Executive Summary : | Depression and related mood disorders (MDD) are the most complex neuropsychiatric disorders, affecting more than 300 million people, and the leading cause of disability and suicide worldwide. The brain reward circuitry, comprising of PFC, hippocampus, amygdala and nucleus accumbens, which are interconnected via different neurotransmitter systems, is believed to be affected in depression. A focus on the monoamine hypothesis has yielded important insights into the neurobiology of MDD, and several antidepressants. The findings of variable antidepressant response and remission in depression suggest that monoamine therapy could be operating sub-optimally. Glutamate (Glu) and -aminobutyric acid (GABA) are the major excitatory and inhibitory neurotransmitters in the mature brain. Several clinical and preclinical studies suggest that the glutamatergic system plays an important role in the pathophysiology of MDD. Ketamine, a non-competitive NMDAR blocker, produces rapid improvement in mood. Although the precise mechanism of ketamine action is elusive, it has been shown that acute sub-anesthetic ketamine increases glutamate efflux in the PFC of mice and rats. This led to the hypothesis that partial antagonism of NMDAR induces antidepressive effects by increasing neurotransmission and neurometabolism in PFC. Electroconvulsive therapy (ECT) is another effective and fast-acting intervention for drug-resistant MDD. However, the underlying molecular mechanisms involved in the rapid-acting antidepressant action of ketamine and ECT remain largely unclear. The major objective of the study is to understand the underlying mechanism of fast-acting antidepressant interventions. More specifically, behavior, astroglial and neurometabolic activity, and protein homeostasis in the neurocircuitry of depression will be evaluated in the control and mouse model of depression after acute or chronic ketamine and ECT interventions. Most importantly, changes at the single cell-type level (neurons, microglia, astrocytes) will be studied. The depression phenotype will be assessed using different behavior assays like sucrose preference, social interaction, and forced swim test. The neuronal and astroglia metabolic activity and neurotransmitter cycling will be evaluated using 1H-[13C]-NMR spectroscopy following an intravenous infusion of [1,6-13C2]glucose and [2-13C]acetate. Changes in brain protein homeostasis, especially phosphoproteome, will be evaluated using isobaric tags for relative and absolute quantification using mass spectrometry. The successful completion of the study will provide a better insight into the molecular mechanism involved in the rapid-acting antidepressant action of ketamine and ECT, and may be helpful useful in the development of novel rapid-acting antidepressant(s). |