Neurotransmitters and prefrontal cortex–limbic system interactions: implications for plasticity and psychiatric disorders

The prefrontal cortex (PFC) efferent projections to limbic areas facilitate a top-down control on the execution of goal-directed behaviours. The PFC sends glutamatergic outputs to limbic areas such as the hippocampus and amygdala which in turn modulate the activity of the nucleus accumbens (NAc). Dopamine and acetylcholine neurons in the brainstem and basal forebrain/septal areas, which send outputs to NAc, hippocampus and amygdala, are also regulated by PFC glutamatergic projections, and seem to be of special relevance in modulating motor, emotional and mnemonic functions. Both the physiological and pathological changes in the PFC influence the activity of these limbic areas and the corresponding final-guided behaviours. We revise our most recent studies on PFC–NAc interactions focussed on the role of dopamine and glutamate receptors in the PFC. Specifically, by performing microinjections/microdialysis studies we found that the activation of D2 dopamine receptors and the blockade of glutamate NMDA receptors in the PFC change the release of dopamine and acetylcholine in the NAc. We suggest the possibility that dopamine and glutamate receptors in the PFC could change the activity of dopamine and acetylcholine function in the hippocampus and amygdala. Finally, it is speculated that changes in the function of the PFC, associated with psychiatric disorders or due to environmental-dependent plasticity, can change PFC–limbic system interactions.     

MicroRNA-137 regulates a glucocorticoid receptor–dependent signalling network: implications for the etiology of schizophrenia

Background

Schizophrenia is a highly heritable neurodevelopmental disorder. A genetic variant of microRNA-137 (miR-137) has yielded significant genome-wide association with schizophrenia, suggesting that this miRNA plays a key role in its etiology. Therefore, a molecular network of interacting miR-137 targets may provide insights into the biological processes underlying schizophrenia.

Methods

We first used bioinformatics tools to obtain and analyze predicted human and mouse miR-137 targets. We then determined miR-137 levels in rat barrel cortex after environmental enrichment (EE), a neuronal plasticity model that induces upregulation of several predicted miR-137 targets. Subsequently, expression changes of these predicted targets were examined through loss of miR-137 function experiments in rat cortical neurons. Finally, we conducted bioinformatics and literature analyses to examine the targets that were upregulated upon miR-137 downregulation.

Results

Predicted human and mouse miR-137 targets were enriched in neuronal processes, such as axon guidance, neuritogenesis and neurotransmission. The miR-137 levels were significantly downregulated after EE, and we identified 5 novel miR-137 targets through loss of miR-137 function experiments. These targets fit into a glucocorticoid receptor–dependent signalling network that also includes 3 known miR-137 targets with genome-wide significant association with schizophrenia.

Limitations

The bioinformatics analyses involved predicted human and mouse miR-137 targets owing to lack of information on predicted rat miR-137 targets, whereas follow-up experiments were performed with rats. Furthermore, indirect effects in the loss of miR-137 function experiments cannot be excluded.

Conclusion

We have identified a miR-137-regulated protein network that contributes to our understanding of the molecular basis of schizophrenia and provides clues for future research into psycho-pharmacological treatments for schizophrenia.     

Isolation rearing or methamphetamine traumatisation induce a “dysconnection” of prefrontal efferents in gerbils: implications for schizophrenia

Summary. A miswiring of prefrontal efferents is generally discussed by the name of “dysconnection” as the anatomical substrate of schizophrenia. Since direct histological confirmation of this hypothesis can hardly be obtained in humans, we used an animal model of schizophrenia to trace prefrontal efferents to distal cortical fields. Mongolian gerbils were intoxicated with a single high dose of methamphetamine on postnatal day 14 and reared in isolation after weaning (day 30). Controls received a saline injection and/or were reared under enriched conditions. Upon reaching adulthood (day 90), biocytin was injected into the medial prefrontal cortex into either deep or superficial laminae. The density of passing fibres and terminal fields in the frontal, parietal and insular cortices was assessed by digital image analysis. Isolation rearing or methamphetamine treatment alone reduced the projections from lamina V/VI to the frontal and from lamina III to the insular cortex, and from both laminae to the parietal cortex. In contrast, isolation rearing of methamphetamine-intoxicated gerbils significantly increased the projections from the deep laminae to the frontal and parietal cortices, compared to isolation-reared controls, with no difference in the efferents from superficial laminae. These results are the first to demonstrate a miswiring of prefrontal efferents in response to adverse systemic influences. They might give a hint at the anatomical basis of “dysconnection” in schizophrenia.     

Can we improve the diagnostic efficiency and predictive power of prodromal symptoms for schizophrenia?

Prodromal symptoms and other variables for a sample of 200 young people who had experienced a first-onset functional psychosis, were analyzed to examine their diagnostic efficiency and predictive power in relation to a diagnosis of schizophrenia. Two different techniques were utilized to generate optimal cut-off points for a number of prodromal symptoms, and optimal decision rules to maximize diagnostic efficiency. The product of the chance-corrected sensitivity and specificity, or the area under the QROC curve, was used to assess the predictive efficiency of a number of prodromal variables, DSM-III-R prodromal variables, pre-psychotic deterioration, pre-morbid functioning, and prodromal duration. The SPAN technique generated a decision rule that performed equivalently to the single variable 'duration of prodrome'. Implications of these results for future research are discussed.     

Socially naïve self-appraisal moderates the relationship between cognitive insight and positive symptoms in schizophrenia

Cognitive insight refers to awareness of one's own thinking. Research has found deficits in cognitive insight in schizophrenia but studies of its links with positive symptoms and delusions have been equivocal. One possibility is that the association of cognitive insight with positive symptoms and delusions is moderated by other factors. To explore this issue this study examined whether level of socially naive self-appraisal moderated the relationship of two forms of cognitive insight, self-reflectivity and self-certainty with delusions and positive symptoms. Participants were 92 adults, with diagnoses of schizophrenia or schizoaffective disorder, who were administered the Positive and Negative Syndrome Scale, self-deceptive subscale from the Marlowe–Crowne Social Desirability Scale and the Beck Cognitive Insight Scale. Stepwise multiple regressions with the interaction term of the predictive and moderator variables suggested that social naiveté moderates the relationship between self-reflectivity and self-certainty with positive symptoms in general. Moreover, association between self-certainty and delusions was also moderated by social naiveté self-appraisal. All models were significant after controlling for willful impression management as well as a measure of executive function. Results suggest that higher levels of self-certainty are a risk factor for having greater positive symptoms including more severe levels of delusions, when one has a view of oneself that is not tempered by the perceptions of others. Concerning lower levels of self-reflectivity it may be that this combined with a socially naïve view of oneself leaves persons less inhibited when they are tempted to accept unusual thoughts and perceptions as accurate. Implications for treatment are discussed.     

Anxious–depressive symptoms in schizophrenia: a new treatment target for pharmacotherapy?

Schizophrenia patients frequently manifest concurrent anxiety and depressive symptoms. Such features exhibit prognostic relevance (i.e. patient morbidity and mortality). Despite this, they remain relatively unstudied and are not universally viewed as therapeutic targets. Conventional neuroleptic agents may not improve these symptoms and may actually worsen them. However, with the introduction of novel pharmacological agents for the treatment of schizophrenia, there is reason to believe that a wider spectrum of symptomatology may be treatment responsive. In this post hoc analysis of the Brief Psychiatric Rating Scale anxiety–depression cluster, olanzapine therapy was associated with a significantly greater baseline-to-end-point improvement in the cluster compared with haloperidol therapy among 1996 randomized, double-blind subjects. Moreover, the olanzapine treatment-effect advantage included both direct (mood symptoms) and indirect (positive, negative, and extrapyramidal symptoms) elements. This study concluded that the novel pharmacology of olanzapine delivered greater therapeutic activity in anxious and depressive symptoms accompanying schizophrenia than did the conventional dopamine D₂ antagonist haloperidol.     

Comprehensive model of how reality distortion and symptoms occur in schizophrenia: Could impairment in learning‐dependent predictive perception account for the manifestations of schizophrenia?

Conventional wisdom has not laid out a clear and uniform profile of schizophrenia as a unitary entity. One of the key first steps in elucidating the neurobiology of this entity would be to characterize the essential and common elements in the group of entities called schizophrenia. Kraepelin in his introduction notes ‘the conviction seems to be more and more gaining ground that dementia praecox on the whole represents, a well characterized form of disease, and that we are justified in regarding the majority of the clinical pictures which are brought together here as the expression of a single morbid process, though outwardly they often diverge very far from one another’. But what is that single morbid process? We suggest that just as the uniform defect in all types of cancer is impaired regulation of cell proliferation, the primary defect in the group of entities called schizophrenia is persistent defective hierarchical temporal processing. This manifests in the form of chronic memory‐prediction errors or deficits in learning‐dependent predictive perception. These deficits account for the symptoms that present as reality distortion (delusions, thought disorder and hallucinations). This constellation of symptoms corresponds with the profile of most patients currently diagnosed as suffering from schizophrenia. In this paper we describe how these deficits can lead to the various symptoms of schizophrenia.     

Religion: a mediator of Anglo-American and Mexican attributional differences toward symptoms of schizophrenia?

This study examined the relationship of religiosity to attributions toward schizophrenia, within a cultural context. Previous research suggests that on self-report measures, Mexicans endorse holding greater moral-religious values than do their Anglo-American counterparts. Research also indicates that Mexicans, relative to Anglo-Americans, tend to hold fewer blameworthy attributions and are less likely to view patients with schizophrenia as responsible for the symptoms of the disorder. In an analog study of 88 Mexican and 88 Anglo-American college students asked to imagine that they have a brother with schizophrenia, this study assessed two competing hypotheses regarding the role of religion in shaping reactions to schizophrenia in a family member. For hypothesis 1, Baron and Kenny's mediational model (1986) was used to assess whether moral religious values may play a direct mediating role between ethnicity and controllability attributions for schizophrenia. In other words, based on observations of previous researchers, this set of analyses assessed whether ethnic differences in controllability attributions might be explained by a religious or spiritual tendency in Mexicans to view negative events, such as mental disability, as rooted in divine factors beyond the patient's personal control. In contrast, a second, competing, hypothesis was also assessed in this study: namely, that greater religiosity would be positively correlated with increasing perceptions of control over the symptoms of schizophrenia. This hypothesis stems from the premise of several investigators that religious individuals may be more likely to perceive another's adversity (such as having schizophrenia) as a punishment for prior wrongdoings or for failure to try to help oneself. Results indicate support for the latter hypothesis. Implications of the paradoxical finding, that Mexicans were both more religious and more external in their attributions, are discussed.     

Comorbidity and pathophysiology of obsessive–compulsive disorder in schizophrenia: Is there evidence for a schizo-obsessive subtype of schizophrenia?

Epidemiologic and neurobiologic evidence suggests that patients with comorbid obsessive-compulsive disorder (OCD) and schizophrenia may represent a special category among patients with schizophrenia. Efforts to examine the neurobiology of this group have focused on neuroimaging studies and neuropsychologic testing. Convergent evidence suggests that there may be a specific pattern of neurobiologic dysfunction in this subgroup of patients accounting for symptom co-expression. This review indicates that future studies should distinguish among (1) apparent obsessive-compulsive symptoms (OCS) that occur only in the context of psychosis and that may overlap with psychotic phenomenology, representing a forme fruste of psychosis; (2) OCS occurring only in the prodromal phase of schizophrenia; (3) neuroleptic-induced OCS or OCD; and (4) OCS or frank OCD occurring concurrently with schizophrenia. We examine the evidence for a putative schizo-obsessive disorder and outline suggestions for identifying OCS in the presence of psychosis.     

Cross-sensory gating in schizophrenia and autism spectrum disorder: EEG evidence for impaired brain connectivity?

Autism spectrum disorders (ASD) and schizophrenia are both neurodevelopmental disorders that have extensively been associated with impairments in functional brain connectivity. Using a cross-sensory P50 suppression paradigm, this study investigated low-level audiovisual interactions on cortical EEG activation, which provides crucial information about functional integrity of connections between brain areas involved in cross-sensory processing in both disorders. Thirteen high functioning adult males with ASD, 13 high functioning adult males with schizophrenia, and 16 healthy adult males participated in the study. No differences in neither auditory nor cross-sensory P50 suppression were found between healthy controls and individuals with ASD. In schizophrenia, attenuated P50 responses to the first auditory stimulus indicated early auditory processing deficits. These results are in accordance with the notion that filtering deficits may be secondary to earlier sensory dysfunction. Also, atypical cross-sensory suppression was found, which implies that the cognitive impairments seen in schizophrenia may be due to deficits in the integrity of connections between brain areas involved in low-level cross-sensory processing.     

Obsessive–compulsive symptoms in schizophrenia: prevalence and associated factors in a Nigerian population

Objectives: The objectives of this study were to determine the prevalence of obsessive–compulsive symptoms (OCS) among subjects with schizophrenia and also to determine their associated factors.

Methods: A cross-sectional study involving 232 patients with schizophrenia were recruited from a teaching hospital in Nigeria. Socio-demographic questionnaire, Obsessive–Compulsive Inventory, Positive and Negative Syndrome Scale and Suicidality module of the MINI International Neuropsychiatric Inventory were administered.

Results: The prevalence of OCS was 54.3% among patients with schizophrenia, and washing symptom was the most common (51.7%). Patients with schizophrenia that had OCS had more severe psychopathologies and higher levels of suicidality. OCS among patients with schizophrenia were also associated with the use of second-generation antipsychotic medications.

Conclusions: OCS are common in schizophrenia. Hence, there is a need for routine screening of patients with schizophrenia for OCS and then, manage them appropriately.     

Apomorphine and the dopamine hypothesis of schizophrenia: a dilemma?

The dopamine (DA) hypothesis of schizophrenia implicates an enhancement of DA function in the pathophysiology of the disorder, at least in the genesis of positive symptoms. Accordingly, apomorphine, a directly acting DA receptor agonist, should display psychotomimetic properties. A review of the literature shows little or no evidence that apomorphine, in doses that stimulate postsynaptic DA receptors, induces psychosis in non-schizophrenic subjects or a relapse or exacerbation of psychotic symptoms in patients with schizophrenia. After a detailed review of the literature reporting psychotogenic effects of apomorphine in patients with Parkinson's disease, an interpretation of these data is difficult, in part because of several confounding factors, such as the concomitant use of drugs known to induce psychosis and the advanced state of the progressive neurological disorder. In the context of the DA hypothesis of schizophrenia, the limited ability of apomorphine to induce psychosis, in contrast to indirectly acting DA agonists that increase synaptic DA, may be explained by the relatively weak affinity of apomorphine for the D3 receptor compared with DA. Alternatively, enhancement of DA function, though necessary, may be insufficient by itself to induce psychosis.     

Self–other integration and distinction in schizophrenia: A theoretical analysis and a review of the evidence

Difficulties in self–other processing lie at the core of schizophrenia and pose a problem for patients’ daily social functioning. In the present selective review, we provide a framework for understanding self–other integration and distinction, and impairments herein in schizophrenia. For this purpose, we discuss classic motor prediction models in relation to mirror neuron functioning, theory of mind, mimicry, self-awareness, and self-agency phenomena. Importantly, we also discuss the role of more recent cognitive expectation models in these phenomena, and argue that these cognitive models form an essential contribution to our understanding of self–other integration and distinction. In doing so, we bring together different lines of research and connect findings from social psychology, affective neuropsychology, and psychiatry to further our understanding of when and how people integrate versus distinguish self and other, and how this goes wrong in schizophrenia patients.