Mapping of pituitary stress-induced gene regulation connects Nrcam to negative emotions

Expression of ANK3 moderates the association between childhood trauma and affective traits in severe mental disorders

“…One plausible explanation is that the expression of genes that shape the trajectory from early adverse events to clinical end-points 6 . Large GWAS studies in severe mental disorders demonstrate an altered ANK3 expression in this group compared to healthy individuals 14 , 15 , and our study suggests an interplay between ANK3 mRNA levels and childhood trauma exposure which increases vulnerability to develop affective symptoms, as is also supported by previous studies showing a direct link between early stress and ANK3 levels 5 , 25 .…”

“…Animal and human studies have also demonstrated that early life stress may alter the methylation status of ANK3 5 , with behavioral correlates, further pointing to ANK3 expression as a candidate moderator of early life stress effects in psychiatric diseases. A recent animal study also showed that repeated social defeat induces a persistent upregulation of ANK3 mRNA in the pituitary gland 25 , strengthening a link between ANK3 expression and early adversities.…”

NrCAM-deficient mice exposed to chronic stress exhibit disrupted latent inhibition, a hallmark of schizophrenia

“…Beside its major neurodevelopmental roles, NrCAM was recently found to be one of the genes regulated by stress in rodents ( Olsen et al, 2022 ); the same study reports that a genetic variant of the human NrCAM gene is associated with negative affect as a result of abusive supervision ( Olsen et al, 2022 ). Interestingly, NrCAM is involved in spine pruning ( Mohan et al, 2019b ; Duncan et al, 2021 ) and synapse remodeling, a phenomenon reported in rodent models of chronic stress ( Duman and Duman, 2015 ; McEwen et al, 2016 ); it is thus plausible that NrCAM alterations are related to the exaggerated synaptic pruning seen during adolescence and young adulthood in SZ ( Selemon and Zecevic, 2015 ; Sellgren et al, 2019 ; Howes and Onwordi, 2023 ).…”

“…The disruption of LI may be the result of genotype-related alterations in the balance of excitation-inhibition in cortical circuits or in neuronal connectivity, both of which may be potentiated as a result of chronic stress. NrCAM has been documented as influencing vulnerability to stress, for example regarding stress-induced headaches ( Sannes et al, 2023 ), stress-induced changes in pituitary function ( Olsen et al, 2022 ), and stress-induced changes in hippocampal neurogenesis ( Li et al, 2021 ). The current study adds to this list that NrCAM is linked to a vulnerability to chronic unpredictable stress associated with impaired latent inhibition, a phenotype relevant to acute schizophrenia-like symptoms.…”

“…Depletion of astrocytic NrCAM reduces the numbers and function of inhibitory synapses ( Takano et al, 2020 ), providing a possible mechanism for the cortical excitation-inhibition imbalance thought to underlie some of the SZ phenotypes ( Howes and Shatalina, 2022 ). Fourth, a recent study assessing pituitary stress-induced gene regulation reported changes in expression for NrCAM and NrCAM-interacting proteins (ANK3, PAK2) after social defeat stress in rodents ( Olsen et al, 2022 ); the same study reports that a variant of the human NrCAM gene is associated with negative affect after abusive supervision ( Olsen et al, 2022 ). Finally, NrCAM is decreased in serum from SZ patients ( Schwarz et al, 2012 ).…”