Altered dopamine ontogeny in the developmentally vitamin D deficient rat and its relevance to schizophrenia

Abstract

Schizophrenia is a heterogeneous group of disorders with unknown etiology. Although abnormalities in multiple neurotransmitter systems have been linked to schizophrenia, alterations in dopamine (DA) neurotransmission remain central to the treatment of this disorder. Given that schizophrenia is considered a neurodevelopmental disorder we have hypothesized that abnormal DA signaling in the adult patient may result from altered DA signaling during fetal brain development. Environmental and genetic risk factors can be modeled in rodents to allow for the investigation of early neurodevelopmental pathogenesis that may lead to clues into the etiology of schizophrenia. To address this we created an animal model of one such risk factor, developmental vitamin D (DVD) deficiency. DVD-deficient adult rats display an altered behavioral profile in response to DA releasing and blocking agents that are reminiscent of that seen in schizophrenia patients. Furthermore, developmental studies revealed that DVD deficiency also altered cell proliferation, apoptosis, and neurotransmission across the embryonic brain. In particular, DVD deficiency reduces the expression of crucial dopaminergic specification factors and alters DA metabolism in the developing brain. We speculate such alterations in fetal brain development may change the trajectory of DA neuron ontogeny to induce the behavioral abnormalities observed in adult offspring. The widespread evidence that both dopaminergic and structural changes are present in people who develop schizophrenia prior to onset also suggest that early alterations in development are central to the disease. Taken together, early alterations in DA ontogeny may represent a core feature in the pathology of schizophrenia. Such a mechanism could bring together evidence from multiple risk factors and genetic vulnerabilities to form a convergent pathway in disease pathophysiology.

Keywords: MK-801; amphetamine; behavior; development; differentiation; dopamine.

FIGURE 1

Temporal profile of developing schizophrenia symptoms. Early alterations in dopamine development due to genetic, environmental or a combination of both lead to abnormalities in dopamine function (positive symptoms) and subsequent alterations in other neurotransmitter systems (negative symptoms). During adolescence and the prodromal phase of the disease clear changes in dopamine function can be observed. Frank psychosis and disease onset are directly related to dopaminergic function and can be effectively treated. The lack of effect of antipsychotic treatment on persisting negative symptoms suggest they are not directly related to dopamine function. Rather, they represent the downstream consequence of early dopamine dysfunction or the extraneous effects of specific genetic and environmental risk factors on other neurotransmitter systems such as glutamate and GABA. These non-specific actions, outside of the core schizophrenia etiology, result in a large heterogeneous profile of negative symptoms in patients.