A? Induces Astrocytic Glutamate Release, Extrasynaptic NMDA Receptor Activation, and Synaptic Loss.

A? induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss.

Proc Natl Acad Sci U S A. 2013 Jun 17;
Talantova M, Sanz-Blasco S, Zhang X, Xia P, Akhtar MW, Okamoto SI, Dziewczapolski G, Nakamura T, Cao G, Pratt AE, Kang YJ, Tu S, Molokanova E, McKercher SR, Hires SA, Sason H, Stouffer DG, Buczynski MW, Solomon JP, Michael S, Powers ET, Kelly JW, Roberts A, Tong G, Fang-Newmeyer T, Parker J, Holland EA, Zhang D, Nakanishi N, Chen HS, Wolosker H, Wang Y, Parsons LH, Ambasudhan R, Masliah E, Heinemann SF, Piña-Crespo JC, Lipton SA

Synaptic loss is the cardinal feature linking neuropathology to cognitive decline in Alzheimer’s disease (AD). However, the mechanism of synaptic damage remains incompletely understood. Here, using FRET-based glutamate sensor imaging, we show that amyloid-? peptide (A?) engages ?7 nicotinic acetylcholine receptors to induce release of astrocytic glutamate, which in turn activates extrasynaptic NMDA receptors (eNMDARs) on neurons. In hippocampal autapses, this eNMDAR activity is followed by reduction in evoked and miniature excitatory postsynaptic currents (mEPSCs). Decreased mEPSC frequency may reflect early synaptic injury because of concurrent eNMDAR-mediated NO production, tau phosphorylation, and caspase-3 activation, each of which is implicated in spine loss. In hippocampal slices, oligomeric A? induces eNMDAR-mediated synaptic depression. In AD-transgenic mice compared with wild type, whole-cell recordings revealed excessive tonic eNMDAR activity accompanied by eNMDAR-sensitive loss of mEPSCs. Importantly, the improved NMDAR antagonist NitroMemantine, which selectively inhibits extrasynaptic over physiological synaptic NMDAR activity, protects synapses from A?-induced damage both in vitro and in vivo. HubMed – depression

Muscarinic acetylcholine receptor activation blocks long-term potentiation at cerebellar parallel fiber-Purkinje cell synapses via cannabinoid signaling.

Proc Natl Acad Sci U S A. 2013 Jun 17;
Rinaldo L, Hansel C

Muscarinic acetylcholine receptors (mAChRs) are known to modulate synaptic plasticity in various brain areas. A signaling pathway triggered by mAChR activation is the production and release of endocannabinoids that bind to type 1 cannabinoid receptors (CB1R) located on synaptic terminals. Using whole-cell patch-clamp recordings from rat cerebellar slices, we have demonstrated that the muscarinic agonist oxotremorine-m (oxo-m) blocks the induction of presynaptic long-term potentiation (LTP) at parallel fiber (PF)-Purkinje cell synapses in a CB1R-dependent manner. Under control conditions, LTP was induced by delivering 120 PF stimuli at 8 Hz. In contrast, no LTP was observed when oxo-m was present during tetanization. PF-LTP was restored when the CB1R antagonist N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (AM251) was coapplied with oxo-m. Furthermore, the suppressive effect of oxo-m on PF-LTP was abrogated by the GDP analog GDP-?-S (applied intracellularly), the phospholipase C inhibitor U-73122, and the diacylglycerol lipase inhibitor tetrahydrolipstatin (THL), suggesting that cannabinoid synthesis results from the activation of Gq-coupled mAChRs present on Purkinje cells. The oxo-m-mediated suppression of LTP was also prevented in the presence of the M3 receptor antagonist DAU 5884, and was absent in M1/M3 receptor double-KO mice, identifying M3 receptors as primary oxo-m targets. Our findings allow for the possibility that cholinergic signaling in the cerebellum-which may result from long-term depression (LTD)-related disinhibition of cholinergic neurons in the vestibular nuclei-suppresses presynaptic LTP to prevent an up-regulation of transmitter release that opposes the reduction of postsynaptic responsiveness. This modulatory capacity of mAChR signaling could promote the functional penetrance of LTD. HubMed – depression

THE LATENT STRUCTURE AND COMORBIDITY PATTERNS OF GENERALIZED ANXIETY DISORDER AND MAJOR DEPRESSIVE DISORDER: A NATIONAL STUDY.

Depress Anxiety. 2013 Jun 14;
Blanco C, Rubio JM, Wall M, Secades-Villa R, Beesdo-Baum K, Wang S

BACKGROUND: There is controversy on whether generalized anxiety disorder (GAD) and major depressive disorder (MDD) constitute the same or separate disorders. This study sought to examine the factor structure of the DSM-IV diagnostic criteria of GAD and MDD and the patterns of comorbidity associated with both disorders. METHODS: Data were drawn from the National Epidemiological Survey on Alcohol and Related conditions (NESARC), a representative sample of the adult general population in the United States (N = 43,093). Sociodemographic and psychiatric comorbidity correlates of GAD, MDD, and co-occurring GAD-MDD were obtained. Exploratory and confirmatory factor analyses of the DSM-IV diagnostic criteria for GAD and MDD were conducted, followed by a Multiple Indicators Multiple Causes (MIMIC) model to examine the invariance of the model across several sociodemographic covariates. RESULTS: A bifactor model with one general factor underlying all the MDD and GAD diagnostic criteria and another factor with large loadings only for the GAD criteria best represented the latent structure. This model showed excellent fit indices (CFI = 1.00, TLI = 1.00, RMSEA < 0.02), and a high degree of invariance across sociodemographic covariates. The comorbidity patterns of individuals with MDD only (n = 4,885), GAD only (n = 947) and GAD-MDD (n = 810) were clearly distinguishable. CONCLUSIONS: The latent structure of the diagnostic criteria of MDD and GAD and their comorbidity patterns suggests that GAD and MDD are closely related but different nosological entities, with distinct latent structures, clinical manifestations, and patterns of comorbidity. HubMed – depression

Adverse Effects Associated with Second-Generation Antipsychotic Long-Acting Injection Treatment: A Comprehensive Systematic Review.

Pharmacotherapy. 2013 Jun 17;
Gentile S

As second-generation antipsychotic long-acting injections (SGA-LAIs) are rapidly replacing depot first-generation antipsychotics as first-line agents in treating schizophrenia spectrum disorders, a systematic assessment of their adverse effects is timely. English-language, peer-reviewed articles reporting original data on the safety and tolerability of SGA-LAIs were identified electronically by searching the MEDLINE, EMBASE, PsycINFO, and DARE databases and the Cochrane Library (January 2001-April 2013). In addition to second-generation (atypical) antipsychotics and long-acting injection (depot) antipsychotics, a separate search was performed for each available drug: aripiprazole LAI, olanzapine pamoate, paliperidone palmitate, and risperidone LAI. Articles were excluded if they were review articles, post hoc analyses, analyses of subsets of patients enrolled in previous trials, single case reports, case series studies, small naturalistic studies (involving less than 50 patients), studies providing no safety data, and studies lasting less than 8 weeks. Of 181 articles identified from the search, 140 were excluded; thus, 41 articles met the inclusion criteria. Predictably, the reviewed information revealed that SGA-LAIs have safety profiles consistent with their oral parent formulations. However, they seem to also show unforeseen and worrisome safety signals. Indeed, the routine use of olanzapine-LAI in clinical practice could be limited not only by the well-known risk of postinjection syndrome, whose clinical management remains a matter of concern, but also by the risk of worsening of psychosis. The reviewed information seems to suggest that worsening of psychotic symptoms and depression could also be associated with both risperidone-LAI and paliperidone palmitate. The leading cause of death among patients enrolled in risperidone-LAI studies was suicide. Given the exponential growth in the clinical use of SGA-LAIs, further studies must be urgently performed in order to confirm or exclude the potential safety signals associated with such drugs. HubMed – depression

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