Currently available medications have significant limitations, most notably low response rate and time lag for treatment response. Recent clinical studies have demonstrated that ketamine, an NMDA receptor antagonist produces a rapid antidepressant response (within hours) and is effective in treatment resistant depressed patients. Molecular and cellular studies in rodent models demonstrate that ketamine rapidly increases synaptogenesis, including increased density and function of spine synapses, in the prefrontal cortex (PFC). Ketamine also produces rapid antidepressant actions in behavioral models of depression, and reverses the deficits in synapse number and behavior resulting from chronic stress exposure. These effects of ketamine are accompanied by stimulation of the mammalian target of rapamycin (mTOR), and increased levels of synaptic proteins. Together these studies indicate that ketamine rapidly reverses the atrophy of spines in the PFC and thereby causes a functional reconnection of neurons that underlies the rapid behavioral responses. These studies identify new targets for rapid acting antidepressants that are safer than ketamine.

Lifetime prevalence (~16%)1 and the economic burden ($100 billion annually)2,3 associated with major depressive disorder (MDD) make it one of the most common and debilitating neurobiological illnesses. To date, the exact cellular and molecular mechanisms underlying the pathophysiology of MDD have not been identified. Here we use whole genome expression profiling of postmortem tissue and demonstrate significantly increased expression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) in the hippocampal subfields of MDD subjects compared to matched controls. MKP-1, also known as DUSP1, is a member of a family of dual-specificity phosphatases (DUSP) that dephosphorylate both threonine and tyrosine residues and thereby serves as a key negative regulator of MAPK cascade4, a major signaling pathway involved in neuronal plasticity, function and survival5,6. The significance of altered MKP-1 was tested in rodent models of depression and demonstrates that increased hippocampal MKP-1 expression, as a result of stress or viral-mediated gene transfer, causes depressive behaviors. Conversely, chronic antidepressant treatment normalizes the stress-induced MKP-1 expression and behavior, and mice lacking MKP-1 are resilient to stress. These postmortem and preclinical studies identify MKP-1 as a critical factor in MDD pathophysiology and as a novel target for therapeutic interventions.

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Major depressive disorder (MDD) affects up to 17% of the population, causing profound personal suffering and economic loss (1). Clinical and pre-clinical studies have revealed that prolonged stress and MDD are associated with neuronal atrophy of cortical and limbic brain regions (2-9), but the molecular mechanisms underlying these morphological alterations have not yet been identified. Here, we show that stress increases levels of REDD1 (regulated in development and DNA damage responses 1), an inhibitor of mTORC1 (mammalian/mechanistic target of rapamycin complex 1) (10), in rat prefrontal cortex (PFC). This is concurrent with a decrease in phosphorylation of signaling targets of mTORC1, which is implicated in protein synthesis-dependent synaptic plasticity. We also found that REDD1 levels are increased in the postmortem PFC of human subjects with MDD relative to matched controls. Mutant mice with a deletion of REDD1 are resilient to the behavioral, synaptic, and mTORC1 signaling deficits caused by chronic unpredictable stress (CUS), while viral-mediated over expression of REDD1 in the rat PFC is sufficient to cause anxiety- and depressive-like behaviors and neuronal atrophy. Taken together, these postmortem and pre-clinical findings identify REDD1 as a critical mediator underlying the atrophy of neurons and depressive behavior caused by chronic stress exposure.

Major depressive disorder (MDD) has been linked to changes in function and activity of the hippocampus, one of the central limbic regions involved in regulation of emotions and mood. The exact cellular and molecular mechanisms underlying hippocampal plasticity in response to stress are yet to be fully characterized. In this study, we examined the genetic profile of micro-dissected subfields of post-mortem hippocampus from subjects diagnosed with MDD and comparison subjects matched for sex, race and age. Gene expression profiles of the dentate gyrus and CA1 were assessed by 48K human HEEBO whole genome microarrays and a subgroup of identified genes was confirmed by real-time polymerase chain reaction (qPCR). Pathway analysis revealed altered expression of several gene families, including cytoskeletal proteins involved in rearrangement of neuronal processes. Based on this and evidence of hippocampal neuronal atrophy in MDD, we focused on the expression of cytoskeletal, synaptic and glutamate receptor genes. Our findings demonstrate significant dysregulation of synaptic function/structure related genes SNAP25, DLG2 (SAP93), and MAP1A, and 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid receptor subunit genes GLUR1 and GLUR3. Several of these human target genes were similarly dysregulated in a rat model of chronic unpredictable stress and the effects reversed by antidepressant treatment. Together, these studies provide new evidence that disruption of synaptic and glutamatergic signalling pathways contribute to the pathophysiology underlying MDD and provide interesting targets for novel therapeutic interventions.

Background Basic and clinical studies report that the expression of Fibroblast Growth Factor-2 (FGF2) is decreased in the Prefrontal Cortex (PFC) of depressed subjects or rodents exposed to stress, and increased following antidepressant treatment. Here, we aim to determine if: 1) FGF2/FGF receptor signaling is sufficient and required for mediating an antidepressant response behaviorally and cellularly; and 2) if the antidepressant actions of FGF2 are mediated specifically by the PFC. Methods The role of FGF2 signaling in behavioral models of depression and anxiety was tested using chronic unpredictable stress (CUS)/sucrose consumption test (SCT), forced swim test (FST) and novelty suppressed feeding test (NSFT). We also assessed the number of bromodeoxyuridine labeled dividing glial cells in the PFC as a cellular index relevant to depression (i.e. decreased by stress and increased by antidepressant treatment). Results Chronic FGF2 infusions (i.c.v.) blocked the deficit in SCT caused by CUS. Moreover, the response to antidepressant treatment in the CUS/SCT, and FST, were abolished upon administration of an inhibitor of FGF receptor activity, SU5402. These results are consistent with the regulation of proliferating cells in the PFC, a portion of which are of oligodendrocyte lineage. Lastly, subchronic infusions of FGF2 into the PFC but not into dorsal striatum produced antidepressant- and anxiolytic-like effects on FST and NSFT respectively. Conclusions These findings demonstrate that FGF2-FGFR signaling is sufficient and necessary for the behavioral, as well as gliogenic actions of antidepressants and highlight the PFC as a brain region sensitive to the antidepressant actions of FGF2.

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Background Despite recent interest in glycogen synthase kinase-3b (GSK-3b) as a target for the treatment of mood disorders, there has been very little work related to these illnesses on the upstream signaling molecules that regulate this kinase, as well as downstream targets. Methods Using a focused microarray approach we examined the influence of different classes of antidepressants on Wnt signaling that controls GSK-3b activity as well as the transcription factors that contribute to the actions of GSK-3b. Results The results demonstrate that Wnt2 is a common target of different classes of antidepressants, and also show differential regulation of Wnt-GSK-3b signaling genes. Increased expression and function of Wnt2 was confirmed by secondary measures. Moreover, using a viral vector approach we demonstrate that increased expression of Wnt2 in the hippocampus is sufficient to produce antidepressant-like behavioral actions in well-established models of depression and treatment response. Conclusions These findings demonstrate that Wnt2 expression and signaling is a common target of antidepressants and that increased Wnt2 is sufficient to produce antidepressant effects.