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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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Real-time changes in extracellular glutamate concentrations in CA3 induced by tail suspension. Extracellular electrical currents were recorded by glutamate-sensitive micro-biosensors implanted in the CA3 and converted to glutamate concentrations. A. Top, a representative electrical current trace recorded at 1Hz by a biosensor after tail suspension (grey area); middle, changes in extracellular glutamate (Glu) concentrations (1-min bin); bottom, histogram of behavioral responses, ‘struggle’ and ‘immobile’ episodes, during 6-min tail suspension. B. Top, extracellular glutamate concentrations (1-min bin) in the CA3 in response to tail suspension. Bottom, rate of change in extracellular glutamate concentrations (2-min bin). n = 4. C. Histological verification of biosensor placement. Black arrow indicating the end of the guide cannula; red arrow indicating the tip of the biosensor with an active length of 1 mm. TST, tail suspension test.
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Figure 1: Real-time changes in extracellular glutamate concentrations in CA3 induced by tail suspension. Extracellular electrical currents were recorded by glutamate-sensitive micro-biosensors implanted in the CA3 and converted to glutamate concentrations. A. Top, a representative electrical current trace recorded at 1Hz by a biosensor after tail suspension (grey area); middle, changes in extracellular glutamate (Glu) concentrations (1-min bin); bottom, histogram of behavioral responses, ‘struggle’ and ‘immobile’ episodes, during 6-min tail suspension. B. Top, extracellular glutamate concentrations (1-min bin) in the CA3 in response to tail suspension. Bottom, rate of change in extracellular glutamate concentrations (2-min bin). n = 4. C. Histological verification of biosensor placement. Black arrow indicating the end of the guide cannula; red arrow indicating the tip of the biosensor with an active length of 1 mm. TST, tail suspension test.

Mentions: Monitoring behavioral activity and real-time changes in extracellular glutamate levels would enable us to establish the temporal relationship between glutamate release and behavioral changes. A microelectrode biosensor was used for real-time measuring of extracellular glutamate concentrations in CA3 in freely behaving mice during the tail suspension behavioral despair test. The high temporal resolution of biosensor allowed the monitoring of the physiological time course of glutamate responses. We found that extracellular glutamate concentrations in CA3 were rapidly increased after the onset of tail suspension, peaked at the end of 6-min session, and declined gradually to baseline within 30 min after its offset (Figure 1A, B). During the 6-min tail suspension, behavioral responses were automatically recorded by a strain gauge transducer. The histogram of real-time movements showed that struggle activity was stronger at the beginning of 6-min tail suspension when the rate of change in glutamate levels was high in CA3 (Figure 1A). Immobile episodes, reflecting a state of behavioral despair, became more frequent and longer toward the end of tail suspension along extracellular accumulation of glutamate in CA3 (Figure 1A). Statistical analyses indicated that there were significant effects of time on extracellular glutamate concentrations (F(36, 111) = 6.758, p < 0.0001) and rate of change in extracellular glutamate concentrations (F(18, 57) = 6.531, p < 0.0001). It appeared that the increase in the rate of change in glutamate concentrations occur only during tail suspension (Figure 1B).


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)

Real-time changes in extracellular glutamate concentrations in CA3 induced by tail suspension. Extracellular electrical currents were recorded by glutamate-sensitive micro-biosensors implanted in the CA3 and converted to glutamate concentrations. A. Top, a representative electrical current trace recorded at 1Hz by a biosensor after tail suspension (grey area); middle, changes in extracellular glutamate (Glu) concentrations (1-min bin); bottom, histogram of behavioral responses, ‘struggle’ and ‘immobile’ episodes, during 6-min tail suspension. B. Top, extracellular glutamate concentrations (1-min bin) in the CA3 in response to tail suspension. Bottom, rate of change in extracellular glutamate concentrations (2-min bin). n = 4. C. Histological verification of biosensor placement. Black arrow indicating the end of the guide cannula; red arrow indicating the tip of the biosensor with an active length of 1 mm. TST, tail suspension test.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Real-time changes in extracellular glutamate concentrations in CA3 induced by tail suspension. Extracellular electrical currents were recorded by glutamate-sensitive micro-biosensors implanted in the CA3 and converted to glutamate concentrations. A. Top, a representative electrical current trace recorded at 1Hz by a biosensor after tail suspension (grey area); middle, changes in extracellular glutamate (Glu) concentrations (1-min bin); bottom, histogram of behavioral responses, ‘struggle’ and ‘immobile’ episodes, during 6-min tail suspension. B. Top, extracellular glutamate concentrations (1-min bin) in the CA3 in response to tail suspension. Bottom, rate of change in extracellular glutamate concentrations (2-min bin). n = 4. C. Histological verification of biosensor placement. Black arrow indicating the end of the guide cannula; red arrow indicating the tip of the biosensor with an active length of 1 mm. TST, tail suspension test.
Mentions: Monitoring behavioral activity and real-time changes in extracellular glutamate levels would enable us to establish the temporal relationship between glutamate release and behavioral changes. A microelectrode biosensor was used for real-time measuring of extracellular glutamate concentrations in CA3 in freely behaving mice during the tail suspension behavioral despair test. The high temporal resolution of biosensor allowed the monitoring of the physiological time course of glutamate responses. We found that extracellular glutamate concentrations in CA3 were rapidly increased after the onset of tail suspension, peaked at the end of 6-min session, and declined gradually to baseline within 30 min after its offset (Figure 1A, B). During the 6-min tail suspension, behavioral responses were automatically recorded by a strain gauge transducer. The histogram of real-time movements showed that struggle activity was stronger at the beginning of 6-min tail suspension when the rate of change in glutamate levels was high in CA3 (Figure 1A). Immobile episodes, reflecting a state of behavioral despair, became more frequent and longer toward the end of tail suspension along extracellular accumulation of glutamate in CA3 (Figure 1A). Statistical analyses indicated that there were significant effects of time on extracellular glutamate concentrations (F(36, 111) = 6.758, p < 0.0001) and rate of change in extracellular glutamate concentrations (F(18, 57) = 6.531, p < 0.0001). It appeared that the increase in the rate of change in glutamate concentrations occur only during tail suspension (Figure 1B).

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