Optogenetic stimulation of infralimbic PFC reproduces ketamine's rapid and sustained antidepressant actions.

Ketamine produces rapid and sustained antidepressant actions in depressed patients, but the precise cellular mechanisms underlying these effects have not been identified. Here we determined if modulation of neuronal activity in the infralimbic prefrontal cortex (IL-PFC) underlies the antidepressant and anxiolytic actions of ketamine. We found that neuronal inactivation of the IL-PFC completely blocked the antidepressant and anxiolytic effects of systemic ketamine in rodent models and that ketamine microinfusion into IL-PFC reproduced these behavioral actions of systemic ketamine. We also found that optogenetic stimulation of the IL-PFC produced rapid and long-lasting antidepressant and anxiolytic effects and that these effects are associated with increased number and function of spine synapses of layer V pyramidal neurons. The results demonstrate that ketamine infusions or optogenetic stimulation of IL-PFC are sufficient to produce long-lasting antidepressant behavioral and synaptic responses similar to the effects of systemic ketamine administration.

Regulation of nucleus accumbens activity by the hypothalamic neuropeptide melanin-concentrating hormone.

The lateral hypothalamus and the nucleus accumbens shell (AcbSh) are brain regions important for food intake. The AcbSh contains high levels of receptor for melanin-concentrating hormone (MCH), a lateral hypothalamic peptide critical for feeding and metabolism. MCH receptor (MCHR1) activation in the AcbSh increases food intake, while AcbSh MCHR1 blockade reduces feeding. Here biochemical and cellular mechanisms of MCH action in the rodent AcbSh are described. A reduction of phosphorylation of GluR1 at serine 845 (pSer(845)) is shown to occur after both pharmacological and genetic manipulations of MCHR1 activity. These changes depend upon signaling through G(i/o), and result in decreased surface expression of GluR1-containing AMPA receptors (AMPARs). Electrophysiological analysis of medium spiny neurons (MSNs) in the AcbSh revealed decreased amplitude of AMPAR-mediated synaptic events (mEPSCs) with MCH treatment. In addition, MCH suppressed action potential firing MSNs through K(+) channel activation. Finally, in vivo recordings confirmed that MCH reduces neuronal cell firing in the AcbSh in freely moving animals. The ability of MCH to reduce cell firing in the AcbSh is consistent with a general model from other pharmacological and electrophysiological studies whereby reduced AcbSh neuronal firing leads to food intake. The current work integrates the hypothalamus into this model, providing biochemical and cellular mechanisms whereby metabolic and limbic signals converge to regulate food intake.

Stress blunts serotonin- and hypocretin-evoked EPSCs in prefrontal cortex: role of corticosterone-mediated apical dendritic atrophy.

Morphological studies show that repeated restraint stress leads to selective atrophy in the apical dendritic field of pyramidal cells in the medial prefrontal cortex (mPFC). However, the functional consequence of this selectivity remains unclear. The apical dendrite of layer V pyramidal neurons in the mPFC is a selective locus for the generation of increased excitatory postsynaptic currents (EPSCs) by serotonin (5-HT) and hypocretin (orexin). On that basis, we hypothesized that apical dendritic atrophy might result in a blunting of 5-HT- and hypocretin-induced excitatory responses. Using a combination of whole-cell recording and two-photon imaging in rat mPFC slices, we were able to correlate electrophysiological and morphological changes in the same layer V pyramidal neurons. Repeated mild restraint stress produced a decrement in both 5-HT- and hypocretin-induced EPSCs, an effect that was correlated with a decrease in apical tuft dendritic branch length and spine density in the distal tuft branches. Chronic treatment with the stress hormone corticosterone, while reducing 5-HT responses and generally mimicking the morphological effects of stress, failed to produce a significant decrease in hypocretin-induced EPSCs. Accentuating this difference, pretreatment of stressed animals with the glucocorticoid receptor antagonist RU486 blocked reductions in 5-HT-induced EPSCs but not hypocretin-induced EPSCs. We conclude: (i) stress-induced apical dendritic atrophy results in diminished responses to apically targeted excitatory inputs and (ii) corticosterone plays a greater role in stress-induced reductions in EPSCs evoked by 5-HT as compared with hypocretin, possibly reflecting the different pathways activated by the two transmitters.

Neurobiology of the Rapid-Acting Antidepressant Effects of Ketamine: Impact and Opportunities.

The discovery of the rapid-acting antidepressant effects of ketamine has 1) led to a paradigm shift in our perception of what is possible in treating severe depression; 2) spurred a wave of basic, translation, and clinical research; and 3) provided an unprecedented investigational tool to conduct longitudinal mechanistic studies that may capture behavioral changes as complex as clinical remission and relapse within hours and days of treatment. Unfortunately, these advances did not yet translate into clinical biomarkers or novel treatments, beyond ketamine. In contrast to slow-acting antidepressants, in which targeting monoaminergic receptors identified several efficacious drugs with comparable mechanisms, the focus on the receptor targets of ketamine has failed in several clinical trials over the past decade. Thus, it is becoming increasingly crucial that we concentrate our effort on the downstream molecular mechanisms of ketamine and their effects on the brain circuitry and networks. Honoring the legacy of our mentor, friend, and colleague Ron Duman, we provide a historical note on the discovery of ketamine and its putative mechanisms. We then detail the molecular and circuits effect of ketamine based on preclinical findings, followed by a summary of the impact of this work on our understanding of chronic stress pathology across psychiatric disorders, with particular emphasis on the role of synaptic connectivity and its brain network effects in the pathology and treatment of clinical depression.

Hypocretin (orexin) induces calcium transients in single spines postsynaptic to identified thalamocortical boutons in prefrontal slice.

In vivo, thalamocortical axons are susceptible to the generation of terminal spikes which antidromically promote bursting in the thalamus. Although neurotransmitters could elicit such ectopic action potentials at thalamocortical boutons, this hypothesis has never been confirmed. Prefrontal cortex is the cortical area most implicated in arousal and is innervated by thalamic neurons that are unusual since they burst rhythmically during waking. We show that a neurotransmitter critical for alertness, hypocretin (orexin), directly excites prefrontal thalamocortical synapses in acute slice. This TTX-sensitive activation of thalamic axons was demonstrated electrophysiologically and by two-photon sampling of calcium transients at single spines in apposition to thalamic boutons anterogradely labeled in vivo. Spines receiving these long-range projections constituted a unique population in terms of the presynaptic excitatory action of hypocretin. By this mechanism, the hypocretin projection to prefrontal cortex may play a larger role in prefrontal or "executive" aspects of alertness and attention than previously anticipated.

Role of cAMP response element-binding protein in the rat locus ceruleus: regulation of neuronal activity and opiate withdrawal behaviors.

The transcription factor cAMP response element-binding protein (CREB) is implicated in mediating the actions of chronic morphine in the locus ceruleus (LC), but direct evidence to support such a role is limited. Here, we investigated the influence of CREB on LC neuronal activity and opiate withdrawal behaviors by selectively manipulating CREB activity in the LC using viral vectors encoding genes for CREBGFP (wild-type CREB tagged with green fluorescent protein), caCREBGFP (a constitutively active CREB mutant), dnCREBGFP (a dominant-negative CREB mutant), or GFP alone as a control. Our results show that in vivo overexpression of CREBGFP in the LC significantly aggravated particular morphine withdrawal behaviors, whereas dnCREBGFP expression attenuated these behaviors. At the cellular level, CREBGFP expression in the LC in vivo and in vitro had no significant effect on neuronal firing at baseline but enhanced the excitatory effect of forskolin (an activator of adenylyl cyclase) on these neurons, which suggests that the cAMP signaling pathway in these neurons was sensitized after CREB expression. Moreover, in vitro studies showed that caCREBGFP-expressing LC neurons fired significantly faster and had a more depolarized resting membrane potential compared with GFP-expressing control cells. Conversely, LC neuronal activity was decreased by dnCREBGFP, and the neurons were hyperpolarized by this treatment. Together, these data provide direct evidence that CREB plays an important role in controlling the electrical excitability of LC neurons and that morphine-induced increases in CREB activity contribute to the behavioral and neural adaptations associated with opiate dependence and withdrawal.

Schizophrenia, hypocretin (orexin), and the thalamocortical activating system.

Diminished connectivity between midline-intralaminar thalamic nuclei and prefrontal cortex has been suggested to contribute to cognitive deficits that are detectable even in early stages of schizophrenia. The midline-intralaminar relay cells comprise the final link in the ascending arousal pathway and are selectively excited by the wake-promoting peptides hypocretin 1 and 2 (orexin A and B). This excitation occurs both at the level of the relay cell bodies and their axon terminals within prefrontal cortex. In rat brain slices, the release of glutamate from midline-intralaminar thalamocortical terminals induces excitatory postsynaptic currents (EPSCs) in layer V pyramidal cells in prefrontal cortex. When hypocretin is infused into medial prefrontal cortex of behaving animals, it improves performance in a complex cognitive task requiring divided attention. Chronic restraint stress causes atrophy of the apical dendritic arbors in layer V prefrontal pyramidal cells and leads to a reduction in hypocretin-induced EPSCs, indicating impairment in excitatory thalamocortical transmission. Thus, taken together with evidence for an underlying loss of excitatory thalamocortical connectivity in schizophrenia, stress in this illness could further exacerbate a breakdown in cortical processing of incoming information from the ascending arousal system.

Hypocretin and nicotine excite the same thalamocortical synapses in prefrontal cortex: correlation with improved attention in rat.

Thalamic projections to prefrontal cortex are important for executive aspects of attention. Using two-photon imaging in prefrontal brain slices, we show that nicotine and the wakefulness neuropeptide hypocretin (orexin) excite the same identified synapses of the thalamocortical arousal pathway within the prefrontal cortex. Although it is known that attention can be improved when nicotine is infused directly into the midlayer of the prefrontal cortex in the rat, the effects of hypocretin on attention are not known. The overlap in thalamocortical synapses excited by hypocretin and nicotine and the lack of direct postsynaptic effects prompted us to compare their effects on a sustained and divided attention task in the rat. Similar to nicotine, infusions of hypocretin-2 peptide into the prefrontal cortex significantly improved accuracy under high attentional demand without effects on other performance measures. We show for the first time that hypocretin can improve attentional processes relevant to executive functions of the prefrontal cortex.

Hallucinogen-induced UP states in the brain slice of rat prefrontal cortex: role of glutamate spillover and NR2B-NMDA receptors.

Psychedelic hallucinogens (eg LSD or DOI) induce disturbances of mood, perception, and cognition through stimulation of serotonin 5-HT2A receptors. While these drugs are not proconvulsant, they have been shown by microdialysis to increase extracellular glutamate in the prefrontal cortex. Electrophysiological studies in the rat prefrontal slice have shown that both LSD and DOI enhance a prolonged, late wave of glutamate release onto layer V pyramidal neurons after an electrical stimulus. Here, we hypothesize that the network activity underlying this UP state involves glutamate spillover from excitatory synapses. To test this hypothesis, we raised the viscosity of the extracellular solution by adding the inert macromolecule dextran (approximately 1 mM) that is known to retard glutamate overflow into the extrasynaptic space. Dextran suppressed the UP state or late excitatory postsynaptic current (EPSC), but neither the fast EPSC, the traditional polysynaptic EPSC, nor a synaptic form of 5-HT2A-mediated transmission (serotonin-induced spontaneous EPSCs). Consistent with the previous work showing that extrasynaptic glutamate transmission in adult depends on NR2B-containing NMDA receptors, we found that NR2B-selective antagonists, ifenprodil and Ro25-6981, also suppressed the late EPSCs. The effect of psychedelic hallucinogens on UP states could be partially mimicked by inhibiting glutamate uptake but only after blocking inhibitory group II metabotropic glutamate receptors. This difference suggests that hallucinogens increase glutamate spillover in a phasic manner unlike glutamate uptake inhibitors. Increases in glutamate spillover have been suggested to recruit synapses not directly in the pathway activated by the electrical stimulus. Such recruitment could account for certain cognitive, affective, and sensory perturbations generated by psychedelic hallucinogens.

Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants.

Depression is a common, devastating illness. Current pharmacotherapies help many patients, but high rates of a partial response or no response, and the delayed onset of the effects of antidepressant therapies, leave many patients inadequately treated. However, new insights into the neurobiology of stress and human mood disorders have shed light on mechanisms underlying the vulnerability of individuals to depression and have pointed to novel antidepressants. Environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology, resulting in dysfunction of the circuitry that is essential for mood regulation and cognitive function. Although current antidepressants, such as serotonin-reuptake inhibitors, produce subtle changes that take effect in weeks or months, it has recently been shown that treatment with new agents results in an improvement in mood ratings within hours of dosing patients who are resistant to typical antidepressants. Within a similar time scale, these new agents have also been shown to reverse the synaptic deficits caused by stress.

Hypocretins (orexins) regulate serotonin neurons in the dorsal raphe nucleus by excitatory direct and inhibitory indirect actions.

The hypocretins (hcrt1 and hcrt2) are expressed by a discrete population of hypothalamic neurons projecting to many regions of the CNS, including the dorsal raphe nucleus (DRN), where serotonin (5-HT) neurons are concentrated. In this study, we investigated responses to hcrts in 216 physiologically identified 5-HT and non-5-HT neurons of the DRN using intracellular and whole-cell recording in rat brain slices. Hcrt1 and hcrt2 induced similar amplitude and dose-dependent inward currents in most 5-HT neurons tested (EC50, approximately 250 nm). This inward current was not blocked by the fast Na+ channel blocker TTX or in a Ca2+-free solution, indicating a direct postsynaptic action. The hcrt-induced inward current reversed near -18 mV and was primarily dependent on external Na+ but not on external or internal Ca2+, features typical of Na+/K+ nonselective cation channels. At higher concentrations, hcrts also increased spontaneous postsynaptic currents in 5-HT neurons (EC50, approximately 450-600 nm), which were TTX-sensitive and mostly blocked by the GABA(A) antagonist bicuculline, indicating increased impulse flow in local GABA interneurons. Accordingly, hcrts were found to increase the basal firing of presumptive GABA interneurons. Immunolabeling showed that hcrt fibers projected to both 5-HT and GABA neurons in the DRN. We conclude that hcrts act directly to excite 5-HT neurons primarily via a TTX-insensitive, Na+/K+ nonselective cation current, and indirectly to activate local inhibitory GABA inputs to 5-HT cells. The greater potency of hcrts in direct excitation compared with indirect inhibition suggests a negative feedback function for the latter at higher levels of hcrt activity.

Brain-derived neurotrophic factor is essential for opiate-induced plasticity of noradrenergic neurons.

Chronic opiate exposure induces numerous neurochemical adaptations in the noradrenergic system, including upregulation of the cAMP-signaling pathway and increased expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. These adaptations are thought to compensate for opiate-mediated neuronal inhibition but also contribute to physical dependence, including withdrawal after abrupt cessation of drug exposure. Little is known about molecules that regulate the noradrenergic response to opiates. Here we report that noradrenergic locus ceruleus (LC) neurons of mice with a conditional deletion of BDNF in postnatal brain respond to chronic morphine treatment with a paradoxical downregulation of cAMP-mediated excitation and lack of dynamic regulation of TH expression. This was accompanied by a threefold reduction in opiate withdrawal symptoms despite normal antinociceptive tolerance in the BDNF-deficient mice. Although expression of TrkB, the receptor for BDNF, was high in the LC, endogenous BDNF expression was absent there and in the large majority of other noradrenergic neurons. Therefore, a BDNF-signaling pathway originating from non-noradrenergic sources is essential for opiate-induced molecular adaptations of the noradrenergic system.

Ketamine Strengthens CRF-Activated Amygdala Inputs to Basal Dendrites in mPFC Layer V Pyramidal Cells in the Prelimbic but not Infralimbic Subregion, A Key Suppressor of Stress Responses.

A single sub-anesthetic dose of ketamine, a short-acting NMDA receptor blocker, induces a rapid and prolonged antidepressant effect in treatment-resistant major depression. In animal models, ketamine (24 h) reverses depression-like behaviors and associated deficits in excitatory postsynaptic currents (EPSCs) generated in apical dendritic spines of layer V pyramidal cells of medial prefrontal cortex (mPFC). However, little is known about the effects of ketamine on basal dendrites. The basal dendrites of layer V cells receive an excitatory input from pyramidal cells of the basolateral amygdala (BLA), neurons that are activated by the stress hormone CRF. Here we found that CRF induces EPSCs in PFC layer V cells and that ketamine enhanced this effect through the mammalian target of rapamycin complex 1 synaptogenic pathway; the CRF-induced EPSCs required an intact BLA input and were generated primarily in basal dendrites. In contrast to its detrimental effects on apical dendritic structure and function, chronic stress did not induce a loss of CRF-induced EPSCs in basal dendrites, thereby creating a relative imbalance in favor of amygdala inputs. The effects of ketamine were complex: ketamine enhanced apical EPSC responses in all mPFC subregions, anterior cingulate (AC), prelimbic (PL), and infralimbic (IL) but enhanced CRF-induced EPSCs only in AC and PL-responses were unchanged in IL, a critical area for suppression of stress responses. We propose that by restoring the strength of apical inputs relative to basal amygdala inputs, especially in IL, ketamine would ameliorate the hypothesized disproportional negative influence of the amygdala in chronic stress and major depression.

Neurokinins activate local glutamatergic inputs to serotonergic neurons of the dorsal raphe nucleus.

It has been proposed that antidepressant effects of neurokinin NK(1) receptor blockade may result from an increase in serotonin (5-HT) transmission. However, the mechanism by which neurokinins influence 5-HT neurons is not known. In this study, local NK(1) and NK(3) receptor-mediated responses in 5-HT neurons of the dorsal raphe nucleus (DRN) were studied using intracellular recording in rat brain slices. Bath application of the NK(1) receptor agonist substance P (SP) or the NK(3) receptor agonists senktide and NKB induced a robust increase in "spontaneous" excitatory postsynaptic currents (EPSCs) in 5-HT neurons. The EPSCs were blocked by the AMPA/kainate glutamate receptor antagonist CNQX and the fast Na(+) channel blocker tetrodotoxin (TTX), indicating that the increase in EPSCs resulted from an increase in impulse flow in local glutamatergic neuronal afferents. The neurokinins agonists had no direct excitatory effects on 5-HT neurons and no NK(1) or NK(3) receptor immunolabeling was found in 5-HT-labeled neurones. However, neurokinins, by increasing excitatory postsynaptic potentials (EPSPs), did increase the spiking of 5-HT neurons. The SP- and NKB-induced EPSCs were preferentially blocked by NK(1) and NK(3) antagonists, and there was minimal cross-desensitization between agonists at the two receptors. We conclude that neurokinins, via distinct NK(1) and NK(3) receptors, could promote 5-HT transmission, at least in part, by exciting a local population of glutamatergic inputs to 5-HT neurons in the DRN. However, these local excitatory effects, viewed within the context of the global effects of neurokinins on 5-HT neurons, reveal important differences between the functional role of NK(1) and NK(3) receptors.

Nicotine induces glutamate release from thalamocortical terminals in prefrontal cortex.

It has been proposed that activation of nicotinic acetylcholine receptors (nAChRs) can activate the prefrontal cortex, enhancing attention and cognition. Nicotine can stimulate the release of several different neurotransmitters in many brain regions. In the present study, we found that stimulation of nAChRs by nicotine or the endogenous agonist, acetylcholine (ACh), induces a large spontaneous increase in glutamate release onto layer V pyramidal neurons of the prefrontal cortex. This release of glutamate, measured by spontaneous excitatory postsynaptic currents (sEPSCs) in the prefrontal cortical slice, depends on intact thalamocortical terminals. It can be suppressed by mu-opioids or eliminated by blocking action potentials. The increase in sEPSCs is sensitive to low concentrations of nicotine, suggesting the involvement of high-affinity (eg alpha(4)beta(2)) nAChRs. Recent work has shown alterations in prefrontal alpha(4)beta(2) nAChRs in autism and schizophrenia, two conditions that are distinguished by abnormal prefrontal cortical activation as well as difficulty in certain aspects of cognition and integrating social and emotional cues. We show that mice lacking the beta(2) nAChR subunit do not show increased sEPSCs with either nicotine or ACh, again implicating high-affinity nicotinic receptors. These findings give new insight into the mechanism by which nicotine affects excitatory neurotransmission to the output neurons of the cerebral cortex in a pathway that is critical for cognitive function and reward expectation.

Medial prefrontal D1 dopamine neurons control food intake.

Although the prefrontal cortex influences motivated behavior, its role in food intake remains unclear. Here, we demonstrate a role for D1-type dopamine receptor-expressing neurons in the medial prefrontal cortex (mPFC) in the regulation of feeding. Food intake increases activity in D1 neurons of the mPFC in mice, and optogenetic photostimulation of D1 neurons increases feeding. Conversely, inhibition of D1 neurons decreases intake. Stimulation-based mapping of prefrontal D1 neuron projections implicates the medial basolateral amygdala (mBLA) as a downstream target of these afferents. mBLA neurons activated by prefrontal D1 stimulation are CaMKII positive and closely juxtaposed to prefrontal D1 axon terminals. Finally, photostimulating these axons in the mBLA is sufficient to increase feeding, recapitulating the effects of mPFC D1 stimulation. These data describe a new circuit for top-down control of food intake.

REDD1 is essential for stress-induced synaptic loss and depressive behavior.

Major depressive disorder (MDD) affects up to 17% of the population, causing profound personal suffering and economic loss. Clinical and preclinical studies have revealed that prolonged stress and MDD are associated with neuronal atrophy of cortical and limbic brain regions, 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 target of rapamycin complex-1; ref. 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 the gene encoding REDD1 are resilient to the behavioral, synaptic and mTORC1 signaling deficits caused by chronic unpredictable stress, whereas viral-mediated overexpression of REDD1 in rat PFC is sufficient to cause anxiety- and depressive-like behaviors and neuronal atrophy. Taken together, these postmortem and preclinical findings identify REDD1 as a critical mediator of the atrophy of neurons and depressive behavior caused by chronic stress exposure.

GSK-3 inhibition potentiates the synaptogenic and antidepressant-like effects of subthreshold doses of ketamine.

A single dose of the short-acting NMDA antagonist ketamine produces rapid and prolonged antidepressant effects in treatment-resistant patients with major depressive disorder (MDD), which are thought to occur via restoration of synaptic connectivity. However, acute dissociative side effects and eventual fading of antidepressant effects limit widespread clinical use of ketamine. Recent studies in medial prefrontal cortex (mPFC) show that the synaptogenic and antidepressant-like effects of a single standard dose of ketamine in rodents are dependent upon activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) signaling pathway together with inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3), which relieves its inhibitory in influence on mTOR. Here, we found that the synaptogenic and antidepressant-like effects of a single otherwise subthreshold dose of ketamine were potentiated when given together with a single dose of lithium chloride (a nonselective GSK-3 inhibitor) or a preferential GSK-3ß inhibitor; these effects included rapid activation of the mTORC1 signaling pathway, increased inhibitory phosphorylation of GSK-3ß, increased synaptic spine density/diameter, increased excitatory postsynaptic currents in mPFC layer V pyramidal neurons, and antidepressant responses that persist for up to 1 week in the forced-swim test model of depression. The results demonstrate that low, subthreshold doses of ketamine combined with lithium or a selective GSK-3 inhibitor are equivalent to higher doses of ketamine, indicating the pivotal role of the GSK-3 pathway in modulating the synaptogenic and antidepressant responses to ketamine. The possible mitigation by GSK-3 inhibitors of the eventual fading of ketamine's antidepressant effects remains to be explored.

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.