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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: The onset of tail suspension stress evoked a rapid increase in glutamate release in hippocampal field CA3, which declined gradually after its offset.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.

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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Effects of intra-CA3 injection of the NMDA receptor antagonist MK-801 on behavioral despair in the tail suspension test. MK-801 (1.0 μg) or vehicle was infused bilaterally into the CA3 30 min prior to the tail suspension test or the locomotion test. A. Left, immobility time during the tail suspension test scored by video analysis; right, individual histograms showing temporal courses of ‘struggle’ and ‘immobile’ episodes during the test following intra-CA3 injection of vehicle or MK-801. n = 9/group. **P < 0.01. B. Locomotor activity. Left, distance travelled in 2-min bin; right, total distance traveled within 30 min. n = 4/group. C. Histological verification of injection sites in the CA3.
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Figure 2: Effects of intra-CA3 injection of the NMDA receptor antagonist MK-801 on behavioral despair in the tail suspension test. MK-801 (1.0 μg) or vehicle was infused bilaterally into the CA3 30 min prior to the tail suspension test or the locomotion test. A. Left, immobility time during the tail suspension test scored by video analysis; right, individual histograms showing temporal courses of ‘struggle’ and ‘immobile’ episodes during the test following intra-CA3 injection of vehicle or MK-801. n = 9/group. **P < 0.01. B. Locomotor activity. Left, distance travelled in 2-min bin; right, total distance traveled within 30 min. n = 4/group. C. Histological verification of injection sites in the CA3.

Mentions: Excessive glutamate release induced by tail suspension is proposed to result in overactivation of NMDA receptors 45, 46. To determine whether NMDA receptor activation is responsible for behavioral despair, mice received intra-CA3 infusion of MK-801 (1.0 μg), a non-competitive NMDA antagonist, 30 min prior to tail suspension. MK-801 significantly reduced behavioral despair, as indicated by decreased immobility time (Figure 2A). There was no significant main effect of MK-801 (F(1, 90) = 0.623, p > 0.1) or interaction between MK-801 and time (F(14, 90) = 0.417, p > 0.5) on locomotor activity, indicating that the effect of MK-801 on behavioral despair is not due to non-specific hyperlocomotion (Figure 2B). These findings suggest that NMDA receptor activation in CA3 may underlie the mechanisms of behavioral despair in the TST. The location of all the microinjection sites is summarized schematically in Figure 2C. Injection sites outside of the region were not included for statistical analyses.


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)

Effects of intra-CA3 injection of the NMDA receptor antagonist MK-801 on behavioral despair in the tail suspension test. MK-801 (1.0 μg) or vehicle was infused bilaterally into the CA3 30 min prior to the tail suspension test or the locomotion test. A. Left, immobility time during the tail suspension test scored by video analysis; right, individual histograms showing temporal courses of ‘struggle’ and ‘immobile’ episodes during the test following intra-CA3 injection of vehicle or MK-801. n = 9/group. **P < 0.01. B. Locomotor activity. Left, distance travelled in 2-min bin; right, total distance traveled within 30 min. n = 4/group. C. Histological verification of injection sites in the CA3.
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Related In: Results  -  Collection

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Figure 2: Effects of intra-CA3 injection of the NMDA receptor antagonist MK-801 on behavioral despair in the tail suspension test. MK-801 (1.0 μg) or vehicle was infused bilaterally into the CA3 30 min prior to the tail suspension test or the locomotion test. A. Left, immobility time during the tail suspension test scored by video analysis; right, individual histograms showing temporal courses of ‘struggle’ and ‘immobile’ episodes during the test following intra-CA3 injection of vehicle or MK-801. n = 9/group. **P < 0.01. B. Locomotor activity. Left, distance travelled in 2-min bin; right, total distance traveled within 30 min. n = 4/group. C. Histological verification of injection sites in the CA3.
Mentions: Excessive glutamate release induced by tail suspension is proposed to result in overactivation of NMDA receptors 45, 46. To determine whether NMDA receptor activation is responsible for behavioral despair, mice received intra-CA3 infusion of MK-801 (1.0 μg), a non-competitive NMDA antagonist, 30 min prior to tail suspension. MK-801 significantly reduced behavioral despair, as indicated by decreased immobility time (Figure 2A). There was no significant main effect of MK-801 (F(1, 90) = 0.623, p > 0.1) or interaction between MK-801 and time (F(14, 90) = 0.417, p > 0.5) on locomotor activity, indicating that the effect of MK-801 on behavioral despair is not due to non-specific hyperlocomotion (Figure 2B). These findings suggest that NMDA receptor activation in CA3 may underlie the mechanisms of behavioral despair in the TST. The location of all the microinjection sites is summarized schematically in Figure 2C. Injection sites outside of the region were not included for statistical analyses.

Bottom Line: The onset of tail suspension stress evoked a rapid increase in glutamate release in hippocampal field CA3, which declined gradually after its offset.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.

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