Early Blockade of CB1 Receptors Ameliorates Schizophrenia-like Alterations in the Neurodevelopmental MAM Model of Schizophrenia

In agreement with the neurodevelopmental hypothesis of schizophrenia, prenatal exposure of Sprague-Dawley rats to the antimitotic agent methylazoxymethanol acetate (MAM) at gestational day 17 produces long-lasting behavioral alterations such as social withdrawal and cognitive impairment in adulthood, mimicking a schizophrenia-like phenotype. These abnormalities were preceded at neonatal age both by the delayed appearance of neonatal reflexes, an index of impaired brain maturation, and by higher 2-arachidonoylglycerol (2-AG) brain levels. Schizophrenia-like deficits were reversed by early treatment [from postnatal day (PND) 2 to PND 8] with the CB1 antagonist/inverse agonist AM251 (0.5 mg/kg/day). By contrast, early CB1 blockade affected the behavioral performance of control rats which was paralleled by enhanced 2-AG content in the prefrontal cortex (PFC). These results suggest that prenatal MAM insult leads to premorbid anomalies at neonatal age via altered tone of the endocannabinoid system, which may be considered as an early marker preceding the development of schizophrenia-like alterations in adulthood.

Being Born in Winter–Spring and at Around the Time of an Influenza Pandemic Are Risk Factors for the Development of Schizophrenia: The Apna Study in Navarre, Spain

Background: We analyzed the relationship between the prevalence of schizophrenia and the season of birth and gestation during a period of an influenza pandemic. Methods: Cross-sectional analysis of a prospective population-based cohort of 470,942 adults. We fitted multivariant logistic regression models to determine whether the season of birth and birth in an influenza-pandemic year (1957, 1968, 1977) was associated with schizophrenia. Results: 2077 subjects had been diagnosed with schizophrenia. Logistic regression identified a significantly greater prevalence of schizophrenia in men than in women (OR = 1.516, CI 95% = 1.388–1.665); in those born in the winter or spring than in those born in the summer or autumn (OR = 1.112, CI 95% = 1.020–1.212); and in those born in a period of an influenza pandemic (OR = 1.335, CI 95% = 1.199–1.486). The increase in risk was also significant when each influenza pandemic year was analyzed separately. However, neither month of birth nor season of birth, when each of the four were studied individually, were associated with a statistically significant increase in that risk. Conclusions: The winter–spring period and the influenza pandemics are independent risk factors for developing schizophrenia. This study contradicts many previous studies and thus revitalizes a locked debate in understanding the neurodevelopmental hypothesis of this disorder.

Impact of Duration of Untreated Psychosis on Cognitive Function in Schizophrenia

Background: Schizophrenia is a chronic and serious clinical syndrome with very aggravating psychopathology involving perception, cognition, emotion, and behaviour. Currently, cognitive dysfunction is seen as a core disorder of schizophrenia. Duration of Untreated Psychosis (DUP) refers to the period from the onset of psychotic symptoms to the first adequate administration of antipsychotics.Aims: This review aims to analyse the impact of DUP on cognitive function in schizophrenia.Methods: PubMed and Google Scholar were searched using the following keyword: (cognitive function) and (neurodevelopmental OR neurotoxicity hypothesis) and (duration of untreated psychosis or DUP) and (schizophrenia or psychosis or psychotic) using the journal publication filter for the 2014-2020 issue. We also used textbooks published in the last 10 years and were related to writing themes.Review: There are two different opinions about the impact of DUP on the cognitive function of schizophrenic patients: (1) the neurodevelopmental hypothesis says there is no impact of the length of DUP on the cognitive function of schizophrenic patients; (2) the neurotoxicity hypothesis says the length of the DUP will impact the patient's cognitive function. Despite differences of opinion about the impact of DUP on cognitive function in schizophrenia, early intervention in schizophrenic patients is important because DUP is associated with worse general disease symptoms, lower likelihood of remission, more severe positive and negative symptoms, and worse social functioning and overall outcomes.Summary: There are differences of opinion about the impact of DUP on cognitive function in schizophrenic patients.

The Neurodevelopmental Hypothesis of Huntington’s Disease

The current dogma of HD pathoetiology posits it is a degenerative disease affecting primarily the striatum, caused by a gain of function (toxicity) of the mutant mHTT that kills neurons. However, a growing body of evidence supports an alternative theory in which loss of function may also influence the pathology.This theory is predicated on the notion that HTT is known to be a vital gene for brain development. mHTT is expressed throughout life and could conceivably have deleterious effects on brain development. The end event in the disease is, of course, neurodegeneration; however the process by which that occurs may be rooted in the pathophysiology of aberrant development. To date, there have been multiple studies evaluating molecular and cellular mechanisms of abnormal development in HD, as well as studies investigating abnormal brain development in HD animal models. However, direct study of how mHTT could affect neurodevelopment in humans has not been approached until recent years. The current review will focus on the most recent findings of a unique study of children at-risk for HD, the Kids-HD study. This study evaluates brain structure and function in children ages 6–18 years old who are at risk for HD (have a parent or grand-parent with HD).

Neural correlates of ethnic minority position and risk for psychosis

It is likely that the chronic stress of social defeat or exclusion contributes to the increased psychosis risk among members of ethnic minorities. Is this idea compatible with the dopamine or neurodevelopmental hypothesis, two dominant hypotheses with regard to pathogenesis? Defeated animals show clear evidence of dopamine sensitization. As for humans, one study showed elevated striatal dopamine function in migrants and their children. Other studies have shown this in other excluded groups, namely, adults with hearing impairment and individuals with a history of childhood trauma. Of note, the perigenual anterior cingulate cortex may play a major role in the processing of social stress and regulates dopaminergic areas implicated in stress sensitization. The authors are not aware of studies in humans that examined whether (proxies for) social exclusion contribute(s) to structural brain changes present at psychosis onset. Animal studies, however, reported that long-term isolation may lead to reductions in brain volume and that social defeat can reduce neurogenesis.

Stress and Schizophrenia

Developing animal models of schizophrenia is challenging because of the uniquely human nature of some of the classic symptoms of the disorder (e.g., hallucinations, delusions, disordered thought). Several efforts have been guided by the neurodevelopmental hypothesis of schizophrenia and have included exposure of animals to stressful stimulation. Other animal models have involved prenatal exposure to maternal immune activation or drugs that disrupt neuronal development, followed by stress during adolescence or in early adulthood to unmask vulnerabilities. Neonatal hippocampal lesions have been employed in other animal models of schizophrenia. Another profitable approach has been to selectively breed laboratory mice or rats for their susceptibility to dopaminergic drugs. A more recent approach has been to develop laboratory mice with targeted alterations in risk genes for schizophrenia that were previously identified in clinical studies. In many cases, the effects of these risk genes are unmasked by exposure of animals to stressful stimulation during specific stages of postnatal development.

Global and Specific Cortical Volume Asymmetries in Individuals With Psychosis Risk Syndrome and Schizophrenia: A Mixed Cross-sectional and Longitudinal Perspective

Cortical volumetric asymmetry (CVA) has been widely observed in individuals with psychosis, and is associated with etiological risk factors (e.g., genetics, neuromaturation) and treatment response. However, it is unclear whether CVA abnormalities emerge before psychotic illness onset. Understanding whether CVA manifests in clinical high-risk (CHR)—compared with healthy controls and schizophrenia patients (SCZ)—over time may inform our understanding of pathogenic factors. A total of 233 individuals: 73 CHR, 112 healthy controls, and 48 SCZ underwent an MRI and clinical interviews. Ninety-four individuals including healthy volunteers (HV) (n = 49) and CHR (n = 45), completed another scan at 12-months. CVA was compared by lobe in a repeated-measure design across groups, then nested by time in a longitudinal model. CHR and SCZ groups showed reduced global CVA compared with the healthy control groups but the CHR and SCZ group did not differ from each other. A group by lobe interaction indicated the presence of lobe specific reductions in frontal and cingulate CVA. Cingulate CVA was reduced in CHR and SCZ groups compared to HC groups but did not differ from each other. Frontal CVA was reduced in the older healthy controls compared with younger-HC and CHR, but did not differ from the similarly aged SZ group. CVA is similarly impacted in SCZ and CHR groups, potentially reflecting pathogenic processes. Longitudinal analyses provided further support for the neurodevelopmental hypothesis as CHR exhibited longitudinal changes in opposite directions from normative neuromaturation in HV, which was related to increasing risk for psychosis in the CHR.

Neurodevelopmental Mechanisms for Psychotic Disorders

The current understanding of the mechanisms underlying psychotic disorders, including schizophrenia, is far from satisfactory and has hampered the establishment of effective treatments, as well as accurate diagnosis and prognosis in patients. A prevailing hypothesis that attempts to understand these mechanisms is the “neurodevelopmental hypothesis.” In this chapter, we address experimental strategies to characterize the biological mechanisms underlying psychotic disorders, including a complementary combination of human cell and animal models that pays attention to the developmental trajectory, in particular key neural circuitries that may underlie behavioral changes relevant to psychotic disorders. In addition, we discuss a “dimensional” approach to understanding psychiatric disorders to more easily translate findings between animal models and human applications.