Transient Downregulation of Dab1 Protein Levels during Development Leads to Behavioral and Structural Deficits: Relevance for Psychiatric Disorders

Abstract

Psychiatric disorders have been hypothesized to originate during development, with genetic and environmental factors interacting in the etiology of disease. Therefore, developmentally regulated genes have received attention as risk modulators in psychiatric diseases. Reelin is an extracellular protein essential for neuronal migration and maturation during development, and its expression levels are reduced in psychiatric disorders. Interestingly, several perinatal insults that increase the risk of behavioral deficits alter Reelin signaling. However, it is not known whether a dysfunction in Reelin signaling during perinatal stages increases the risk of psychiatric disorders. Here we used a floxed dab1 allele to study whether a transient decrease in Dab1, a key component of the Reelin pathway, is sufficient to induce behavioral deficits related to psychiatric disorders. We found that transient Dab1 downregulation during perinatal stages leads to permanent abnormalities of structural layering in the neocortex and hippocampus. In contrast, conditional inactivation of the dab1 gene in the adult brain does not result in additional layering abnormalities. Furthermore, perinatal Dab1 downregulation causes behavior impairments in adult mice, such as deficits in memory, maternal care, pre-pulse inhibition, and response to cocaine. Some of these deficits were also found to be present in adolescence. We also show that D-cycloserine rescues the cognitive deficits observed in floxed dab1 mice with layering alterations in the hippocampus and neocortex. Our results indicate a causal relation between the downregulation of Dab1 protein levels during development and the structural and behavioral deficits associated with psychiatric diseases in the adult.

Gene expression dynamics following mithramycin treatment: A possible model for post‐chemotherapy cognitive impairment

“…Out of the 30 qRT‐PCR validated genes, 3 showed a significant correlation between expression and behavioural responses. A significant negative correlation was observed between the percentage of errors in the T‐maze test and the expression levels of the following genes in the PFC: NDUFV2, which encodes for mitochondrial Complex I subunit ( R = −0.781, P < .01) (Figure A); Ywhae, encoding for 14‐3‐3 ε protein which is an adapter protein implicated in the regulation of a large spectrum of both general and specialized signalling pathways and has been implicated in schizophrenia and Alzheimer disease ( R = −0.703, P < .01) (Figure B); DAB1, which is involved in directing neuronal positioning in the developing brain ( R = −0.582, P < .05) (Figure C). In addition, a significant negative correlation was observed between the anxiety index and PFC NDUFV2 gene expression levels ( R = −0.580, P < .05) (Figure D).…”

“…DAB1 encodes for a protein, which functions as a key regulator of the Reelin signalling pathway. Transient downregulation of DAB1 during development has been shown to cause cognitive deficit in mice and its dysfunction to be associated with neuropsychiatric disorders, Alzheimer's disease and cognitive symptoms in schizophrenia . YWHAE gene product belongs to the 14‐3‐3 family of proteins, which are involved in diverse vital cellular processes.…”

Reading LINEs within the cocaine addicted brain

“…The L1s in DAB1 (Figure 1d) and TBCK (Figure 1f) are intriguing because the encoded proteins interact with signal transduction pathways that are affected by cocaine (Sutton & Caron, 2015; Teixeira et al., 2014). Dab1 knockout mice exhibit greater locomotor sensitization in response to repeated cocaine administration than their wild type counterparts (Teixeira et al., 2014).…”

“…Dab1 knockout mice exhibit greater locomotor sensitization in response to repeated cocaine administration than their wild type counterparts (Teixeira et al., 2014). TBCK regulates the mammalian target of rapamycin pathway (Liu, Yan, & Zhou, 2013) that is documented as being important for cocaine (i.e., dopamine)‐mediated signal transduction (Shi et al., 2014; Sutton & Caron, 2015).…”

Glutathione peroxidase‐1 overexpressing transgenic mice are protected from neurotoxicity induced by microcystin‐leucine‐arginine

“…Digital images of fluorescent Nissl‐stained neurons were acquired at 50 × and 100 × magnification, using a confocal laser scanning microscope (LSM 780 NLO; Carl Zeiss, Inc., Oberkochen, Germany; Chuncheon Center, Korea Basic Science Institute, Chuncheon, Republic of Korea). Hippocampal neuronal loss was evaluated by the thickness of the pyramidal cell layer in the CA1 and CA3 regions . ImageJ version 1.47 software (National Institutes of Health, Bethesda, Maryland) was employed to measure the thickness of these cell layers using “set scale,” “draw straight line,” and “measure” commands.…”