The rapid antidepressant response after ketamine administration in treatment resistant depressed patients suggests a possible new approach for treating mood disorders compared to the weeks or months required for standard medications. However, the mechanisms underlying this action of ketamine have not been identified. We observed that ketamine rapidly activated the mammalian target of rapamycin (mTOR) pathway, leading to increased synaptic signaling proteins and increased number and function of new spine synapses in the prefrontal cortex of rat. Moreover, blockade of mTOR signaling completely blocked ketamine-induction of synaptogenesis and behavioral responses in models of depression. Our results demonstrate that these effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamine.

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.he NMDA receptor antagonist ketamine produces rapid and robust therapeutic responses in treatment-resistant (1, 2) as well as bipolar depressed patients (3). Preclinical studies report that ketamine also rapidly increases the number and function of spine synapses in the medial prefrontal cortex (mPFC) and that these effects are associated with rapid antidepressant behavioral responses in rodent models (4). These findings represent a major advance for the treatment of depression, although the widespread use of ketamine is limited by side effects (e.g., psychotomimetic and dissociative symptoms) and abuse potential. Further studies of the mechanisms underlying the actions of ketamine could lead to novel rapid antidepressant treatments with fewer side effects.Neuroimaging studies in humans demonstrate that ketamine increases the activity of PFC (5-7), consistent with evidence of rapid increases of glutamate transmission in rodent PFC (8, 9). In addition, depressed patients are reported to have reduced activity in the PFC (10) that is normalized with treatment (11). Rodent studies also demonstrate that long-term stress causes neuronal atrophy of mPFC neurons (12, 13) that is rapidly reversed by ketamine (14). Subregions of the mPFC, including infralimbic (IL) and prelimbic (PrL), have been implicated in diverse cognitive and emotional processes, including fear learning, extinction, and anxiety (15-18). However, the role of PFC activity in the behavioral responses to ketamine has not been examined.Here we examined the antidepressant behavioral effects of neuronal inactivation or direct infusions of ketamine into the IL-PFC and compared these effects with PrL-PFC. Using optogenetics, we also examined the antidepressant and anxiolytic effects of neuronal activation in IL-PFC and determined the impact on pyramidal cell spine number and function to assess long-term neuroplasticity. Methods and MaterialsAnimals, Surgery Microinfusions, and Optical Stimulation. Adult male Spra...

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Activation of the G-protein-coupled receptor GPR54 by kisspeptins during normal puberty promotes the central release of gonadotropinreleasing hormone (GnRH) that, in turn, leads to reproductive maturation. In humans and mice, a loss of function mutations of GPR54 prevents the onset of puberty and leads to hypogonadotropic hypogonadism and infertility. Using electrophysiological, morphological, molecular, and retrograde-labeling techniques in brain slices prepared from vGluT2-GFP and GnRH-GFP mice, we demonstrate the existence of two physiologically distinct subpopulations of GnRH neurons. The first subpopulation is comprised of septal GnRH neurons that colocalize vesicular glutamate transporter 2 and green fluorescent protein and is insensitive to metabotropic glutamate receptor agonists, but is exquisitely sensitive to kisspeptin which closes potassium channels to dramatically initiate a long-lasting activation in neurons from prepubertal and postpubertal mice of both sexes. A second subpopulation is insensitive to kisspeptin but is uniquely activated by group I metabotropic glutamate receptor agonists. These two physiologically distinct classes of GnRH cells may subserve different functions in the central control of reproduction and fertility.

The noradrenergic neurons of the locus coeruleus (LC) play an important role in modulating arousal and selective attention. A similar function has been attributed to the hypocretin neurons of the hypothalamus which maintain a strong synaptic projection to the LC. As the LC can be difficult to detect in the embryonic and neonatal mouse brain, we used a new transgenic mouse with strong GFP expression in the LC under the regulation of a mouse prion promoter. GFP colocalized with immunoreactive tyrosine hydroxylase in sections and dispersed cultures of the LC, allowing visualization and whole cell or single‐unit recording from the LC in early stages of cellular development. GFP expression in the LC had no apparent effect on cellular physiology, including resting membrane potential, input resistance, spike threshold, depolarization‐induced spike frequency increase, current‐voltage relations, or hypocretin responses. In slices of the mature mouse and rat LC, hypocretin‐1 and −2 increased spike frequency, with hypocretin‐1 being an order of magnitude more potent. In the postnatal day (P) 0‐2 developing mouse slice during a developmental period when spikes could be elicited in some cells, other developing LC neurons showed rhythmic, subthreshold oscillations (≈1 Hz) in membrane potential (2.9‐7.4 mV amplitude); others were arrhythmic. Hypocretin‐1 depolarized the membrane potential, resulting in the appearance of spikes in developing LC cells that showed no spikes under control conditions. In the presence of TTX and glutamate receptor antagonists, hypocretin‐1‐mediated inward currents were blocked by substitution of choline‐Cl for NaCl, suggesting an excitatory mechanism based on an inward cation current. Hypocretin‐1 initiated strong regular membrane voltage oscillations in arrhythmic immature neurons. Hypocretin increased the temporal synchrony of action potentials studied with dual‐cell recording in P1‐P5 mouse LC slices, consistent with the view that synchrony of LC output, associated with improved cognitive performance, may be increased by hypocretin. Together these data suggest that the hypothalamus, via hypocretin projections, may therefore be in a position to enhance arousal and modulate plasticity in higher brain centres through the developing LC.

It has been proposed that antidepressant effects of neurokinin

Together, these findings provide fundamentally new insight into the molecular and cellular basis of opiate dependence.

BDNF is thought to provide critical trophic support for serotonin neurons. In order to determine postnatal effects of BDNF on the serotonin system, we examined a line of conditional mutant mice that have normal brain content of BDNF during prenatal development but later depletion of this neurotrophin in the postnatal period. These mice show a behavioral phenotype that suggests serotonin dysregulation. However, as shown here, the presynaptic serotonin system in the adult conditional mutant mice appeared surprisingly normal from histological, biochemical, and electrophysiological perspectives. By contrast, a dramatic and unexpected postsynaptic 5-HT2A deficit in the mutant mice was found. Electrophysiologically, serotonin neurons appeared near normal except, most notably, for an almost complete absence of expected 5-HT2A -mediated glutamate and GABA postsynaptic potentials normally displayed by these neurons. Further analysis showed that BDNF mutants had much reduced 5-HT2A receptor protein in dorsal raphe nucleus and a similar deficit in prefrontal cortex, a region that normally shows a high level of 5-HT2A receptor expression. Recordings in prefrontal slice showed a marked deficit in 5-HT2A -mediated excitatory postsynaptic currents, similar to that seen in the dorsal raphe. These findings suggest that postnatal levels of BDNF play a relatively limited role in maintaining presynaptic aspects of the serotonin system and a much greater role in maintaining postsynaptic 5-HT2A and possibly other receptors than previously suspected.