Forebrain glutamatergic neurons mediate leptin action on depression-like behaviors and synaptic depression

Abstract

The glutamatergic system has been implicated in the pathophysiology of depression and the mechanism of action of antidepressants. Leptin, an adipocyte-derived hormone, has antidepressant-like properties. However, the functional role of leptin receptor (Lepr) signaling in glutamatergic neurons remains to be elucidated. In this study, we generated conditional knockout mice in which the long form of Lepr was ablated selectively in glutamatergic neurons located in the forebrain structures, including the hippocampus and prefrontal cortex (Lepr cKO). Lepr cKO mice exhibit normal growth and body weight. Behavioral characterization of Lepr cKO mice reveals depression-like behavioral deficits, including anhedonia, behavioral despair, enhanced learned helplessness and social withdrawal, with no evident signs of anxiety. In addition, loss of Lepr in forebrain glutamatergic neurons facilitates N-methyl--aspartate (NMDA)-induced hippocampal long-term synaptic depression (LTD), whereas conventional LTD or long-term potentiation (LTP) was not affected. The facilitated LTD induction requires activation of the NMDA receptor GluN2B (NR2B) subunit as it was completely blocked by a selective GluN2B antagonist. Moreover, Lepr cKO mice are highly sensitive to the antidepressant-like behavioral effects of the GluN2B antagonist but resistant to leptin. These results support important roles for Lepr signaling in glutamatergic neurons in regulating depression-related behaviors and modulating excitatory synaptic strength, suggesting a possible association between synaptic depression and behavioral manifestation of behavioral depression.

A model for streamlining psychotherapy in the RDoC era: the example of ‘Engage’

“…In animals, precipitants of depression, including chronic stress, alter gene expression and the morphology, functional activity, and connectivity of networks mediating reward-related depression-like behaviors (11). The molecular and cellular basis of these behaviors includes changes in glutamatergic and GABAergic synaptic plasticity, dopamine neuron excitability, epigenetic and transcriptional mechanisms, and neurotrophic factors (12-18). Tools, such as mutations in mice, gene transfer and optogenetics, have made it possible to identify specific proteins acting within specific cells within reward circuits in mediating depression-like behavior.…”

Adiponectin is critical in determining susceptibility to depressive behaviors and has antidepressant-like activity

“…Social interaction test was performed as described previously (29,58). The test was conducted in a 40 × 40 cm open field arena enclosed in a dark testing chamber and illuminated with infrared light.…”

“…Behavioral tests, including sucrose preference, learned helplessness, hot plate, tail suspension test, forced swim test, locomotor activity, visual cliff, and olfactory function, were performed as described previously (58)(59)(60). For experimental details, see SI Materials and Methods.…”

Role of glutamate and advantages of combining memantine with a 5HT6 ligand in a model of depression

“…Clinical evidence suggests that glutamatergic transmission is abnormal in depressed patients [15,29]. Stressors increase glutamate levels and affect the structure and morphology of the rodent brain [10]. It has been suggested that antidepressants modulate monoaminergic and glutamatergic neurotransmission as well [27].…”

“…However, in addition to acetylcholine and monoamine neurotransmitters, 5-HT 6 receptor antagonist increases glutamate levels as well [8]. Various preclinical and clinical studies indicate that glutamate is increased in conditions of stress and play a role in depression [9,10]. SB271046, a 5-HT 6 antagonist increases the glutamate levels in the dorsal lateral frontal cortex (dlfc) and hippocampus.…”