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

Kesby JP, Cui X, Burne TH, Eyles DW - Front Cell Neurosci (2013)

Bottom Line: 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.Such a mechanism could bring together evidence from multiple risk factors and genetic vulnerabilities to form a convergent pathway in disease pathophysiology.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, School of Medicine, University of California San Diego La Jolla, CA, USA.

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.

No MeSH data available.


Related in: MedlinePlus

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.
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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.

Mentions: The premise that no single genetic vulnerability or molecular factor “causes” schizophrenia is well accepted amongst the research community and is confirmed by both the heterogeneity of the symptom profile and the lack of a diagnostic marker. A common endpoint, that includes aspects of DA dysfunction (Di Forti et al., 2007; Murray et al., 2008; Howes and Kapur, 2009), remains highly supported by the clinical evidence and allows for a specific outcome to investigate the etiology of the disease. However, we postulate that a common DA endpoint may arise precisely because it is central to the developmental pathology (Figure 1). The dopaminergic system is one of the most organized neurotransmitter systems in the brain and is fundamental for a range of functions involved in cognition, motivation and reward (Smith and Kieval, 2000; Aldridge et al., 2004; Nicola, 2007). Furthermore, alterations in DA signaling have a range of cascading effects on other neurotransmitter systems such as glutamate (e.g., NMDA) and GABA. Therefore, even small alterations in DA function or organization have the potential to lead to complex cognitive outcomes when coupled with other general and variable insults such as altered genetic architecture, drug use, stress or adolescent maturation. In addition, these secondary stressors may individually produce differing phenotypes and thus heterogeneity in symptom profile.


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

Kesby JP, Cui X, Burne TH, Eyles DW - Front Cell Neurosci (2013)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3713405&req=5

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.
Mentions: The premise that no single genetic vulnerability or molecular factor “causes” schizophrenia is well accepted amongst the research community and is confirmed by both the heterogeneity of the symptom profile and the lack of a diagnostic marker. A common endpoint, that includes aspects of DA dysfunction (Di Forti et al., 2007; Murray et al., 2008; Howes and Kapur, 2009), remains highly supported by the clinical evidence and allows for a specific outcome to investigate the etiology of the disease. However, we postulate that a common DA endpoint may arise precisely because it is central to the developmental pathology (Figure 1). The dopaminergic system is one of the most organized neurotransmitter systems in the brain and is fundamental for a range of functions involved in cognition, motivation and reward (Smith and Kieval, 2000; Aldridge et al., 2004; Nicola, 2007). Furthermore, alterations in DA signaling have a range of cascading effects on other neurotransmitter systems such as glutamate (e.g., NMDA) and GABA. Therefore, even small alterations in DA function or organization have the potential to lead to complex cognitive outcomes when coupled with other general and variable insults such as altered genetic architecture, drug use, stress or adolescent maturation. In addition, these secondary stressors may individually produce differing phenotypes and thus heterogeneity in symptom profile.

Bottom Line: 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.Such a mechanism could bring together evidence from multiple risk factors and genetic vulnerabilities to form a convergent pathway in disease pathophysiology.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, School of Medicine, University of California San Diego La Jolla, CA, USA.

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.

No MeSH data available.


Related in: MedlinePlus