Presynaptic homeostatic plasticity (PHP) compensates for impaired postsynaptic neurotransmitter receptor function through a rapid, persistent adjustment of neurotransmitter release, an effect that can exceed 200%. An unexplained property of PHP is the preservation of short-term plasticity (STP), thereby stabilizing activity-dependent synaptic information transfer. We demonstrate that the dramatic potentiation of presynaptic release during PHP is achieved while simultaneously maintaining a constant ratio of primed to super-primed synaptic vesicles, thereby preserving STP. Mechanistically, genetic, biochemical and electrophysiological evidence argue that a constant ratio of primed to super-primed synaptic vesicles is achieved by the concerted action of three proteins: Unc18, Syntaxin1A and RIM. Our data support a model based on the regulated availability of Unc18 at the presynaptic active zone, a process that is restrained by Syntaxin1A and facilitated by RIM. As such, regulated vesicle priming/super-priming enables PHP to stabilize both synaptic gain and the activity-dependent transfer of information at a synapse.

There is an increasing interest in the putative role of glucagon-like peptide 1 receptor (GLP-1R) agonists as novel therapeutic agents for mental disorders. Herein, we investigated the expressions of GLP-1R and GLP-2R genes, and its relationship with body mass index (BMI), in the post-mortem brain tissue of patients with mood (MD) and psychotic disorders. Brain samples were localized to the dorsolateral prefrontal cortex (dlPFC) (n = 459) and hippocampus (n = 378). After adjustment for age, sex, ethnicity, post-mortem interval (PMI) and BMI, we observed significant differences, between healthy controls and MD subjects, in GLP-1R and GLP-2R gene expression in the dlPFC (β = 1.504, p = 0.004; and β = 1.305, p = 0.011, respectively); whereas in the hippocampus, only GLP-1R expression was significantly associated with MD (β = -1.28, p = 0.029). No significant differences were found in relation to schizophrenia. In addition, we observed a moderating effect of MD diagnosis on the associations between BMI, GLP-1R and GLP-2R expression values in the dlPFC (β = -0.05, p = 0.003; and β = -0.04, p = 0.004, respectively). There was a similar moderating effect for GLP-1R in the hippocampus (β = 0.043, 95% CI 0.003; 0.08 p = 0.03), but in an opposite direction than observed in the dlPFC. This is the first evidence of abnormal gene expression of GLP-1R and GLP-2R in postmortem brain of individuals with MD, providing a rationale for further inquiry and proof of principle interventional studies.

Although longer duration of untreated psychosis (DUP) is associated with poor response to antipsychotic treatment, it remains unclear whether it independently influences time to symptomatic remission in first-episode psychosis (FEP). This study examined rate of symptomatic remission, and explored if DUP, premorbid functioning, global functioning, insight and socio-demographic characteristics were independently associated with time to symptomatic remission in FEP.This prospective study enrolled 126 FEP patients (aged 18-65) between June 2009 and September 2012. Subjects were followed-up monthly over 18 months after they had received antipsychotic medication. Remission in positive and negative symptoms was defined as in the Remission in Schizophrenia Working Group (RSWG) criteria. Subjects were defined as "in symptomatic remission" if they remitted in both negative and positive symptoms. At baseline, the following explanatory variables were measured: socio-demographic characteristics; DUP as short (≤5 months) and long (>5 months); premorbid functioning as deteriorating, stable poor, and stable good according to Cannon-Spoor Premorbid Adjustment Scale; global functioning as "worst (1-10) to serious (41-50)" and "moderate (51-60) to superior (91-100)," according to the Global Assessment of Functioning Scale; and insight as poor (≤8) and good (≥9) according to the Insight Scale (Birchwood). Univariate and multivariable analyses were used to generate results.Out of 126 subjects, 98 (78%) completed follow-up, of which 70 (71.4%) achieved symptomatic remission within mean duration of 8.05 (4.54) months. Besides, having long DUP and separated/divorced/widowed (adjusted hazard ratio [aHR] = 0.07, 95%CI = [0.01, 0.46]), long DUP and poor insight (aHR = 0.18, 95%CI = [0.04, 0.89]), poor insight and separated/divorced/widowed (aHR = 0.09, 95%CI = [0.01, 0.70]), deteriorating premorbid functioning (aHR = 0.47, 95%CI = [0.23, 0.97]), family history of psychiatric disorders (aHR = 0.52, 95%CI = (0.30, 0.93]), and being male (aHR = 0.47, 95%CI = [0.24, 0.92]) delayed symptomatic remission.These results propose that psychological interventions and social support for mental health problems are warranted and may enhance better response to antipsychotic medications among separated/divorced/widowed patients with long DUP or poor insight, and poor insight patients with long DUP. Deteriorating premorbid functioning, family history of psychiatric disorders and being male continue being important risk factors for poor odds of remission.