Increased burst‐firing of ventral tegmental area dopaminergic neurons in d‐amino acid oxidase knockout mice in vivo

d ‐Amino acid oxidase (DAO) degrades the N‐methyl‐d ‐aspartate (NMDA) receptor co‐agonist d ‐serine, and is implicated in schizophrenia as a risk gene and therapeutic target. In schizophrenia, the critical neurochemical abnormality affects dopamine, but to date there is little evidence that DAO impacts on the dopamine system. To address this issue, we measured the electrophysiological properties of dopaminergic (DA) and non‐DA neurons in the ventral tegmental area (VTA) of anaesthetised DAO knockout (DAO^?/?) and DAO heterozygote (DAO^+/?) mice as compared with their wild‐type (DAO^+/+) littermates. Genotype was confirmed at the protein level by western blotting and immunohistochemistry. One hundred and thirty‐nine VTA neurons were recorded in total, and juxtacellular labelling of a subset revealed that neurons immunopositive for tyrosine hydroxylase had DA‐like electrophysiological properties that were distinct from those of neurons that were tyrosine hydroxylase‐immunonegative. In DAO^?/? mice, approximately twice as many DA‐like neurons fired in a bursting pattern than in DAO^+/? or DAO^+/+ mice, but other electrophysiological properties did not differ between genotypes. In contrast, non‐DA‐like neurons had a lower firing rate in DAO^?/? mice than in DAO^+/? or DAO^+/+ mice. These data provide the first direct evidence that DAO modulates VTA DA neuron activity, which is of interest for understanding both the glutamatergic regulation of dopamine function and the therapeutic potential of DAO inhibitors. The increased DA neuron burst‐firing probably reflects increased availability of d ‐serine at VTA NMDA receptors, but the site, mechanism and mediation of the effect requires further investigation, and may include both direct and indirect processes.     

d‐amino acid oxidase knockout (Dao−/−) mice show enhanced short‐term memory performance and heightened anxiety,but no sleep or circadian rhythm disruption

d ‐amino acid oxidase (DAO, DAAO) is an enzyme that degrades d ‐serine, the primary endogenous co‐agonist of the synaptic N‐methyl‐d ‐aspartate receptor. Convergent evidence implicates DAO in the pathophysiology and potential treatment of schizophrenia. To better understand the functional role of DAO, we characterized the behaviour of the first genetically engineered Dao knockout (Dao^?/?) mouse. Our primary objective was to assess both spatial and non‐spatial short‐term memory performance. Relative to wildtype (Dao^+/+) littermate controls, Dao^?/? mice demonstrated enhanced spatial recognition memory performance, improved odour recognition memory performance, and enhanced spontaneous alternation in the T‐maze. In addition, Dao^?/? mice displayed increased anxiety‐like behaviour in five tests of approach/avoidance conflict: the open field test, elevated plus maze, successive alleys, light/dark box and novelty‐suppressed feeding. Despite evidence of a reciprocal relationship between anxiety and sleep and circadian function in rodents, we found no evidence of sleep or circadian rhythm disruption in Dao^?/? mice. Overall, our observations are consistent with, and extend, findings in the natural mutant ddY/Dao^? line. These data add to a growing body of preclinical evidence linking the inhibition, inactivation or deletion of DAO with enhanced cognitive performance. Our results have implications for the development of DAO inhibitors as therapeutic agents.     

Effect of D-amino acid oxidase activator (DAOA; G72) on brain function during verbal fluency

Background. The D ‐Amino acid oxidase activator (G72 or DAOA) is believed to play a key role in the regulation of central glutamatergic transmission which is seen to be altered in psychosis. It is thought to regulate D ‐amino acid oxidase (DAO), which metabolizes D ‐serine, a co‐agonist of NMDA‐type glutamate receptors and to be involved in dendritic arborization. Linkage, genetic association and expression studies have implicated the G72 gene in both schizophrenia and bipolar disorder. Aims. To examine the influence of G72 variation on brain function in the healthy population. Method. Fifty healthy volunteers were assessed using functional magnetic resonance imaging while performing a verbal fluency task. Regional brain activation and task‐dependent functional connectivity during word generation was compared between different rs746187 genotypes. Results. G72 rs746187 genotype had a significant effect on activation in the left postcentral and supramarginal gyri (FWE P < 0.05), and on the task‐dependent functional coupling of this region with the retrosplenial cingulate gyrus (FWE P < 0.05). Conclusions. Our results may reflect an effect of G72 on glutamatergic transmission, mediated by an influence on D ‐amino acid oxidase activity, on brain areas particularly relevant to the hypoglutamatergic model of psychosis. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.     

The emerging role of glutamate in the pathophysiology and treatment of schizophrenia

OBJECTIVE: Research has implicated dysfunction of glutamatergic neurotransmission in the pathophysiology of schizophrenia. This review evaluates evidence from preclinical and clinical studies that brain glutamatergic neurotransmission is altered in schizophrenia, may affect symptom expression, and is modulated by antipsychotic drugs. METHOD: A comprehensive review of scientific articles published over the last decade that address the role of glutamate in the pathophysiology of schizophrenia was carried out. RESULTS: Glutamatergic neurons are the major excitatory pathways linking the cortex, limbic system, and thalamus, regions that have been implicated in schizophrenia. Postmortem studies have revealed alterations in pre- and postsynaptic markers for glutamatergic neurons in several brain regions in schizophrenia. The N-methyl-D-aspartic acid (NMDA) subtype of glutamate receptor may be particularly important as blockade of this receptor by the dissociative anesthetics reproduces in normal subjects the symptomatic manifestations of schizophrenia, including negative symptoms and cognitive impairments, and increases dopamine release in the mesolimbic system. Agents that indirectly enhance NMDA receptor function via the glycine modulatory site reduce negative symptoms and variably improve cognitive functioning in schizophrenic subjects receiving typical antipsychotics. CONCLUSIONS: Dysfunction of glutamatergic neurotransmission may play an important role in the pathophysiology of schizophrenia, especially of the negative symptoms and cognitive impairments associated with the disorder, and is a promising target for drug development.     

Maternal immune activation leads to increased nNOS immunoreactivity in the brain of postnatal day 2 rat offspring

Neuronal nitric oxide synthase (nNOS) is a key arginine metabolising enzyme in the brain, and nNOS‐derived nitric oxide (NO) plays an important role in regulating glutamatergic neurotransmission. NO and its related molecules are involved in the pathogenesis of schizophrenia, and human genetic studies have identified schizophrenia risk genes encoding nNOS. This study systematically investigated how maternal immune activation (MIA; a risk factor for schizophrenia) induced by polyinosinic:polycytidylic acid affected nNOS‐immunoreactivity in the brain of the resulting male and female offspring at the age of postnatal day (PND) 2. Immunohistochemistry revealed a markedly increased intensity of nNOS‐positive cells in the CA3 and dentate gyrus subregions of the hippocampus, the somatosensory cortex, and the striatum, but not the frontal cortex and hippocampal CA1 region, in the MIA offspring when compared to control group animals. There were no sex differences in the effect. Given the role of nNOS in glutamatergic neurotransmission and its functional relationship with glutamate NMDA receptors, increased nNOS immunoreactivity may indicate the up‐regulation of NMDA receptor function in MIA rat offspring at an early postnatal age. Future research is required to determine whether these changes contribute to the neuronal and behavioral dysfunction observed in both juvenile and adult MIA rat offspring.     

A novel Na+‐Independent alanine‐serine‐cysteine transporter 1 inhibitor inhibits both influx and efflux of D‐Serine

NMDA receptor dysfunctions are hypothesized to underlie the pathophysiology of schizophrenia, and treatment with D‐serine (D‐Ser), an NMDA receptor coagonist, may improve the clinical symptoms of schizophrenia. Thus, upregulating the synaptic D‐Ser level is a novel strategy for schizophrenia treatment. Na⁺‐independent alanine‐serine‐cysteine transporter 1 (asc‐1) is a transporter responsible for regulating the extracellular D‐Ser levels in the brain. In this study, we discovered a novel asc‐1 inhibitor, (+)‐amino(1‐(3,5‐dichlorophenyl)‐3,5‐dimethyl‐1H‐pyrazol‐4‐yl)acetic acid (ACPP), and assessed its pharmacological profile. ACPP inhibited the D‐[³H]Ser uptake in human asc‐1‐expressing CHO cells and rat primary neurons with IC₅₀ values of 0.72 ± 0.13 and 0.89 ± 0.30 μM, respectively. In accordance with the lower asc‐1 expression levels in astrocytes, ACPP did not inhibit D‐Ser uptake in rat primary astrocytes. In a microdialysis study, ACPP dose dependently decreased the extracellular D‐Ser levels in the rat hippocampus under the same conditions in which the asc‐1 inhibitor S‐methyl‐L‐cysteine (SMLC) increased it. To obtain insights into this difference, we conducted a D‐[³H]Ser efflux assay using asc‐1‐expressing CHO cells. ACPP inhibited D‐[³H]Ser efflux, whereas SMLC increased it. These results suggest that ACPP is a novel inhibitor of asc‐1. © 2016 Wiley Periodicals, Inc.     

Searching for cognitive enhancement in the Morris water maze: better and worse performance in D‐amino acid oxidase knockout (Dao−/−) mice

A common strategy when searching for cognitive‐enhancing drugs has been to target the N‐methyl‐d ‐aspartate receptor (NMDAR), given its putative role in synaptic plasticity and learning. Evidence in favour of this approach has come primarily from studies with rodents using behavioural assays like the Morris water maze. D‐amino acid oxidase (DAO) degrades neutral D‐amino acids such as D‐serine, the primary endogenous co‐agonist acting at the glycine site of the synaptic NMDAR. Inhibiting DAO could therefore provide an effective and viable means of enhancing cognition, particularly in disorders like schizophrenia, in which NMDAR hypofunction is implicated. Indirect support for this notion comes from the enhanced hippocampal long‐term potentiation and facilitated water maze acquisition of ddY/Dao⁻ mice, which lack DAO activity due to a point mutation in the gene. Here, in Dao knockout (Dao^−/−) mice, we report both better and worse water maze performance, depending on the radial distance of the hidden platform from the side wall of the pool. Dao^−/− mice displayed an increased innate preference for swimming in the periphery of the maze (possibly due to heightened anxiety), which facilitated the discovery of a peripherally located platform, but delayed the discovery of a centrally located platform. By contrast, Dao^−/− mice exhibited normal performance in two alternative assays of long‐term spatial memory: the appetitive and aversive Y‐maze reference memory tasks. Taken together, these results question the proposed relationship between DAO inactivation and enhanced long‐term associative spatial memory. They also have generic implications for how Morris water maze studies are performed and interpreted.     

Electrophysiological Identification of the Functional Presynaptic Nerve Terminals on an Isolated Single Vasopressin Neurone of the Rat Supraoptic Nucleus

Release of arginine vasopressin (AVP) and oxytocin from magnocellular neurosecretory cells (MNCs) of the supraoptic nucleus (SON) is under the control of glutamate‐dependent excitation and GABA‐dependent inhibition. The possible role of the synaptic terminals attached to SON neurones has been investigated using whole‐cell patch‐clamp recording in in vitro rat brain slice preparations. Recent evidence has provided new insights into the repercussions of glial environment modifications on the physiology of MNCs at the synaptic level in the SON. In the present study, excitatory glutamatergic and inhibitory GABAergic synaptic inputs were recorded from an isolated single SON neurone cultured for 12 h, using the whole‐cell patch clamp technique. Neurones expressed an AVP‐enhanced green fluorescent protein (eGFP) fusion gene in MNCs. In addition, native synaptic terminals attached to a dissociated AVP‐eGFP neurone were visualised with synaptic vesicle markers. These results suggest that the function of presynaptic nerve terminals may be evaluated directly in a single AVP‐eGFP neurone. These preparations would be helpful in future studies aiming to electrophysiologically distinguish between the functions of synaptic terminals and glial modifications in the SON neurones.     

Dermatoglyphic asymmetries and fronto-striatal dysfunction in young adults reporting non-clinical psychosis

Mittal VA, Dean DJ, Pelletier A. Dermatoglyphic asymmetries and fronto‐striatal dysfunction in young adults reporting non‐clinical psychosis. Objective: Growing evidence indicates that non‐clinical psychotic‐like experiences occur in otherwise healthy individuals, suggesting that psychosis may occur on a continuum. However, little is known about how the diathesis for formal psychosis maps on to individuals at the non‐clinical side of this continuum. Our current understanding of the pathophysiology of schizophrenia implicates certain key factors such as early developmental abnormalities and fronto‐striatal dysfunction. To date, no studies have examined these core factors in the context of non‐clinical psychosis. Method: A total of 221 young adults were assessed for distressing attenuated positive symptoms (DAPS), dermatoglyphic asymmetries (a marker of early developmental insult), and procedural memory (a proxy for fronto‐striatal function). Results: Participants reporting DAPS (n = 16; 7.2%) and no‐DAPS (n = 205; 92.7%) were split into two groups. The DAPS group showed significantly elevated depression, elevated dermatoglyphic asymmetries, and a pattern of procedural learning consistent with other studies with formally psychotic patients. Conclusion: The results indicate that the non‐clinical side of the psychosis continuum also shares key vulnerability factors implicated in schizophrenia, suggesting that both early developmental disruption and abnormalities in fronto‐striatal function are core aspects underlying the disorder.     

Trace amine-associated receptor 1 (TAAR1) agonism as a new treatment strategy for schizophrenia and related disorders

Schizophrenia remains a major health burden, highlighting the need for new treatment approaches. We consider the potential for targeting the trace amine (TA) system. We first review genetic, preclinical, and clinical evidence for the role of TAs in the aetiopathology of schizophrenia. We then consider how the localisation and function of the trace amine-associated receptor 1 (TAAR1) position it to modulate key brain circuits for the disorder. Studies in rodents using Taar1 knockout (TAAR1-KO) and overexpression models show that TAAR1 agonism inhibits midbrain dopaminergic and serotonergic activity, and enhances prefrontal glutamatergic function. TAAR1 agonists also reduce hyperactivity, attenuate prepulse inhibition (PPI) deficits and social withdrawal, and improve cognitive measures in animal models. Finally, we consider findings from clinical trials of TAAR1 agonists and how this approach may address psychotic and negative symptoms, tolerability issues, and other unmet needs in the treatment of schizophrenia.     

Functional and immunocytochemical characterization of D‐serine transporters in cortical neuron and astrocyte cultures

D‐serine is an endogenous coagonist of N‐methyl‐D‐aspartate (NMDA) receptors that plays an important role in synaptic function, neuronal development, and excitotoxicity. Mechanisms of D‐serine transport are important in regulation of extracellular D‐serine concentration and therefore of these critical processes. D‐serine can be transported with low affinity through the Na⁺‐dependent amino acid transporter termed ASCT2, whereas high‐affinity D‐serine uptake has been reported through the Na⁺‐independent transporter termed asc‐1. We investigated immunoreactivity for ASCT2 and asc‐1 and D‐serine transport kinetics in cultured cortical neurons and astrocytes to gain insight into how D‐serine transporters regulate CNS D‐serine levels. Both neurons and astrocytes exhibited low‐affinity Na⁺‐dependent D‐serine uptake (K_T > 1 mM) with broad substrate selectivity that was consistent with uptake through ASCT2. Both neurons and astrocytes also stained positively for ASCT2 in immunocytochemistry studies. Neurons but not astrocytes stained positively for the high‐affinity D‐serine transporter asc‐1, but no evidence of functional asc‐1 could be detected in neurons with conditions that produced such activity in cortical synaptosomes. These data support ASCT2 function in both neuron and astrocyte cultures and identify a discrepancy between observed asc‐1 immunoreactivity and lack of functional asc‐1 activity in neuron cultures. Together these findings further our knowledge of the processes that govern D‐serine regulation. © 2009 Wiley‐Liss, Inc.     

Impact of schizophrenia‐risk gene dysbindin 1 on brain activation in bilateral middle frontal gyrus during a working memory task in healthy individuals

Working memory (WM) dysfunction is a hallmark feature of schizophrenia. Functional imaging studies using WM tasks have documented both prefrontal hypo‐ and hyperactivation in schizophrenia. Schizophrenia is highly heritable, and it is unclear which susceptibility genes modulate WM and its neural correlates. A strong linkage between genetic variants in the dysbindin 1 gene and schizophrenia has been demonstrated. The aim of this study was to investigate the influence of the DTNBP1 schizophrenia susceptibility gene on WM and its neural correlates in healthy individuals. Fifty‐seven right‐handed, healthy male volunteers genotyped for DTNBP1 SNP rs1018381 status were divided in heterozygous risk‐allele carriers (T/C) and homozygous noncarriers (C/C). WM was assessed by a 2‐back vs. 0‐back version of the Continuous Performance Test (CPT), while brain activation was measured with fMRI. DTNBP1 SNP rs1018381 carrier status was determined and correlated with WM performance and brain activation. Despite any differences in behavioral performance, risk‐allele carriers exhibited significantly increased activation of the bilateral middle frontal gyrus (BA 9), a part of the dorsolateral prefrontal cortex (DLPFC), compared to noncarriers. This difference did not correlate with WM performance. The fMRI data provide evidence for an influence of genetic variation in DTNBP1 gene region tagged by SNP rs1018381 on bilateral middle frontal gyrus activation during a WM task. The increased activation in these brain areas may be a consequence of “inefficient” or compensatory DLPFC cognitive control functions. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.     

Converging effects of diverse treatment modalities on frontal cortex in schizophrenia: A review of longitudinal functional magnetic resonance imaging studies

ObjectivesA variety of treatment options exist for schizophrenia, but the effects of these treatments on brain function are not clearly understood. To facilitate the development of more effective treatment strategies, it is important to identify how brain function in schizophrenia patients is affected by the diverse therapeutic approaches that are currently available. The aim of the present article is to systematically review the evidence for functional brain changes associated with different treatment modalities for schizophrenia.MethodsWe searched PubMed for longitudinal functional MRI (fMRI) studies reporting on the effects of antipsychotic medications (APM), repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), cognitive remediation therapy (CRT) and cognitive behavioral therapy for psychosis (CBTp) on brain function in schizophrenia.ResultsThirty six studies fulfilled the inclusion criteria. Functional alterations were observed in diverse brain regions. Across intervention modalities, changes in fMRI parameters were reported most commonly in frontal brain regions including prefrontal cortex, anterior cingulate and inferior frontal cortex.ConclusionsWe conclude that current treatments for schizophrenia commonly induce functional brain alterations in frontal brain regions. However, interpretability is limited by inconsistency in task and region of interest selection, and failures to replicate. Further task independent fMRI studies examining treatment effects with whole brain analysis are needed to deepen our insights.     

Comorbid substance use disorder in schizophrenia: A selective overview of neurobiological and cognitive underpinnings

Although individuals with schizophrenia show a lifetime prevalence of 50% for suffering from a comorbid substance use disorder, substance abuse usually represents an exclusion criterion for studies on schizophrenia. This implies that surprisingly little is known about a large group of patients who are particularly difficult to treat. The aim of the present work is to provide a brief and non‐exhaustive overview of the current knowledgebase about neurobiological and cognitive underpinnings for dual diagnosis schizophrenia patients. Studies published within the last 20 years were considered using computerized search engines. The focus was on nicotine, caffeine, alcohol, cannabis and cocaine being among the most common substances of abuse. All drugs of abuse target dopaminergic, glutamatergic and GABAergic transmission which are also involved in the pathophysiology of schizophrenia. Current literature suggests that neurocognitive function might beless disrupted in substance‐abusing compared to non‐abusing schizophrenia patients, but in particular the neuroimaging database on this topic is sparse. Detrimental effects on brain structure and function were shown for patients for whom alcohol is the main substance of abuse. It is as yet unclear whether this finding might be an artifact of age differences of patient subgroups with different substance abuse patterns. More research is warranted on the specific neurocognitive underpinnings of schizophrenia patients abusing distinct psychoactive substances. Treatment programs might either benefit from preserved cognitive function as a resource or specifically target cognitive impairment in different subgroups of addicted schizophrenia patients.     

Interaction between effects of genes coding for dopamine and glutamate transmission on striatal and parahippocampal function

The genes for the dopamine transporter (DAT) and the D‐Amino acid oxidase activator (DAOA or G72) have been independently implicated in the risk for schizophrenia and in bipolar disorder and/or their related intermediate phenotypes. DAT and G72 respectively modulate central dopamine and glutamate transmission, the two systems most robustly implicated in these disorders. Contemporary studies have demonstrated that elevated dopamine function is associated with glutamatergic dysfunction in psychotic disorders. Using functional magnetic resonance imaging we examined whether there was an interaction between the effects of genes that influence dopamine and glutamate transmission (DAT and G72) on regional brain activation during verbal fluency, which is known to be abnormal in psychosis, in 80 healthy volunteers. Significant interactions between the effects of G72 and DAT polymorphisms on activation were evident in the striatum, parahippocampal gyrus, and supramarginal/angular gyri bilaterally, the right insula, in the right pre‐/postcentral and the left posterior cingulate/retrosplenial gyri (P < 0.05, FDR‐corrected across the whole brain). This provides evidence that interactions between the dopamine and the glutamate system, thought to be altered in psychosis, have an impact in executive processing which can be modulated by common genetic variation. Hum Brain Mapp 34:2244–2258, 2013. © 2012 Wiley Periodicals, Inc.     

Iron deficiency with or without anemia impairs prepulse inhibition of the startle reflex

Iron deficiency (ID) during early life causes long‐lasting detrimental cognitive sequelae, many of which are linked to alterations in hippocampus function, dopamine synthesis, and the modulation of dopaminergic circuitry by the hippocampus. These same features have been implicated in the origins of schizophrenia, a neuropsychiatric disorder with significant cognitive impairments. Deficits in sensorimotor gating represent a reliable endophenotype of schizophrenia that can be measured by prepulse inhibition (PPI) of the acoustic startle reflex. Using two rodent model systems, we investigated the influence of early‐life ID on PPI in adulthood. To isolate the role of hippocampal iron in PPI, our mouse model utilized a timed (embryonic day 18.5), hippocampus‐specific knockout of Slc11a2, a gene coding an important regulator of cellular iron uptake, the divalent metal transport type 1 protein (DMT‐1). Our second model used a classic rat dietary‐based global ID during gestation, a condition that closely mimics human gestational ID anemia (IDA). Both models exhibited impaired PPI in adulthood. Furthermore, our DMT‐1 knockout model displayed reduced long‐term potentiation (LTP) and elevated paired‐pulse facilitation (PPF), electrophysiological results consistent with previous findings in the IDA rat model. These results, in combination with previous findings demonstrating impaired hippocampus functioning and altered dopaminergic and glutamatergic neurotransmission, suggest that iron availability within the hippocampus is critical for the neurodevelopmental processes underlying sensorimotor gating. Ultimately, evidence of reduced PPI in both of our models may offer insights into the roles of fetal ID and the hippocampus in the pathophysiology of schizophrenia. © 2013 Wiley Periodicals, Inc.     

A Brain‐wide association study of DISC1 genetic variants reveals a relationship with the structure and functional connectivity of the precuneus in schizophrenia

The Disrupted in Schizophrenia Gene 1 (DISC1) plays a role in both neural signaling and development and is associated with schizophrenia, although its links to altered brain structure and function in this disorder are not fully established. Here we have used structural and functional MRI to investigate links with six DISC1 single nucleotide polymorphisms (SNPs). We employed a brain‐wide association analysis (BWAS) together with a Jacknife internal validation approach in 46 schizophrenia patients and 24 matched healthy control subjects. Results from structural MRI showed significant associations between all six DISC1 variants and gray matter volume in the precuneus, post‐central gyrus and middle cingulate gyrus. Associations with specific SNPs were found for rs2738880 in the left precuneus and right post‐central gyrus, and rs1535530 in the right precuneus and middle cingulate gyrus. Using regions showing structural associations as seeds a resting‐state functional connectivity analysis revealed significant associations between all 6 SNPS and connectivity between the right precuneus and inferior frontal gyrus. The connection between the right precuneus and inferior frontal gyrus was also specifically associated with rs821617. Importantly schizophrenia patients showed positive correlations between the six DISC‐1 SNPs associated gray matter volume in the left precuneus and right post‐central gyrus and negative symptom severity. No correlations with illness duration were found. Our results provide the first evidence suggesting a key role for structural and functional connectivity associations between DISC1 polymorphisms and the precuneus in schizophrenia. Hum Brain Mapp 35:5414–5430, 2014. © 2014 Wiley Periodicals, Inc.     

Brain GABA levels across psychiatric disorders: A systematic literature review and meta‐analysis of 1H‐MRS studies

The inhibitory gamma‐aminobutyric acid (GABA) system is involved in the etiology of most psychiatric disorders, including schizophrenia, autism spectrum disorder (ASD) and major depressive disorder (MDD). It is therefore not surprising that proton magnetic resonance spectroscopy (¹H‐MRS) is increasingly used to investigate in vivo brain GABA levels. However, integration of the evidence for altered in vivo GABA levels across psychiatric disorders is lacking. We therefore systematically searched the clinical ¹H‐MRS literature and performed a meta‐analysis. A total of 40 studies (N = 1,591) in seven different psychiatric disorders were included in the meta‐analysis: MDD (N = 437), schizophrenia (N = 517), ASD (N = 150), bipolar disorder (N = 129), panic disorder (N = 81), posttraumatic stress disorder (PTSD) (N = 104), and attention deficit/hyperactivity disorder (ADHD) (N = 173). Brain GABA levels were lower in ASD (standardized mean difference [SMD] = ?0.74, P = 0.001) and in depressed MDD patients (SMD = ?0.52, P = 0.005), but not in remitted MDD patients (SMD = ?0.24, P = 0.310) compared with controls. In schizophrenia this finding did not reach statistical significance (SMD = ?0.23, P = 0.089). No significant differences in GABA levels were found in bipolar disorder, panic disorder, PTSD, and ADHD compared with controls. In conclusion, this meta‐analysis provided evidence for lower brain GABA levels in ASD and in depressed (but not remitted) MDD patients compared with healthy controls. Findings in schizophrenia were more equivocal. Even though future ¹H‐MRS studies could greatly benefit from a longitudinal design and consensus on the preferred analytical approach, it is apparent that ¹H‐MRS studies have great potential in advancing our understanding of the role of the GABA system in the pathogenesis of psychiatric disorders. Hum Brain Mapp 37:3337–3352, 2016. © 2016 Wiley Periodicals, Inc.     

A review of the effects of nicotine on schizophrenia

It is increasingly appreciated that amongst psychiatric cigarette smokers, those with schizophrenia have elevated rates of smoking compared to the general population. Nicotine seems to improve cognitive functions critically affected in schizophrenia. There is substantial evidence that nicotine could be used by patients with schizophrenia as a "self-medication" to improve deficits in attention, cognition, and information processing. Perhaps nicotine has influence on intensity of side effects of antipsychotic medication. Nicotine treatment modulates both dopaminergic and glutamatergic neurotransmission, and these effects are specific both to brain region and functional system. Understanding how and why schizophrenic individuals use nicotine may lead to the development of new treatments for both schizophrenia and nicotine dependence.