Modulation of the activity of N-methyl-d-aspartate receptors as a novel treatment option for depression: current clinical evidence and therapeutic potential of rapastinel (GLYX-13).

Classical monoaminergic antidepressants show several disadvantages, such as protracted onset of therapeutic action. Conversely, the fast and sustained antidepressant effect of the N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine raises vast interest in understanding the role of the glutamate system in mood disorders. Indeed, numerous data support the existence of glutamatergic dysfunction in major depressive disorder (MDD). Drawback to this short-latency therapy is its side effect profile, especially the psychotomimetic action, which seriously hampers the common and widespread clinical use of ketamine. Therefore, there is a substantial need for alternative glutamatergic antidepressants with milder side effects. In this article, we review evidence that implicates NMDARs in the prospective treatment of MDD with focus on rapastinel (formerly known as GLYX-13), a novel synthetic NMDAR modulator with fast antidepressant effect, which acts by enhancing NMDAR function as opposed to blocking it. We summarize and discuss current clinical and animal studies regarding the therapeutic potential of rapastinel not only in MDD but also in other psychiatric disorders, such as obsessive-compulsive disorder and posttraumatic stress disorder. Additionally, we discuss current data concerning the molecular mechanisms underlying the antidepressant effect of rapastinel, highlighting common aspects as well as differences to ketamine. In 2016, rapastinel received the Breakthrough Therapy designation for the treatment of MDD from the US Food and Drug Administration, representing one of the most promising alternative antidepressants under current investigation.

Impact of actin filament stabilization on adult hippocampal and olfactory bulb neurogenesis.

Rearrangement of the actin cytoskeleton is essential for dynamic cellular processes. Decreased actin turnover and rigidity of cytoskeletal structures have been associated with aging and cell death. Gelsolin is a Ca(2+)-activated actin-severing protein that is widely expressed throughout the adult mammalian brain. Here, we used gelsolin-deficient (Gsn(-/-)) mice as a model system for actin filament stabilization. In Gsn(-/-) mice, emigration of newly generated cells from the subventricular zone into the olfactory bulb was slowed. In vitro, gelsolin deficiency did not affect proliferation or neuronal differentiation of adult neural progenitors cells (NPCs) but resulted in retarded migration. Surprisingly, hippocampal neurogenesis was robustly induced by gelsolin deficiency. The ability of NPCs to intrinsically sense excitatory activity and thereby implement coupling between network activity and neurogenesis has recently been established. Depolarization-induced [Ca(2+)](i) increases and exocytotic neurotransmitter release were enhanced in Gsn(-/-) synaptosomes. Importantly, treatment of Gsn(-/-) synaptosomes with mycotoxin cytochalasin D, which, like gelsolin, produces actin disassembly, decreased enhanced Ca(2+) influx and subsequent exocytotic norepinephrine release to wild-type levels. Similarly, depolarization-induced glutamate release from Gsn(-/-) brain slices was increased. Furthermore, increased hippocampal neurogenesis in Gsn(-/-) mice was associated with a special microenvironment characterized by enhanced density of perfused vessels, increased regional cerebral blood flow, and increased endothelial nitric oxide synthase (NOS-III) expression in hippocampus. Together, reduced filamentous actin turnover in presynaptic terminals causes increased Ca(2+) influx and, subsequently, elevated exocytotic neurotransmitter release acting on neural progenitors. Increased neurogenesis in Gsn(-/-) hippocampus is associated with a special vascular niche for neurogenesis.

Serum brain-derived neurotrophic factor and peripheral indicators of the serotonin system in underweight and weight-recovered adolescent girls and women with anorexia nervosa.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) mutant mice show hyperphagia and hyperleptinemia. Animal and cell-culture experiments suggest multiple interrelations between BDNF and the serotonin (5-HT) system. We studied serum BDNF in patients with anorexia nervosa and its associations with peripheral indicators of the 5-HT system. To control for secondary effects of acute malnutrition, we assessed acutely underweight patients with anorexia nervosa (acAN) in comparison to long-term weight-recovered patients with the disorder (recAN) and healthy controls. METHODS: We determined serum BDNF, platelet 5-HT content and platelet 5-HT uptake in 33 patients in the acAN group, 20 patients in the recAN group and 33 controls. Plasma leptin served as an indicator of malnutrition. RESULTS: Patients in the acAN group were aged 14-29 years and had a mean body mass index (BMI) of 14.9 (standard deviation [SD] 1.4) kg/m(2). Those in the recAN group were aged 15-29 years and had a mean BMI of 20.5 (SD 1.3) kg/m(2) and the controls were aged 15-26 years and had a BMI of 21.4 (SD 2.1) kg/m(2). The mean serum BDNF levels were significantly increased in the recAN group compared with the acAN group (8820, SD 3074 v. 6161, SD 2885 pg/mL, U = 154.5, p = 0.001). There were no significant associations between BDNF and either platelet 5-HT content or platelet 5-HT uptake. Among patients with anorexia nervosa, we found significant positive linear relations between BDNF and BMI (r = 0.312, p = 0.023) and between BDNF and leptin (r = 0.365, p = 0.016). LIMITATIONS: We measured the signal proteins under study in peripheral blood. CONCLUSION: Serum BDNF levels in patients with anorexia nervosa depend on the state of illness and the degree of hypoleptinemia. Upregulation of BDNF in weight-recovered patients with anorexia nervosa could be part of a regenerative process after biochemical and molecular neuronal injury due to prolonged malnutrition. Associations between the BDNF and the 5-HT system in humans remain to be established.

Folate deficiency induces neurodegeneration and brain dysfunction in mice lacking uracil DNA glycosylase.

Folate deficiency and resultant increased homocysteine levels have been linked experimentally and epidemiologically with neurodegenerative conditions like stroke and dementia. Moreover, folate deficiency has been implicated in the pathogenesis of psychiatric disorders, most notably depression. We hypothesized that the pathogenic mechanisms include uracil misincorporation and, therefore, analyzed the effects of folate deficiency in mice lacking uracil DNA glycosylase (Ung-/-) versus wild-type controls. Folate depletion increased nuclear mutation rates in Ung-/- embryonic fibroblasts, and conferred death of cultured Ung-/- hippocampal neurons. Feeding animals a folate-deficient diet (FD) for 3 months induced degeneration of CA3 pyramidal neurons in Ung-/- but not Ung+/+ mice along with decreased hippocampal expression of brain-derived neurotrophic factor protein and decreased brain levels of antioxidant glutathione. Furthermore, FD induced cognitive deficits and mood alterations such as anxious and despair-like behaviors that were aggravated in Ung-/- mice. Independent of Ung genotype, FD increased plasma homocysteine levels, altered brain monoamine metabolism, and inhibited adult hippocampal neurogenesis. These results indicate that impaired uracil repair is involved in neurodegeneration and neuropsychiatric dysfunction induced by experimental folate deficiency.