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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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Related in: MedlinePlus

Distribution of LepRb cells in the hippocampus and effect of leptin on glutamate release in CA3. A. LepRb-tdTomato cells are largely restricted to the granule cell layer of the dentate gyrus (DG) and extend axonal projections to the CA3 region. B. Fluorescent immunohistochemistry showing the exclusive colocalization of LepRb-tdTomato with Prox1, a marker of granule neurons, in DG. C. c-Fos expression (green) in LepRb-tdTomato granule cells (red) following 10-min tail suspension or forced swim. Sale bars = 50 μm in B and 20 μm in C.
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Figure 3: Distribution of LepRb cells in the hippocampus and effect of leptin on glutamate release in CA3. A. LepRb-tdTomato cells are largely restricted to the granule cell layer of the dentate gyrus (DG) and extend axonal projections to the CA3 region. B. Fluorescent immunohistochemistry showing the exclusive colocalization of LepRb-tdTomato with Prox1, a marker of granule neurons, in DG. C. c-Fos expression (green) in LepRb-tdTomato granule cells (red) following 10-min tail suspension or forced swim. Sale bars = 50 μm in B and 20 μm in C.

Mentions: CA3 neurons receive massive glutamatergic inputs from granule neurons in DG. To reveal the distribution of LepRb neurons and their axonal projections, we generated a report line of mice that expressed the tdTomato fluorescent protein specifically in LepRb cells. This protein is among the brightest fluorescent proteins that are currently available 47. It is uniformly distributed throughout the cells and their processes 48, allowing us to visualize dendrites and axonal projections. We found that LepRb-tdTomato cells were largely restricted to the granule cell layer in DG with sparse cells observed in CA3 (Figure 3A). LepRb-tdTomato was exclusively colocalized with Prox1, a granule neuron marker (Figure 3B). The axonal terminals of LepRb granule neurons were extended to CA3 (Figure 3A), suggesting that LepRb neurons participate in modulating CA3 activity.


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)

Distribution of LepRb cells in the hippocampus and effect of leptin on glutamate release in CA3. A. LepRb-tdTomato cells are largely restricted to the granule cell layer of the dentate gyrus (DG) and extend axonal projections to the CA3 region. B. Fluorescent immunohistochemistry showing the exclusive colocalization of LepRb-tdTomato with Prox1, a marker of granule neurons, in DG. C. c-Fos expression (green) in LepRb-tdTomato granule cells (red) following 10-min tail suspension or forced swim. Sale bars = 50 μm in B and 20 μm in C.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Distribution of LepRb cells in the hippocampus and effect of leptin on glutamate release in CA3. A. LepRb-tdTomato cells are largely restricted to the granule cell layer of the dentate gyrus (DG) and extend axonal projections to the CA3 region. B. Fluorescent immunohistochemistry showing the exclusive colocalization of LepRb-tdTomato with Prox1, a marker of granule neurons, in DG. C. c-Fos expression (green) in LepRb-tdTomato granule cells (red) following 10-min tail suspension or forced swim. Sale bars = 50 μm in B and 20 μm in C.
Mentions: CA3 neurons receive massive glutamatergic inputs from granule neurons in DG. To reveal the distribution of LepRb neurons and their axonal projections, we generated a report line of mice that expressed the tdTomato fluorescent protein specifically in LepRb cells. This protein is among the brightest fluorescent proteins that are currently available 47. It is uniformly distributed throughout the cells and their processes 48, allowing us to visualize dendrites and axonal projections. We found that LepRb-tdTomato cells were largely restricted to the granule cell layer in DG with sparse cells observed in CA3 (Figure 3A). LepRb-tdTomato was exclusively colocalized with Prox1, a granule neuron marker (Figure 3B). The axonal terminals of LepRb granule neurons were extended to CA3 (Figure 3A), suggesting that LepRb neurons participate in modulating CA3 activity.

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