Glutamate Levels and Resting Cerebral Blood Flow in Anterior Cingulate Cortex Are Associated at Rest and Immediately Following Infusion of S-Ketamine in Healthy Volunteers

Progressive loss of brain tissue is seen in some patients with schizophrenia and might be caused by increased levels of glutamate and resting cerebral blood flow (rCBF) alterations. Animal studies suggest that the normalisation of glutamate levels decreases rCBF and prevents structural changes in hippocampus. However, the relationship between glutamate and rCBF in anterior cingulate cortex (ACC) of humans has not been studied in the absence of antipsychotics and illness chronicity. Ketamine is a noncompetitive N-methyl-D-aspartate receptor antagonist that transiently induces schizophrenia-like symptoms and neurobiological disturbances in healthy volunteers (HVs). Here, we used S-ketamine challenge to assess if glutamate levels were associated with rCBF in ACC in 25 male HVs. Second, we explored if S-ketamine changed the neural activity as reflected by rCBF alterations in thalamus (Thal) and accumbens that are connected with ACC. Glutamatergic metabolites were measured in ACC with magnetic resonance (MR) spectroscopy and whole-brain rCBF with pseudo-continuous arterial spin labelling on a 3-T MR scanner before, during, and after infusion of S-ketamine (total dose 0.375 mg/kg). In ACC, glutamate levels were associated with rCBF before (p < 0.05) and immediately following S-ketamine infusion (p = 0.03), but not during and after. S-Ketamine increased rCBF in ACC (p < 0.001) but not the levels of glutamate (p = 0.96). In subcortical regions, S-ketamine altered rCBF in left Thal (p = 0.03). Our results suggest that glutamate levels in ACC are associated with rCBF at rest and in the initial phase of an increase. Furthermore, S-ketamine challenge transiently induces abnormal activation of ACC and left Thal that both are implicated in the pathophysiology of schizophrenia. Future longitudinal studies should investigate if increased glutamate and rCBF are related to the progressive loss of brain tissue in initially first-episode patients

Differential Effects of Aripiprazole and Amisulpride on Negative and Cognitive Symptoms in Patients With First-Episode Psychoses

INTRODUCTION: Aripiprazole is hypothesized to have an effect on negative and cognitive symptoms in schizophrenia. Likewise, amisulpride is one of the only second-generation antipsychotics with which an effect on negative symptoms is reported. In the present study, we compare the effect of aripiprazole and amisulpride in initially antipsychotic-naïve patients with first-episode psychoses. METHODS: Psychopathology and cognitive measures from two consecutive cohorts of antipsychotic-naïve first episode psychotic patients were obtained before and after 6 weeks of antipsychotic monotherapy with either aripiprazole or amisulpride. Matched healthy controls were included to account for retest effects on the cognitive measures. Analyses of variance (repeated-measures ANOVA) were performed to detect effect of time and possible cohort(*)time interactions. RESULTS: Longitudinal data was obtained from 47 and 48 patients treated for 6 weeks with amisulpride or aripiprazole, respectively. For the Wallwork negative symptom dimension, there was a cohort(*)time interaction [F((1, 93)) = 4.29, p = 0.041] and a significant effect of time [F((1, 93)) = 6.03, p = 0.016], which was driven by an improvement in patients treated with aripiprazole [t((47)) = 4.1, p 0.5). For the eight cognitive measures, no cohort(*)time interaction was found and neither was cognitive improvement in any of the cohorts when accounting for retest effect. CONCLUSION: Patients treated with aripiprazole improved on negative symptoms, which was not the case for patients treated with amisulpride. This may point to a general effect of a partial D2 receptor agonist on negative symptoms in patients with first-episode psychoses. There was, however, no improvement in cognitive functions

Nectin-1 binds and signals through the fibroblast growth factor receptor

Nectins belong to a family of immunoglobulin (Ig)-like cell-adhesion molecules comprising four members, nectin-1 through nectin-4. Nectins are involved in formation of the mechanical adhesive puncta adherentia junctions of synapses. Nectins share the same overall structural topology with an extracellular region containing three Ig modules, a transmembrane region, and a cytoplasmic region. In nectin-1, the first and second Ig module in the extracellular region are necessary for the trans-interaction with nectin-3 and formation of cis-dimers, respectively. The function of the third Ig module of nectin-1 remains unknown. We here report the structure in solution of the third, membrane-proximal Ig module of mouse nectin-1 (nectin-1 Ig3) solved by means of nuclear magnetic resonance (NMR) spectroscopy. It belongs to the C1 set of the Ig superfamily. Nectin-1 Ig3 was produced as a recombinant protein and induced neurite outgrowth in primary cultures of hippocampal and cerebellar granule neurons, an effect abolished by treatment with the fibroblast growth factor receptor (FGFR) inhibitor SU5402, or by transfection with a dominant-negative FGFR1 construct. We showed by surface plasmon resonance (SPR) analysis that nectin-1 Ig3 directly interacted with various isoforms of FGFR. Nectin-1 Ig3 induced phosphorylation of FGFR1c in the same manner as the whole nectin-1 ectodomain, and promoted survival of cerebellar granule neurons induced to undergo apoptosis. Finally, we constructed a peptide, nectide, by employing in silico modeling of various FGFR ligand-binding sites. Nectide mimicked all the effects of nectin-1 Ig3. We suggest that FGFR is a downstream signaling partner of nectin-1

Associations Between Cognitive Function and Levels of Glutamatergic Metabolites and Gamma-Aminobutyric Acid in Antipsychotic-Naïve Patients With Schizophrenia or Psychosis

BACKGROUND: Abnormal glutamate and GABA (gamma-aminobutyric acid) levels have been found in the early phase of schizophrenia and may underlie cognitive deficits. However, the association between cognitive function and levels of glutamatergic metabolites and GABA has not been investigated in a large group of antipsychotic-naïve patients. METHODS: In total, 56 antipsychotic-naïve patients with schizophrenia or psychotic disorder and 51 healthy control subjects underwent magnetic resonance spectroscopy to measure glutamate, glutamate+glutamine (Glx), and GABA levels in dorsal anterior cingulate cortex (ACC) and glutamate and Glx levels in left thalamus. The cognitive domains of attention, working memory, and IQ were assessed. RESULTS: The whole group of antipsychotic-naïve patients had lower levels of GABA in dorsal ACC (p = .03), and the subgroup of patients with a schizophrenia diagnosis had higher glutamate levels in thalamus (p = .01), but Glx levels in dorsal ACC and thalamus did not differ between groups. Glx levels in dorsal ACC were positively associated with working memory (logarithmically transformed: b = −.016 [higher score indicates worse performance], p = .005) and attention (b = .056, p = .035) in both patients and healthy control subjects, although the association with attention did not survive adjustment for multiple comparisons. CONCLUSIONS: The findings suggest a positive association between glutamatergic metabolites and cognitive function that do not differ between patients and healthy control subjects. Moreover, our data indicate that decreased GABAergic levels in dorsal ACC are involved in schizophrenia and psychotic disorder, whereas increased glutamate levels in thalamus seem to be implicated in schizophrenia pathophysiology. The findings imply that first-episode patients with cognitive deficits may gain from glutamate-modulating compounds