PACAP counteracts ketamine induced apoptosis and ER stress.

NSCs were plated as single cells and treated with 400 μM ketamine alone or with 100 nM PACAP and 400 μM ketamine. After 24 hours incubation, cells were harvested for Western blot analysis (A, B) or harvested for mRNA extraction and quantitative RT-PCR experiments (C). To obtain quantitative measurements Bcl-2 protein levels and cleaved caspase-3 were normalized against coomassie blue. Data are shown as mean ±SEM (A, n = 5–6; B, n = 3–5, C, n = 4–6). Kruskal-Wallis followed by Dunn’s test. Differences were considered significant at P<0.05. * denotes P<0.05 compared with control, # denotes P<0.05 compared to 400 μM ketamine.</p

PACAP Protects Adult Neural Stem Cells from the Neurotoxic Effect of Ketamine Associated with Decreased Apoptosis, ER Stress and mTOR Pathway Activation

<div><p>Ketamine administration is a well-established approach to mimic experimentally some aspects of schizophrenia. Adult neurogenesis dysregulation is associated with psychiatric disorders, including schizophrenia. The potential role of neurogenesis in the ketamine-induced phenotype is largely unknown. Recent results from human genetic studies have shown the pituitary adenylate cyclase-activating polypeptide (PACAP) gene is a risk factor for schizophrenia. Its potential role on the regulation of neurogenesis in experimental model of schizophrenia remains to be investigated. We aimed to determine whether ketamine affects the viability of adult neural stem cells (NSC). We also investigated whether the detrimental effect mediated by ketamine could be counteracted by PACAP. NSCs were isolated from the subventricular zone of the mouse and exposed to ketamine with/without PACAP. After 24 hours, cell viability, potential involvement of apoptosis, endoplasmic reticulum (ER) stress, mTOR and AMPA pathway activation were assessed by quantitative RT-PCR and Western blot analysis. We show that ketamine impairs NSC viability in correlation with increased apoptosis, ER stress and mTOR activation. The results also suggest that the effect of ketamine occurs <i>via</i> AMPA receptor activation. Finally, we show that PACAP counteracted the decreased NSC viability induced by ketamine <i>via</i> the specific activation of the PAC-1 receptor subtype. Our study shows that the NSC viability may be negatively affected by ketamine with putative importance for the development of a schizophrenia phenotype in the ketamine induced animal model of schizophrenia. The neuroprotective effect via PAC-1 activation suggests a potentially novel pharmacological target for the treatment of schizophrenia, <i>via</i> neurogenesis normalization.</p></div

Ketamine decreases NSC viability in a dose-dependent manner.

<p>NSCs were plated as single cells treated with 50 μM, 200 μM, 400 μM and 1 mM ketamine. To measure cell viability, intracellular ATP levels were measured after 24 hours. Data are shown as mean ±SEM (n = 22–35). Kruskal-Wallis followed by Dunn’s test was used. Differences were considered significant at P <0.05. * denotes P<0.05 compared with control.</p

Ketamine-induced cell death is counteracted by PACAP <i>via</i> PAC-1 receptor activation.

<p>NSCs were plated as single cells. Cells were incubated with 400 μM ketamine and PACAP (100 nM) or agonist for PAC-1; Max-4 (30 nM). After 24 hour incubation, intracellular ATP levels were measured for cell viability. Data are shown as mean ±SEM (n = 13–39). Kruskal-Wallis followed by Dunn’s test was used. Differences were considered significant at P<0.05. * denotes P<0.05 compared with control, # denotes P<0.05 compared to 400 μM ketamine.</p

A schematic diagram showing a proposed signaling pathway for PACAP mediated suppression of ketamine induced neurotoxicity of NSCs <i>in vitro</i>.

<p>A schematic diagram showing a proposed signaling pathway for PACAP mediated suppression of ketamine induced neurotoxicity of NSCs <i>in vitro</i>.</p

Ketamine impairs NSC viability <i>via</i> AMPA receptor activation.

<p>NSCs were plated as single cells and treated with 400 μM ketamine or pre-treated with 10 μM NBQX prior to 400 μM ketamine exposure. After 24 hour incubation, intracellular ATP levels were measured. Data are shown as mean ±SEM (n = 23–39). Kruskal-Wallis followed by Dunn’s test was used. Differences were considered significant at P<0.05. * denotes P<0.05 compared with control, # denotes P<0.05 compared to ketamine.</p

Thirteen-year follow-up of long-term treated psychotic disorder: personality aspects

Personality is an aspect that can affect the symptoms and social function in individuals with psychotic disorders. Several studies have investigated personality in schizophrenia and other long-term psychotic disorders. No study has examined the stability of personality traits exceeding five years in patients with schizophrenia and related disorders. The aim of this study was to investigate the stability of personality traits over a 13-year period among patients with schizophrenia and related disorders and healthy individuals and to evaluate case-control differences. At three occasions during a 13-year period patients with schizophrenia and related disorders (n = 28) and healthy individuals (n = 57) completed Swedish universities Scales of Personality (SSP). Mean-level change and case-control differences were investigated for all the individuals using within- and between-subject analyses, respectively. Analyses were performed on three occasions for all 13 subscales and the three overall factors of SSP. Also, correlations, means, and SDs were calculated. Tests of within-subject correlations showed differences in two subscales: Lack of Assertiveness, which were influenced by age, and Physical Trait Aggression, where patients’ ratings were stable, whereas controls rated themselves less aggressive at a higher age. Between-subjects correlations showed differences regarding diagnosis, time, age, gender, or age × gender in nine of the 13 subscales as well as in factor Neuroticism. Long-term follow-up showed generally high stability of personality traits measured with SSP. Between-subject analyses over the 13 years showed that patients differed compared to controls for the SSP factor Neuroticism as well as the subscale Detachment, which is in accordance with previous studies within this population.</p

PACAP counteracts ketamine induced mTOR activation.

<p>NSCs were plated as single cells and treated with 400 μM alone or with 100 nM PACAP and 400 μM ketamine. Cells were treated as indicated and after 1, 2, 6 and 24 hour incubation cells were harvested for Western blot experiments <b>(A)</b>. Cells were treated as indicated and incubated for 1 and 2 hours and harvested for Western blot experiments <b>(B)</b>. To obtain quantitative measurements p-mTOR were normalized against total-mTOR. Data are shown as mean ±SEM (A, n = 4–8; B, n = 3–5). Kruskal-Wallis followed by Dunn’s test or Fisher LSD test was used. Differences were considered significant at P<0.05. * denotes P<0.05 compared with control, # denotes P<0.05 compared to ketamine + 1 hour or ketamine + 2 hours.</p

DataSheet_1_Microstructural White Matter and Links With Subcortical Structures in Chronic Schizophrenia: A Free-Water Imaging Approach.pdf

Schizophrenia is a severe mental disorder with often a chronic course. Neuroimaging studies report brain abnormalities in both white and gray matter structures. However, the relationship between microstructural white matter differences and volumetric subcortical structures is not known. We investigated 30 long-term treated patients with schizophrenia and schizoaffective disorder (mean age 51.1 ± 7.9 years, mean illness duration 27.6 ± 8.0 years) and 42 healthy controls (mean age 54.1 ± 9.1 years) using 3 T diffusion and structural magnetic resonance imaging. The free-water imaging method was used to model the diffusion signal, and subcortical volumes were obtained from FreeSurfer. We applied multiple linear regression to investigate associations between (i) patient status and regional white matter microstructure, (ii) medication dose or clinical symptoms on white matter microstructure in patients, and (iii) for interactions between subcortical volumes and diagnosis on microstructural white matter regions showing significant patient-control differences. The patients had significantly decreased free-water corrected fractional anisotropy (FAt), explained by decreased axial diffusivity and increased radial diffusivity (RDt) bilaterally in the anterior corona radiata (ACR) and the left anterior limb of the internal capsule (ALIC) compared to controls. In the fornix, the patients had significantly increased RDt. In patients, positive symptoms were associated with localized increased free-water and negative symptoms with localized decreased FAt and increased RDt. There were significant interactions between patient status and several subcortical structures on white matter microstructure and the free-water compartment for left ACR and fornix, and limited to the free-water compartment for right ACR and left ALIC. The Cohen's d effect sizes were medium to large (0.61 to 1.20, absolute values). The results suggest a specific pattern of frontal white matter axonal degeneration and demyelination and fornix demyelination that is attenuated in the presence of larger structures of the limbic system in patients with chronic schizophrenia and schizoaffective disorder. Findings warrant replication in larger samples.</p

Comparison of Y chromosome SNP/CN probe intensities between a male, a female and a male with an isodicentric Y chromosome.

<p>The Y axis denotes the log ratio of the average signal intensities for each 20 consecutive SNP/CN probes, while the X axis denotes the genomic position on the Y chromosome, in million base pairs. The signals for a control male are represented in black, female signals are in blue and the signals for the male with an isodicentric Y chromosome are in yellow. Only probes corresponding to the male specific Y region are included.</p