Parvalbumin inhibitory interneurons (PVIs) are crucial for maintaining proper excitatory/inhibitory balance and high-frequency neuronal synchronization. Their activity supports critical developmental trajectories, sensory and cognitive processing, and social behavior. Despite heterogeneity in the etiology across schizophrenia and autism spectrum disorder, PVI circuits are altered in these psychiatric disorders. Identifying mechanism(s) underlying PVI deficits is essential to establish treatments targeting in particular cognition. On the basis of published and new data, we propose oxidative stress as a common pathological mechanism leading to PVI impairment in schizophrenia and some forms of autism. A series of animal models carrying genetic and/or environmental risks relevant to diverse etiological aspects of these disorders show PVI deficits to be all accompanied by oxidative stress in the anterior cingulate cortex. Specifically, oxidative stress is negatively correlated with the integrity of PVIs and the extracellular perineuronal net enwrapping these interneurons. Oxidative stress may result from dysregulation of systems typically affected in schizophrenia, including glutamatergic, dopaminergic, immune and antioxidant signaling. As convergent end point, redox dysregulation has successfully been targeted to protect PVIs with antioxidants/redox regulators across several animal models. This opens up new perspectives for the use of antioxidant treatments to be applied to at-risk individuals, in close temporal proximity to environmental impacts known to induce oxidative stress.

Schizophrenia is characterized by reduced hippocampal volume, decreased dendritic spine density, altered neuroplasticity signaling pathways, and cognitive deficits associated with impaired hippocampal function. We sought to determine whether this diverse pathology could be linked to NMDA receptor (NMDAR) hypofunction, and thus used the serine racemase-null mutant mouse (SR −/− ), which has less than 10% of normal brain D-serine, an NMDAR coagonist. We found that D-serine was necessary for the maintenance of long-term potentiation in the adult hippocampal dentate gyrus and for full NMDAR activity on granule cells. SR −/− mice had reduced dendritic spines and hippocampal volume. These morphological changes were paralleled by diminished BDNF/Akt/mammalian target of rapamycin (mTOR) signaling and impaired performance on a traceconditioning memory task. Chronic D-serine treatment normalized the electrophysiological, neurochemical, and cognitive deficits in SR −/− mice. These results demonstrate that NMDAR hypofunction can reproduce the numerous hippocampal deficits associated with schizophrenia, which can be reversed by chronic peripheral D-serine treatment.miR-132 | MeCP2 | glycogen synthase 3 kinase | CREB S chizophrenia is a severe psychiatric disorder that affects 1% of the population worldwide (1). There are widespread morphological, neurochemical, and functional changes in the brain in schizophrenia that have been linked to its symptomatic features (2). For example, the hippocampus of patients with schizophrenia exhibits reduced dendritic spine density (3), atrophy (4), and impaired activation while performing cognitive tasks (5). The neuroplasticity deficits observed in schizophrenia could be caused by a constellation of factors.Impaired neurotrophic signaling could be one mechanism underlying these abnormalities. BDNF regulates a complex array of processes, including neurite outgrowth and spine density, by signaling through tropomyosin receptor kinase B (TrkB), its highaffinity receptor (6). In postmortem studies, BDNF mRNA and protein (7-9) levels, as well as TrkB mRNA (7, 10, 11) and protein (12), are reduced in subjects with schizophrenia. V-akt murine thymoma viral oncogene (Akt) is a kinase downstream of TrkB. Not only is the Akt1 isoform a putative schizophrenia risk gene (13), its expression (14, 15) and the amount of phosphorylated Akt (p-Akt) (16) in the dentate gyrus (DG) are reduced in schizophrenia.Aberrant microRNA (miR) processing might also be contributing to the pathophysiology of schizophrenia (17). These noncoding RNAs regulate neural plasticity by controlling the translation of target mRNA transcripts. Expression of the neuron-enriched miR-132 is reduced in schizophrenia (18); it regulates basal and activityinduced neurite outgrowth (19), and is up-regulated in vivo in response to external stimuli (20, 21). Importantly, both BDNF (22) and miR-132 (17) expression are increased by NMDAR receptor (NMDAR) activation.Pharmacologic and biochemical evidence has converged to support NMDAR hypofunct...

d-Serine, a co-agonist at the NMDA receptor (NMDAR), is synthesized from l-serine by the enzyme serine racemase (SR), which is heavily expressed in the forebrain. Although SR was originally reported to be localized exclusively to astrocytes, recent conditional knock out results demonstrate that little SR is expressed in forebrain astrocytes. As a consequence, the cellular location of its product, d-serine, in the brain is also uncertain. Immunocytochemistry now indicates that SR is expressed primarily in forebrain glutamatergic neurons with the remainder in GABAergic interneurons. We utilized SR deficient (SR–/–) mice, which have <15 % of normal d-serine levels, to validate and optimize a d-serine immunohistochemical method. Nearly all of the d-serine in neocortex and hippocampus (HP) is found in neurons, with virtually no d-serine co-localizing with two astrocyte markers. Interestingly, only a subset of the d-serine positive neurons contained SR in the neocortex and HP. Greater than half of the d-serine positive neurons were GABAergic interneurons, with a majority of these neurons containing parvalbumin and/or somatostatin. Only ∼25–40 % of interneurons expressed SR in the neocortex and HP. Finally, we demonstrate in human post-mortem neocortex that SR is found in both excitatory and inhibitory neurons, but not in S100β-containing astrocytes. In sum, these findings conclusively demonstrate that the majority of d-serine is both synthesized and stored in neurons. It will be important to determine the functional significance for the separation of synthesis and storage of d-serine in neurons, as well as the presence of this NMDAR co-agonist in GABAergic interneurons.

Rationale Adolescents are often described as “lacking brakes” resulting in an increase in several behaviors associated with risk for addiction. Prefrontal cortex dopamine and cortico-limbic interaction play an important role in addiction, and we have previously shown that the dopamine D1 receptor is elevated on prelimbic prefrontal output neurons in adolescent rats. We hypothesized that a constellation of risk-related behaviors are mediated by prefrontal output neuron expression of D1. Objectives We aimed to determine the role of the dopamine D1 receptor in behavioral and neural correlates of risk for addiction that are often observed in adolescents. Therefore high-risk behaviors as well as subcortical D2 receptor expression were investigated in adult animals with experimentally elevated D1 on prefrontal glutamatergic neurons. Methods A lentiviral vector that selectively expressed the D1 receptor within glutamate neurons was injected in the prelimbic prefrontal cortex of adult male rats. Place conditioning to cocaine, alcohol, and nicotine, as well as delay discounting, novelty preferences, anxiety, cocaine self-administration, and sucrose preferences were assessed. Results Virally-mediated D1 overexpression in adults leads to stronger drug-cue associations, greater consumption of sweet solutions, elevates bias towards immediate satisfaction rather than delaying gratification, decreases anxiety and causes rats to work harder for and take more cocaine. Furthermore elevated cortical D1 reduces D2 receptors in the accumbens (a putative risk marker). Conclusions Together, these data suggest a common mechanism for increased motivational drive to seek and consume substances with hedonic value, consistent with adolescent addictive processes.

The objective of this study was to evaluate cross-sectional relationships among symptoms of psychological stress, sleep, and physiological arousal during non-rapid eye movement (NREM) sleep in a sample of 30 patients with chronic, primary insomnia (mean age, 30.2 years, 60% female). Study measures included indexes of subjective stress, visually scored sleep, and physiological arousal during NREM sleep: quantitative electroencephalogram (QEEG) and quantitative electrocardiogram (QEKG) measures. Psychological stress was more strongly related to indexes of physiological arousal during NREM sleep than to visually scored measures of sleep. Higher levels of perceived stress were associated with decreased EEG delta power (rho = -0.50, p < .01) and increased EEG beta power (rho = 0.38, p < .05). Increased frequency of stress-related avoidance behaviors was associated with decreased EKG high-frequency power (rho = -0.46, p < .05). Although QEEG measures were significantly correlated with sleep maintenance (QEEG delta power rho = 0.45, p < .01; QEEG beta power rho = -0.54, p < .01) and time spent in delta sleep (QEEG delta power rho = 0.65, p < .001; QEEG beta power rho = -0.65, p < .001), QEKG measures were unrelated to visually scored measures of sleep. Perceived stress and stress-related avoidance behaviors were associated with multiple indexes of physiological arousal during NREM sleep in patients with chronic, primary insomnia.

Cytochrome P4501A2 (CYP1A2) is involved in the metabolism of several drugs and is induced by smoking. We aimed to determine the interindividual change in CYP1A2 activity after smoking cessation and to relate it to CYP1A2 genetic polymorphisms. CYP1A2 activity was determined from the paraxanthine:caffeine ratio in 194 smokers and in 118 of them who had abstained from smoking during a 4-week period. The participants were genotyped for CYP1A2*1F, *1D, and *1C polymorphisms. Smokers had 1.55-fold higher CYP1A2 activity than nonsmokers (P < 0.0001). The individual change in CYP1A2 activity after smoking cessation ranged from 1.0-fold (no change) to a 7.3-fold decrease in activity. In five participants with low initial CYP1A2 activity, an increase was observed after smoking cessation. Before smoking cessation, the following factors were found to influence CYP1A2 activity: CYP1A2*1F (P = 0.005), CYP1A2*1D (P = 0.014), the number of cigarettes/day (P = 0.012), the use of contraceptives (P < 0.001), and -163A/-2467T/-3860G haplotype (P = 0.002). After quitting smoking, only CYP1A2*1F (P = 0.017) and the use of contraceptives (P = 0.05) had an influence. No influence of CYP1A2 polymorphisms on the inducibility of CYP1A2 was observed.

Binge eating and substance dependence are disorders characterized by a loss of control over consummatory behaviors. Given the common characteristics of these two types of disorders, it is not surprising that the comorbidity between eating disorders and substance abuse disorders is high (20–40%; Conason et al., 2006). It is unknown, however, whether loss of control in one disorder predisposes an individual to loss of control in the other. The present study, therefore, used a rodent model to test whether a history of binge eating would augment subsequent responding for cocaine. Using the limited access protocol described by Corwin et al. (1998), 45 adult male Sprague-Dawley rats were maintained on one of four dietary protocols for a period of six weeks: chow only (Chow; n=9), continuous access to an optional source of dietary fat (Ad Lib; n=12), 1-h access to an optional source of dietary fat daily (Daily; n=12), or 1-h access to an optional source of dietary fat on Monday, Wednesday, and Friday (MWF; n=12). All four groups also had unrestricted access to a nutritionally complete diet of chow and water. Fat-bingeing behaviors developed in the MWF rats, the group with the most restricted access to the optional fat. Thereafter, cocaine-seeking and –taking behaviors were assessed in all rats using a self-administration protocol modified from that described by Deroche-Gamonet et al. (2004), which focus on the motivation for and preoccupation with obtaining and consuming drug (assessed using a progressive ratio (PR) schedule of reinforcement) and persistence in responding for drug during periods of signaled drug non-availability (SNA). Rats with the MWF history tended to take more cocaine late in fixed ratio (FR) training, they persisted in their efforts to obtain cocaine in the face of signaled non-availability, worked harder for cocaine on a PR schedule of reinforcement, and exhibited more goal-directed behavior towards the cocaine-associated operandum. These results demonstrate a link between binge-type intake of fat and the development of drug-seeking and -taking behaviors, suggesting that a history of fat bingeing may predispose individuals to exhibit more robust “addiction-like” behaviors toward a substance of abuse. Thus, it appears that conditions promoting excessive behavior toward one substance (e.g., a palatable fatty food) beget excessive behavior toward another (e.g., cocaine).

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