Synaptic dysfunction in depression: potential therapeutic targets,”

Basic and clinical studies demonstrate that depression is associated with reduced size of brain regions that regulate mood and cognition, including the prefrontal cortex and the hippocampus, and decreased neuronal synapses in these areas. Antidepressants can block or reverse these neuronal deficits, although typical antidepressants have limited efficacy and delayed response times of weeks to months. A notable recent discovery shows that ketamine, a N-methyl-D-aspartate receptor antagonist, produces rapid (within hours) antidepressant responses in patients who are resistant to typical antidepressants. Basic studies show that ketamine rapidly induces synaptogenesis and reverses the synaptic deficits caused by chronic stress. These findings highlight the central importance of homeostatic control of mood circuit connections and form the basis of a synaptogenic hypothesis of depression and treatment response. D espite extensive research, the neurobiology of major depressive disorder (MDD) remains poorly understood due to lack of biomarkers, relatively low rates of heritability, and heterogeneity of precipitating factors, including stress (1-3). Studies of antidepressant mechanisms and the development of more effective therapeutic agents have also progressed slowly. The widely prescribed serotonin selective reuptake inhibitors (SSRIs), derived from drugs developed more than 50 years ago, take weeks to months to produce a therapeutic response and are only moderately effective, leaving more than one-third of depressed individuals resistant to drug treatments (3). However, basic and clinical studies have begun to shed light on this widespread, debilitating illness that is characterized by loss of pleasure (anhedonia); decreased cognition and memory; and disrupted sleeping, eating, ambulation, and sexual activity. There are consistent reports of decreased size of brain regions implicated in depression, as well as neuronal atrophy, including loss of synapses in MDD and rodent chronic stress models. Recent studies report what is arguably the most important discovery in half a century: the therapeutic agent ketamine that produces rapid (within hours) antidepressant actions in treatmentresistant depressed patients (4, 5). Notably, the rapid antidepressant actions of ketamine are associated with fast induction of synaptogenesis in rodents and reversal of the atrophy caused by chronic stress (6, 7). We propose a hypothesis that depression is caused by disruption of homeostatic mechanisms that control synaptic plasticity, resulting in destabilization and loss of synaptic connections in mood and emotion circuitry. We compare and contrast the mechanisms underlying typical antidepressants and ketamine, particularly the induction of synaptogenesis. Together, these studies provide a framework for current and future studies of the neurobiology of depression and for the treatment and prevention of MDD and other stressrelated illnesses. Neuronal Atrophy and Synaptic Loss in Depression Brain-imaging studies of depressed patients provide strong and consistent evidence of decreased volume of cortical and limbic brain regionssuch as the prefrontal cortex (PFC) and the hippocampus-that control emotion, mood, and cognition, suggestive of neuronal atrophy that is related to length of illness and time of treatment (8, 9). Functional imaging studies report reductions of connectivity of the hippocampus and the PFC, as well as other brain regions, although there are also reports of increased connectivity of some regions, indicating a more complex disruption of brain circuits (10, 11), possibly due to dysregulation of reciprocal connections (9). Accordingly, it has been proposed that dysregulation rather than an overall increase or decrease of connectivity within PFC networks and their target limbic regions are responsible for the disturbances in emotional, cognitive, and autonomic regulation in mood disorders (9). Also, whereas imaging provides connectivity information on a particular brain region, it does not provide information on the integrity and efficiency of connections, which will require further analysis. Postmortem studies of MDD report a reduction in the size but not number of pyramidal neurons in the dorsal lateral (dl) PFC (12). There is also evidence that GABAergic interneurons (GABA, g-aminobutyric acid) are decreased in the dlPFC, along with consistent reports of decreased glia (12, 13). Similar reductions in neuronal cell body size and neuropil have been reported in the hippocampus of patients with MDD (14). Magnetic resonance spectroscopy demonstrates altered levels of GABA and glutamate cycling, indicating an imbalance of these major neurotransmitters in MDD patients (15). Studies of neuronal morphology in human postmortem brain tissue have been hampered by poor fixation and tissue condition, but we recently reported that the number of synapses, determined by electron microscopy, is decreased in the dlPFC of depressed patients (16). Evidence in support of a reduction of synapse number is provided by reports of decreased levels of synaptic signaling proteins in MDD patients, including decreased levels of glutamate receptor subtypes, presynaptic neurotransmitter vesicle-associated proteins, and postsynaptic structural and functional proteins in the dlPFC, the hippocampus, and other forebrain structures Stress Causes Neuronal Atrophy and Decreases Synaptic Density Rodent studies have provided detailed evidence of neuronal atrophy, reduced synaptic density, and cell loss in models of depression and stress Atrophy of PFC pyramidal neurons is observed after as little as 1 week of restraint stress (20 to 30 min per day), indicating that these cells are particularly sensitive Depressio