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

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

Alzheimers Res Ther

BACKGROUND: Vitamin D deficiency is associated with an increased risk of Alzheimer's disease and increased beta-amyloid (Abeta) in animals. Hence we sought to investigate the relationship between plasma 25-hydroxyvitamin D (25(OH)D) and cerebral Abeta in older adults with subjective memory complaints. METHODS: This is a secondary analysis of the Multidomain Alzheimer Preventive Trial. Participants were 178 dementia-free individuals aged 70 years or older with data on plasma 25(OH)D and cerebral Abeta load assessed by [(18)F]-florbetapir positron emission tomography. Plasma 25(OH)D was measured at study baseline using a commercially available electro-chemiluminescence competitive binding assay. Standard uptake value ratios (SUVRs) were generated using the cerebellum as a reference. Brain regions assessed included the cortex, anterior cingulate, anterior putamen, caudate, hippocampus, medial orbitofrontal cortex, occipital cortex, parietal cortex, pons, posterior cingulate, posterior putamen, precuneus, semioval centre and temporal cortex. Associations were explored using fully adjusted multiple linear regression models. RESULTS: Participants had a mean (SD) age of 76.2 years (4.4) and 59.6% were female. The mean (SD) plasma 25(OH)D level was 22.4 ng/ml (10.8) and the mean (SD) cortical SUVR was 1.2 (0.2). We did not find any cross-sectional associations (p > 0.05) between baseline 25(OH)D levels and Abeta in any of the brain regions studied. CONCLUSIONS: These preliminary results suggest that circulating 25(OH)D is not associated with cerebral Abeta in older adults. Further longitudinal studies with the measurement of mid-life vitamin D status are required to explore the relationship between vitamin D and Abeta accrual over time, thereby circumventing the shortfalls of a cross-sectional study

Developmental vitamin D deficiency alters dopamine-mediated behaviors and dopamine transporter function in adult female rats

Developmental vitamin D (DVD) deficiency has been proposed as a risk factor for schizophrenia. DVD deficiency in neonatal rats is associated with alterations in cellular development, dopamine metabolism, and brain morphology. DVD-deficient adult rats show novelty-induced hyperlocomotion and an enhanced locomotor response to MK-801, which can be ameliorated by pretreatment with the antipsychotic drug haloperidol. In this study, we examined locomotor responses of male and female juvenile and adult rats to a dose range of amphetamine. We also measured dopamine receptor and monoamine transporter densities in adult brain. Female DVD-deficient adult rats displayed an enhanced sensitivity to amphetamine-induced locomotion, an increased dopamine transporter density in the caudate-putamen and increased affinity in the nucleus accumbens compared with control females. By contrast, there were no differences between control and DVD-deficient male rats. Taken together, this suggests an alteration in the development of the dopamine system and on dopamine-mediated behaviors in female DVD-deficient rats, and this may be relevant to the underlying neurobiology of schizophrenia