle) and 4 leptin-treated mice (blue open circle). B. Temporal changes in glutamate concentrations in 1-min bin. C. Rate of change in glutamate concentrations (μM/min). n = 4-5/group. ***P < 0.001 compared to saline-treated controls during 6-min tail suspension. ###P < 0.001 indicating significant overall difference between two treatment groups.
Mentions: The observation of LepRb granule neurons in DG projecting to CA3 suggests that leptin may modulate glutamate release in CA3 evoked by tail suspension. To test this possibility, mice received an i.p. leptin injection (1.0 mg/kg) 30 min before the TST and changes in extracellular glutamate levels in CA3 were monitored using microelectrode biosensors. There was a significant main effect of leptin treatment on extracellular glutamate concentrations during the 6-min TST (F(1, 49) = 18.883, p < 0.001) and within 32 min after the onset of TST (F(1, 231) = 32.759, p < 0.001). Tail suspension-evoked glutamate release in CA3 was significantly inhibited by leptin treatment (Figure 4). After cessation of tail suspenstion stress, the increased glutamate levels returned to baseline within a shorter period of time in the leptin-treated group in comparison with the vehicle treatment (Figure 4A, B). Leptin-induced inhibition of rate of changes in extracellular glutamate levels occur largely within the first min of tail suspension (Figure 4C).

Bottom Line: A subpopulation of granule neurons that innervated the CA3 region expressed leptin receptors and these cells were not activated by stress.Leptin treatment dampened tail suspension-evoked glutamate release in CA3.On the other hand, intra-CA3 infusion of NMDA blocked the antidepressant-like effect of leptin in reversing behavioral despair in both the tail suspension and forced swim tests, which involved activation of Akt signaling in DG.

View Article: PubMed Central - PubMed

Affiliation: 1] Institute for Metabolic and Neuropsychiatric Disorders, Binzhou Medical University Hospital, Binzhou, China [2] Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.

ABSTRACT
Compelling evidence supports the important role of the glutamatergic system in the pathophysiology of major depression and also as a target for rapid-acting antidepressants. However, the functional role of glutamate release/transmission in behavioral processes related to depression and antidepressant efficacy remains to be elucidated. In this study, glutamate release and behavioral responses to tail suspension, a procedure commonly used for inducing behavioral despair, were simultaneously monitored in real time. The onset of tail suspension stress evoked a rapid increase in glutamate release in hippocampal field CA3, which declined gradually after its offset. Blockade of N-methyl-D-aspartic acid (NMDA) receptors by intra-CA3 infusion of MK-801, a non-competitive NMDA receptor antagonist, reversed behavioral despair. A subpopulation of granule neurons that innervated the CA3 region expressed leptin receptors and these cells were not activated by stress. Leptin treatment dampened tail suspension-evoked glutamate release in CA3. On the other hand, intra-CA3 infusion of NMDA blocked the antidepressant-like effect of leptin in reversing behavioral despair in both the tail suspension and forced swim tests, which involved activation of Akt signaling in DG. Taken together, these results suggest that the DG-CA3 glutamatergic pathway is critical for mediating behavioral despair and antidepressant-like responses to leptin.

Show MeSH
Related in: MedlinePlus