Modeling the neurochemical prodrome in schizophrenia: Evidence from animal models.

Modeling the neurochemical prodrome in schizophrenia: Evidence from animal models.

2014-09-01 00:00:00

The idea of a prodromal state in schizophrenia is controversial. Yet the evidence continues to mount that there are early pre-symptomatic behavioural, brain structural and even neurochemical changes in the brains of individuals “at risk” of progressing to clinical schizophrenia. As basic researchers we turn to animal models in an attempt to understand what neurobiological mechanisms may be acting to create such phenotypes in an attempt to find convergent pathways in which to intervene and hopefully arrest the condition. The authors are well-known for their work on modelling the gestational epidemiological risk-factors for this disease in rodents. Recently they have refocused their efforts to try and understand the basic mechanisms operating proximal to the gestational insult with a view to the possibility that this may have altered the trajectory of certain brain circuits. In this quest they have independently discovered that disparate developmental risk factors produce early alterations to dopaminergic circuits.

Using the Developmental Vitamin D (DVD) deficiency and maternal immune activation (MIA) models we have examined embryonic brains during gestation for early changes in factors that are responsible for specifying dopaminergic cellular fate and late gestation for indices of a more mature dopaminergic phenotype. Surprisingly we uncover a similar pattern of delayed early maturation of dopamine systems i.e. decreased expression of the essential dopamine specification factor, Nurr1, in both models followed by an apparent overcompensation towards late gestation with an increase in striatal dopamine and its synthetic enzyme tyrosine hydroxylase.

The striking overlap in early factors related to the ontogeny of dopamine systems suggests to us that this could possibly be a putative mechanism for the increased subcortical hyperdopaminergia seen in patients. We are now combining our efforts in order to establish whether there is any convergent evidence for abnormal dopaminergic connectivity in these models. We are also considering whether there are any early functional deficits in dopaminergic synthesis and release similar to that seen in prodromal patients.

Speakers: Darryl Eyles
Conference: MAPrc
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