Schizophrenia: do all roads lead to dopamine or is this where they start? Evidence from two epidemiologically informed developmental rodent models

Abstract

The idea that there is some sort of abnormality in dopamine (DA) signalling is one of the more enduring hypotheses in schizophrenia research. Opinion leaders have published recent perspectives on the aetiology of this disorder with provocative titles such as ‘Risk factors for schizophrenia—all roads lead to dopamine' or ‘The dopamine hypothesis of schizophrenia—the final common pathway'. Perhaps, the other most enduring idea about schizophrenia is that it is a neurodevelopmental disorder. Those of us that model schizophrenia developmental risk-factor epidemiology in animals in an attempt to understand how this may translate to abnormal brain function have consistently shown that as adults these animals display behavioural, cognitive and pharmacological abnormalities consistent with aberrant DA signalling. The burning question remains how can in utero exposure to specific (environmental) insults induce persistent abnormalities in DA signalling in the adult? In this review, we summarize convergent evidence from two well-described developmental animal models, namely maternal immune activation and developmental vitamin D deficiency that begin to address this question. The adult offspring resulting from these two models consistently reveal locomotor abnormalities in response to DA-releasing or -blocking drugs. Additionally, as adults these animals have DA-related attentional and/or sensorimotor gating deficits. These findings are consistent with many other developmental animal models. However, the authors of this perspective have recently refocused their attention on very early aspects of DA ontogeny and describe reductions in genes that induce or specify dopaminergic phenotype in the embryonic brain and early changes in DA turnover suggesting that the origins of these behavioural abnormalities in adults may be traced to early alterations in DA ontogeny. Whether the convergent findings from these two models can be extended to other developmental animal models for this disease is at present unknown as such early brain alterations are rarely examined. Although it is premature to conclude that such mechanisms could be operating in other developmental animal models for schizophrenia, our convergent data have led us to propose that rather than all roads leading to DA, perhaps, this may be where they start.

Vitamin D regulates tyrosine hydroxylase expression: N-cadherin a possible mediator

“…These findings strongly suggest that 1,25(OH) 2 D 3 is a direct differentiation agent for dopaminergic neurons. Schizophrenia is regarded as a neurodevelopmental disease and alterations in the early ontogeny of dopamine systems have been proposed to be a central etiological feature of the disease (Eyles et al, 2012). The direct modulation of TH by 1,25(OH) 2 D 3 as demonstrated here might help us to better understand the etiology for the epidemiological link between DVD-deficiency and schizophrenia.…”

Sex differences in animal models of schizophrenia shed light on the underlying pathophysiology

“…Although no animal model can replicate all aspects of the complexities of human neuropsychiatric disorders such as schizophrenia, these can be deconstructed into more simplified endophenotypes that embody the major symptom domains (van den Buuse 2010; Eyles et al 2012). For example, schizophrenia is characterized by: positive symptoms, including hallucinations and delusions; negative symptoms, including social withdrawal, and anhedonia; and cognitive impairments.…”

Prenatal lipopolysaccharide disrupts maternal behavior, reduces nest odor preference in pups, and induces anxiety: Studies of F1 and F2 generations

“…Meyer et al (2007) suggested that immunological activation at different times of prenatal development may have distinct neurodevelopmental consequences. Maternal infections in late pregnancy may especially affect late neurodevelopmental programs in the developing fetus, thereby inducing a more restricted pathological phenotype in the grown offspring, or spare the emergence of postnatal brain and behavioral pathology (Meyer et al, 2006), such as schizophrenia (Eyles et al, 2012;Meyer et al, 2011) and attentional impairments (Vuillermot et al, 2012).…”