Pilleriin Sikka

D-amino acid oxidase activity and expression are increased in schizophrenia

D-amino acid oxidase (DAO, DAAO) metabolises the NMDA receptor (NMDAR) modulator D-serine.1 Enhanced DAO activity is thus a potential cause of reduced D-serine and thence impaired NMDAR functioning in schizophrenia,2 and an explanation for the genetic contribution that DAO may make to the disorder.3,4 Here we report that DAO activity, and expression, are increased in the cerebellum in schizophrenia, but not in bipolar disorder, and are not related to SNPs in DAO or its putative activator gene G72/G30.3 We measured DAO enzyme activity, and DAO mRNA by qRT-PCR, using established methods, in cerebellar tissue from subjects with schizophrenia, bipolar disorder, and controls, from the Stanley Microarray Collection (Supplementary Table 1). We genotyped subjects for two schizophrenia-associated tag SNPs in DAO and G72/G30. We used cerebellar tissue from rats administered haloperidol or clozapine for 14 days to investigate antipsychotic effects on DAO activity. For demographic and methodological details, see Supplementary Materials. As shown in Fig. 1A, DAO activity differed between groups (F2,100=4.79, p=0.010), being increased in schizophrenia compared to controls (+37%, p=0.027) and compared to bipolar disorder (+57%, p=0.004). The latter groups did not differ (p=0.45). DAO activity was not correlated with post mortem interval, brain pH, or antipsychotic exposure (Supplementary Fig. 1) or age (R=0.03, p=0.79). DAO activity was unrelated to alcohol or substance misuse history (using a five-point scale), smoking, sex, or suicide. DAO activity increased with duration of schizophrenia (R=0.34, p=0.05, n=35). Within the bipolar disorder group, DAO activity did not vary according to a history of psychotic symptoms. DAO activity correlated with DAO mRNA (R=0.43, p=0.0001, n=97). DAO affinity showed no group differences (Fig. 1B). DAO activity in rat cerebellum was unaffected by antipsychotics (Supplementary Table 2). Figure 1 Cerebellar DAO activity and expression in 35 control subjects (CON, white bars), 35 with schizophrenia (SCZ, black bars), and 34 with bipolar disorder (BPD, shaded bars). A) DAO activity (Vmax, nmol D-proline/min/mg protein) is higher in subjects with ... Normalised DAO mRNA differed between groups (F2,88=3.84, p=0.025), being increased compared to controls in schizophrenia (p=0.01) and bipolar disorder (p=0.04; Fig. 1C). DAO mRNA was not related to antipsychotic exposure, post mortem interval, brain pH, or RIN, but was affected by death-to-refrigeration interval (Supplementary Fig. 1). Neither DAO activity nor DAO mRNA were influenced by the DAO or G72/G30 SNPs (Supplementary Table 3), apart from a trend for higher DAO activity in allele 2 carriers of G72/G30 rs3918342 (p=0.08 vs 1/1 homozygotes). There were no genotype-by-diagnosis interactions. Our data show an elevation of DAO activity in schizophrenia accompanied by increased gene expression. The activity increase confirms the results of a pilot study,5 and the elevated DAO mRNA replicates findings in a separate cohort.6 There were no correlations of DAO activity or expression with medication exposure, and no effect of haloperidol or clozapine on DAO activity in rat brain. Other confounders (e.g. smoking) did not have a demonstrable influence either. Hence, within the constraints of a post mortem study, our findings appear related to the diagnosis of schizophrenia. We focused on the cerebellum because DAO is abundant and active therein; it will be important to ascertain whether DAO activity is affected elsewhere in schizophrenia, but problematic since forebrain DAO activity is extremely low, despite robust expression. Parenthetically, this discrepancy is complemented by a difference in the cellular localization of DAO: it is glial in the cerebellum, but mainly neuronal in the cerebral cortex.6 Elevated DAO activity will presumably enhance metabolism of D-serine and, other things being equal, contribute to a reduced synaptic availability of D-serine, potentially impairing NMDAR function.1 As such, our findings support the hypothesized involvement of DAO, and thence D-serine, in the NMDAR hypofunction of schizophrenia and its potential therapeutic amelioration.2,7,8 Clearly any such conclusions are tentative, since many other factors likely also influence D-serine availability, e.g. its synthesis by serine racemase,6,9 and its release and reuptake.10 Alterations in these processes could counteract – or exacerbate – enhanced DAO activity. Moreover, since DAO also metabolises other D-amino acids,1 D-serine is not the only substrate that might be affected by an increase in DAO activity. For example, D-alanine is present in the cerebellum, is an NMDAR modulator, and may be therapeutically beneficial in schizophrenia.7 Overall, whilst a primary effect on D-serine, and thence NMDARs, is an attractive interpretation of the DAO increase in schizophrenia, further studies are needed to confirm the biochemical consequences, as well as the causes, of the elevation. (See Supplementary Materials for further discussion). As the DAO and G72/G30 SNPs did not influence DAO activity or expression, our data provide no evidence that they are functional (nor indexing SNPs that are), nor have we identified a mechanism whereby variation in these genes might confer schizophrenia susceptibility. There may be other SNPs that are relevant in this respect; alternatively, the DAO SNPs might operate at other places and times, whilst G72/G30 SNPs could act via a DAO-independent pathway. In summary, DAO activity and expression are increased in schizophrenia, but not related to DAO or G72/G30 genotype. Any pathophysiological consequences of increased DAO activity seem most likely to impact on D-serine metabolism and thence NMDAR function, but this remains to be established.

What is an altered state of consciousness

“Altered State of Consciousness” (ASC) has been defined as a changed overall pattern of conscious experience, or as the subjective feeling and explicit recognition that ones own subjective experience has changed. We argue that these traditional definitions fail to draw a clear line between altered and normal states of consciousness (NSC). We outline a new definition of ASC and argue that the proper way to understand the concept of ASC is to regard it as a representational notion: the alteration that has happened is not an alteration of consciousness (or subjective experience) per se, but an alteration in the informational or representational relationships between consciousness and the world. An altered state of consciousness is defined as a state in which the neurocognitive background mechanisms of consciousness have an increased tendency to produce misrepresentations such as hallucinations, delusions, and memory distortions. Paradigm examples of such generally misrepresentational, temporary, and reversible states are dreaming, psychotic episodes, psychedelic drug experiences, some epileptic seizures, and hypnosis in highly hypnotizable subjects. The representational definition of ASC should be applied in the theoretical and empirical studies of ASCs to unify and clarify the conceptual basis of ASC research.

D-Serine metabolism in C6 glioma cells: Involvement of alanine-serine-cysteine transporter (ASCT2) and serine racemase (SRR) but not D-amino acid oxidase (DAO)

D‐serine is an endogenous N‐methyl‐D‐aspartate (NMDA) receptor coagonist. It is synthesized from L‐serine by serine racemase (SRR), but many aspects of its metabolism remain unclear, especially in the forebrain, which lacks active D‐amino acid oxidase (DAO), the major D‐serine degradative enzyme. Candidate mechanisms include SRR operating in α,β‐eliminase mode (converting D‐serine to pyruvate) and regulation by serine transport, in which the alanine‐serine‐cysteine transporter ASCT2 is implicated. Here we report studies in C6 glioma cells, which “simulate” the forebrain, in that the cells express SRR and ASCT2 but lack DAO activity. We measured D‐serine, ASCT2, SRR, and DAO expression and DAO activity in two situations: after incubation of cells for 48 hr with serine isomers and after increased or decreased SRR expression by transfection and RNA interference, respectively. Incubation with serine enantiomers decreased [3H]D‐serine uptake and ASCT2 mRNA and increased SRR immunoreactivity but did not alter DAO immunoreactivity, and DAO activity remained undetectable. SRR overexpression increased D‐serine and pyruvate and decreased [3H]D‐serine uptake and ASCT2 mRNA but did not affect DAO. SRR knockdown did not alter any of the parameters. Our data suggest that D‐serine transport mediated by ASCT2 contributes prominently to D‐serine homeostasis when DAO activity is absent. The factors regulating D‐serine are important for understanding normal NMDA receptor function and because D‐serine, along with DAO and SRR, is implicated in the pathogenesis and treatment of schizophrenia.

The Existence of a Hypnotic State Revealed by Eye Movements

Hypnosis has had a long and controversial history in psychology, psychiatry and neurology, but the basic nature of hypnotic phenomena still remains unclear. Different theoretical approaches disagree as to whether or not hypnosis may involve an altered mental state. So far, a hypnotic state has never been convincingly demonstrated, if the criteria for the state are that it involves some objectively measurable and replicable behavioural or physiological phenomena that cannot be faked or simulated by non-hypnotized control subjects. We present a detailed case study of a highly hypnotizable subject who reliably shows a range of changes in both automatic and volitional eye movements when given a hypnotic induction. These changes correspond well with the phenomenon referred to as the “trance stare” in the hypnosis literature. Our results show that this ‘trance stare’ is associated with large and objective changes in the optokinetic reflex, the pupillary reflex and programming a saccade to a single target. Control subjects could not imitate these changes voluntarily. For the majority of people, hypnotic induction brings about states resembling normal focused attention or mental imagery. Our data nevertheless highlight that in some cases hypnosis may involve a special state, which qualitatively differs from the normal state of consciousness.

Dream emotions: a comparison of home dream reports with laboratory early and late REM dream reports

The aim of this study was to compare the emotional content of dream reports collected at home upon morning awakenings with those collected in the laboratory upon early and late rapid eye movement (REM) sleep awakenings. Eighteen adults (11 women, seven men; mean age = 25.89 ± 4.85) wrote down their home dreams every morning immediately upon awakening during a 7‐day period. Participants also spent two non‐consecutive nights in the sleep laboratory where they were awoken 5 min into each continuous REM sleep stage, upon which they gave a verbal dream report. The content of a total of 151 home and 120 laboratory dream reports was analysed by two blind judges using the modified Differential Emotions Scale. It was found that: (1) home dream reports were more emotional than laboratory early REM dream reports, but not more emotional than laboratory late REM dream reports; (2) home dream reports contained a higher density of emotions than laboratory (early or late REM) dream reports; and (3) home dream reports were more negative than laboratory dream reports, but differences between home and early REM reports were larger than those between home and late REM reports. The results suggest that differences between home and laboratory dream reports in overall emotionality may be due to the time of night effect. Whether differences in the density of emotions and negative emotionality are due to sleep environment or due to different reporting procedures and time spent in a sleep stage, respectively, remains to be determined in future studies.

Peace of mind and anxiety in the waking state are related to the affective content of dreams

Waking mental well-being is assumed to be tightly linked to sleep and the affective content of dreams. However, empirical research is scant and has mostly focused on ill-being by studying the dreams of people with psychopathology. We explored the relationship between waking well-being and dream affect by measuring not only symptoms of ill-being but also different types and components of well-being. Importantly, this is the first time peace of mind was investigated as a distinct aspect of well-being in a Western sample and in relation to dream content. Healthy participants completed a well-being questionnaire, followed by a three-week daily dream diary and ratings of dream affect. Multilevel analyses showed that peace of mind was related to positive dream affect, whereas symptoms of anxiety were related to negative dream affect. Moreover, waking measures were better related to affect expressed in dream reports rather than participants’ self-ratings of dream affect. We propose that whereas anxiety may reflect affect dysregulation in waking and dreaming, peace of mind reflects enhanced affect regulation in both states of consciousness. Therefore, dream reports may possibly serve as markers of mental health. Finally, our study shows that peace of mind complements existing conceptualizations and measures of well-being.