Disrupted-in-Schizophrenia-1 is essential for normal hypothalamic-pituitary-interrenal (HPI) axis function
2017
Psychiatric disorders arise due to an interplay of genetic and environmental factors, including stress. Studies in rodents have
shown that mutants for Disrupted-In-Schizophrenia-1 (DISC1), a well-accepted genetic risk factor for mental illness, display
abnormal behaviours in response to stress, but the mechanisms through which DISC1 affects stress responses remain poorly
understood. Using two lines of zebrafish homozygous mutant for disc1, we investigated behaviour and functioning of the
hypothalamic-pituitary-interrenal (HPI) axis, the fish equivalent of the hypothalamic-pituitary-adrenal (HPA) axis. Here, we
show that the role of DISC1 in stress responses is evolutionarily conserved and that DISC1 is essential for normal functioning
of the HPI axis. Adult zebrafish homozygous mutant for disc1 show aberrant behavioural responses to stress. Our studies
reveal that in the embryo, disc1 is expressed in neural progenitor cells of the hypothalamus, a conserved region of the vertebrate
brain that centrally controls responses to environmental stressors. In disc1 mutant embryos, proliferating rx3þ hypothalamic
progenitors are not maintained normally and neuronal differentiation is compromised: rx3-derived ff1bþ neurons,
implicated in anxiety-related behaviours, and corticotrophin releasing hormone (crh) neurons, key regulators of the stress axis,
develop abnormally, and rx3-derived pomcþ neurons are disorganised. Abnormal hypothalamic development is associated
with dysfunctional behavioural and neuroendocrine stress responses. In contrast to wild type siblings, disc1 mutant larvae
show altered crh levels, fail to upregulate cortisol levels when under stress and do not modulate shoal cohesion, indicative of
abnormal social behaviour. These data indicate that disc1 is essential for normal development of the hypothalamus and for
the correct functioning of the HPA/HPI axis.
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