12 research outputs found
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
PACAP is an endogenous protective factor - insights from PACAP-deficient mice
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a
widespread neuropeptide with a diverse array of biological
functions. Not surprisingly, the lack of endogenous PACAP
therefore results in a variety of abnormalities. One of the
important effects of PACAP is its neuroprotective and general
cytoprotective role. PACAP protects neurons and other tissues
against ischemic, toxic, and traumatic lesions. Data obtained
from PACAP-deficient mice provide evidence that endogenous
PACAP also has protective functions. Mice lacking PACAP are more
vulnerable to different in vitro and in vivo insults. The
present review summarizes data on the increased sensitivity of
PACAP-deficient mice against harmful stimuli. Mice lacking PACAP
respond with a higher degree of injury in cerebral ischemia,
autoimmune encephalomyelitis, and axonal lesion. Retinal
ischemic and excitotoxic injuries also produce increased cell
loss in PACAP-deficient mice. In peripheral organs, kidney cell
cultures from PACAP-deficient mice are more sensitive to
oxidative stress and in vitro hypoxia. In vivo, PACAP-deficient
mice have a negative histological outcome and altered cytokine
response in kidney and small intestine ischemia/reperfusion
injury. Large intestinal inflammation, toxic lesion of the
pancreas, and doxorubicin-induced cardiomyopathy are also more
severe with a lack of endogenous PACAP. Finally, an increased
inflammatory response has been described in subacute endotoxin-
induced airway inflammation and in an oxazolone-induced allergic
contact dermatitis model. In summary, lack of endogenous PACAP
leads to higher vulnerability in a number of injuries in the
nervous system and peripheral organs, supporting the hypothesis
that PACAP is part of the endogenous cytoprotective machinery