Intranasal oxytocin reduces psychotic symptoms and improves Theory of Mind and social perception in schizophrenia.

Oxytocin has numerous prosocial and antipsychotic-like effects in animals. Prosocial effects of acute intranasal oxytocin administration have also been reported in human subjects. We conducted a randomized, placebo-controlled trial testing the effects of twice daily intranasal oxytocin treatment for 14 days on psychotic symptoms and social cognition in patients with schizophrenia. PANSS scores declined significantly and several social cognition measures improved significantly or nearly significantly in oxytocin (N=11) but not placebo (N=9) recipients. Our results suggest that, in addition to reducing classic psychotic symptoms, oxytocin may diminish certain social cognition deficits that are not improved by current antipsychotic medications.

Pro-apoptotic Par-4 and dopamine D2 receptor in temporal cortex in schizophrenia, bipolar disorder and major depression.

Although the etiology of schizophrenia remains unknown, diverse neuropathological evidence suggests a disorder of synaptic connectivity. Apoptosis is a form of cell death that helps determine synaptic circuitry during neurodevelopment and altered regulation of apoptosis has been implicated in schizophrenia. Prostate apoptosis response-4 (Par-4) is an upstream regulator of apoptosis preferentially localized to synapses. Brain Par-4 levels are upregulated in response to pro-apoptotic stimuli in rodent models and in patients with classic neurodegenerative diseases. Recently, Par-4 was also found to form a complex with the dopamine D2 receptor (D2DR) in competition with the calcium-binding protein calmodulin, implicating Par-4 as an important regulatory component in normal dopamine signaling. Interestingly, mutant mice with disrupted Par-4/D2DR interaction demonstrated depressive-like behaviors, suggesting a potential role for Par-4 in both depression and schizophrenia. In this study, Par-4, D2DR and calmodulin protein levels were measured using semiquantitative Western blotting in postmortem temporal cortex in subjects with schizophrenia, major depression and bipolar disorder. Compared to normal controls, mean Par-4 levels appeared slightly lower in schizophrenia and bipolar disorder. However, in major depression, Par-4 was decreased by 67% compared to normal controls. No differences were found between any groups for calmodulin or for the D2DR 48 kDa band. The D2DR 98 kDa band was lower by 50% in the schizophrenia compared to control groups. Changes in the Par-4/D2DR signaling pathway represent a novel mechanism that may link apoptotic and dopamine signaling pathways in major depression and schizophrenia.

Antipsychotic drugs for first-episode schizophrenia: a comparative review.

Increasingly, it is recognized that first-episode schizophrenia represents a critical stage of illness during which the effectiveness of therapeutic interventions can affect long-term outcome. In this regard, the advent of clozapine and subsequent atypical antipsychotic drugs held promise for improved outcomes in patients with first-episode schizophrenia, given the expectation of improved therapeutic efficacy and a more benign side effect burden compared with typical antipsychotic drugs. A growing number of large clinical trials have evaluated the merits of atypical antipsychotic drugs in the early stages of psychosis. A number of conclusions can be drawn from studies completed to date, with the caveat that data are either limited or unavailable for the antipsychotic drugs most recently approved by the US FDA. Studies of atypical antipsychotic drugs support data obtained with typical agents indicating that positive symptoms of psychosis are very treatment responsive and generally at lower doses than in chronic illness. It also appears that first-episode patients tend to stay on atypical antipsychotic drugs longer than on typical agents when all-cause discontinuation criteria are considered as the primary outcome measure. However, there are few differential advantages of clinical efficacy among the individual atypical antipsychotic drugs and there is little evidence to support distinct therapeutic advantages for negative symptoms or cognitive symptoms for atypical agents. Furthermore, while new-onset psychosis patients are particularly susceptible to extrapyramidal symptoms, they are also prone to gain weight and related metabolic adverse effects associated with many, but not all, atypical antipsychotic drugs. Recent data indicating that certain atypical antipsychotic drugs may have a sparing effect on cortical grey matter loss in first-episode schizophrenia is intriguing, given the potential long-term benefits. In summary, atypical antipsychotic drugs represent an incremental advance for patients in first-episode schizophrenia, especially in the area of neurological tolerability. However, metabolic concerns associated with many atypical agents along with limited benefits in cognition and negative symptom domains highlight the persistent therapeutic needs of these patients.

Regulation of complexin 1 and complexin 2 in the developing human prefrontal cortex.

Complexin 1 (CX1) and complexin 2 (CX2) are presynaptic proteins that modulate neurotransmitter release and are used as markers of inhibitory and excitatory synapses, respectively. The aim of this study was to gain insight into the development of inhibitory and excitatory synapses in human prefrontal cortex (PFC) by examining the expression of CX1 and CX2 in postmortem tissues. Relative complexin protein levels were measured by Western blotting in postmortem dorsolateral prefrontal cortex (DLPFC) of 42 subjects without neurological or psychiatric disease ranging in age from 18 gestational weeks to 25 years. Samples were batched a priori into fetal, 0-12 month, 1-5 years, 6-10 years, 11-15 years, 16-20 years, and 21-25 years age groups. CX1 and CX2 expression and CX2/CX1 demonstrated a significant effect of age group by ANOVA. Group CX1 level increased progressively across development and was lowest in the fetal group and highest in the young adult group, whereas group CX2 level increased between the fetal and the 6-10 years groups and then plateaued. Consistent with these divergent patterns, there was a significant effect of age group on CX2/CX1, which was higher in fetal and infant groups than in the young adult group. Furthermore, regression analysis demonstrated linear relationships of CX1 and CX2/CX1 with age, whereas CX2 was better described as having a curvilinear relationship with age. These data indicate that complexin expression increases during synaptic maturation in human DLPFC and that an increase in the influence of inhibitory synapses relative to that of excitatory synapses occurs during development in this cortical region.

Developmental regulation of the NMDA receptor subunits, NR3A and NR1, in human prefrontal cortex.

Subunit composition of N-methyl-D-aspartate-type glutamate receptors (NMDARs) dictates their function, yet the ontogenic profiles of human NMDAR subunits from gestation to adulthood have not been determined. We examined NMDAR mRNA and protein development in human dorsolateral prefrontal cortex (DLPFC), an area in which NMDARs are critical for higher cognitive processing and NMDAR hypofunction is hypothesized in schizophrenia. Using quantitative reverse transcriptase-polymerase chain reaction and western blotting, we found NR1 expression begins low prenatally, peaks in adolescence, yet remains high throughout life, suggesting lifelong importance of NMDAR function. In contrast, NR3A levels are low during gestation, surge soon after birth, and decline progressively through adolescence and into adulthood. Because NR3A subunits uniquely attenuate NMDAR-mediated currents, limit calcium influx, and suppress dendritic spine formation, high levels during early childhood may be important for regulating neuroprotection and activity-dependent sculpting of synapses. We also examined whether subunit changes underlie reduced NMDAR activity in schizophrenia. Our results reveal normal NR1 and NR3A protein levels in DLPFC from schizophrenic patients, indicating that NMDAR hypofunction is unlikely to be maintained by gross changes in NR3A-containing NMDARs or overall NMDAR numbers. These data provide insights into NMDAR functions in the developing CNS and will contribute to designing pharmacotherapies for neurological disorders.

Differential effects of phencyclidine application on secretogranin II expression in organotypic slices of rat prefrontal cortex.

Phencyclidine (PCP) is a non-competitive NMDA glutamate receptor antagonist that induces psychotomimetic effects in humans and experimental animals. Chronic PCP exposure elicits signs of persistently altered frontal brain activity and related behaviors which are also seen in patients with schizophrenia. Secretogranin II (sg II) belongs to the chromogranin family of proteins that exist in large dense core vesicles in nervous tissue. In the brain, 90% of sg II is processed to the small peptide secretoneurin. We previously detected differential effects of single-dose and subchronic PCP administration on sg II expression in the rat prefrontal cortex (PFC). In the present study, we applied PCP to organotypic PFC slices. PCP application for 28 h induced decreased tissue and culture medium secretoneurin content. In contrast, incubation with the adenylate cyclase activator forskolin caused significantly increased secretoneurin levels after 8 h. PCP for 4 h followed by 24 h without PCP resulted in increased culture medium secretoneurin content but no change in tissue levels. sg II mRNA expression was decreased after 28 h PCP application in cortical neurons. Immunohistochemical and TUNEL staining profiles indicated that the alterations were not due to neurodegeneration. PCP for 5 days changed neither the secretoneurin tissue or culture medium levels, nor the sg II mRNA expression. These results demonstrate that PCP modulates sg II expression in PFC tissue in the absence of afferent inputs and that the nature of these changes is dependent upon the duration of exposure to and/or withdrawal from PCP.

GDNF and TGF-beta1 promote cell survival in serum-free cultures of primary rat microglia.

Recent evidence indicates that glial cell line-derived neurotrophic factor (GDNF) may influence microglial survival, proliferation, and activation, but this has not yet been tested on isolated primary microglia. We compared the effects of individual and combined application of 10 ng/ml GDNF and 1 ng/ml transforming growth factor-beta1 (TGF-beta1) on total cell number, 5-bromo-2'-deoxyuridine (BrdU) incorporation, DNA nick-end labelling (TUNEL staining), and nitrite and lactate dehydrogenase (LDH) secretion in serum-free cultures of primary rat microglia. GDNF as well as TGF-beta1 enhanced the total number of lectin-positive cells and decreased the number of TUNEL-positive nuclei, while no effect on proliferation was observed. Both factors suppressed the secretion of nitrite during the first 4 days of culturing, and GDNF but not TGF-beta1 reduced the secretion of LDH in 2-week-old cultures. These findings suggest that GDNF and TGF-beta1 support survival of primary microglia in vitro.

Reduction of chromogranin B-like immunoreactivity in distinct subregions of the hippocampus from individuals with schizophrenia.

Synaptic disturbances may play a key role in the pathophysiology of schizophrenia. This study was designed to further investigate possible synaptic alterations in the brains of chronic schizophrenic patients. Chromogranin B was applied as a marker for large dense core vesicles and synapsin I as a protein associated with the synaptic vesicle membrane. The distribution and density of chromogranin B-and synapsin I-like immunoreactivity in subregions of the hippocampus was compared between controls (n = 16) and patients with schizophrenia (n = 17). The overall distribution of hippocampal chromogranin B- and synapsin I-like immunoreactivity was similar in controls and in schizophrenic patients with the highest densities in the terminal field of mossy fibers and in the inner molecular layer of the dentate gyrus. In schizophrenic hippocampi, a significant reduction in the density of chromogranin B-like immunoreactivity was found in the CA4 and CA3 but not in the CA1 area of the dentate gyrus based on computerized image analysis. The loss of immunoreactivity was localized to mossy fibers and terminals surrounding hilar interneurons. Double-labelling immunohistochemistry revealed that synapsin I was co-expressed with chromogranin B in these neuronal structures and was also significantly reduced in schizophrenic hippocampi. The present study demonstrates an area-specific reduction of chromogranin B which is paralleled by a decrease of synapsin I. The loss of presynaptic proteins involved in distinct steps of exocytosis may cause complex synaptic disturbances in specific hippocampal subregions resulting in an imbalanced neurotransmitter availability in schizophrenic patients.

Glial cell line-derived neurotrophic factor enhances survival of GM-CSF dependent rat GMIR1-microglial cells.

Microglial activation and proliferation occur in nearly all forms of brain injury. The aim of this study was to investigate the influence of glial cell-line derived neurotrophic factor (GDNF) on proliferation and/or survival in a GMIR1 rat microglial cell line, which proliferates in response to granulocyte-macrophage-colony stimulating factor (GM-CSF). Endogenous GDNF and its receptor, GFRalpha-1, were detected in GMIR1 cells by ELISA and immunohistochemistry/Western blot, respectively. Recombinant GDNF strongly enhanced GMIR1 cell numbers and BrdU-incorporation, an effect inhibited by GDNF blocking antibodies. Inhibition of cAMP/cGMP dependent protein kinase enhanced the GDNF-induced GMIR1 cell number. The results suggest that GDNF has synergistic survival promoting effects on microglia potentially via autocrine mechanisms.

Down-regulation of complement receptor 3 and major histocompatibility complex I and II antigen-like immunoreactivity accompanies ramification in isolated rat microglia.

Isolated primary microglia are highly activated in conventional culture systems. This has restricted studies to the use of late stage measures of activation rather than highly sensitive immunophenotypic and morphological criteria that mark even very early stages of microglial activation in vivo. In the present study, serum-free, serine- and glycine-free medium and poly-L-lysine coated surfaces have been used to demonstrate for the first time isolated rat microglia which (i) downregulate their immunoreactivity for antibodies recognizing complement receptor 3 and major histocompatibility complex antigens while differentiating into ramified cells, and (ii) respond to a subset of modulators with upregulation of complement receptor 3-like immunoreactivity. During 2 weeks of culturing under basal conditions, ramification was accompanied by strong downregulation of OX-42, OX-18 and OX-6 immunoreactivity (antibodies recognizing complement receptor 3 and major histocompatibility complex class I and II antigens, respectively). Ramified cells had lower level immunoreactivity for all three markers than non-ramified cells. High OX-42 immunoreactivity was also associated with morphological signs of activation previously described in vivo. Enhanced OX-42 immunoreactivity was induced by applying either serine and glycine or lipopolysaccharide (LPS) while granulocyte macrophage-colony stimulating factor increased cell number without affecting OX-42 immunoreactivity. LPS induced alterations were apparent within 24 h, were transient, and did not include changes in OX-18 or OX-6 immunoreactivity, cell number or proportion of ramified cells. The results attest to the special efficacy of this culture method for the investigation of the early microglial reaction by use of highly sensitive immunophenotypic criteria.