Overexpression of Reelin Prevents the Manifestation of Behavioral Phenotypes Related to Schizophrenia and Bipolar Disorder

Abstract

Despite the impact of schizophrenia and mood disorders, which in extreme cases can lead to death, recent decades have brought little progress in the development of new treatments. Recent studies have shown that Reelin, an extracellular protein that is critical for neuronal development, is reduced in schizophrenia and bipolar disorder patients. However, data on a causal or protective role of Reelin in psychiatric diseases is scarce. In order to study the direct influence of Reelin's levels on behavior, we subjected two mouse lines, in which Reelin levels are either reduced (Reelin heterozygous mice) or increased (Reelin overexpressing mice), to a battery of behavioral tests: open-field, black–white box, novelty-suppressed-feeding, forced-swim-test, chronic corticosterone treatment followed by forced-swim-test, cocaine sensitization and pre-pulse inhibition (PPI) deficits induced by N-methyl--aspartate (NMDA) antagonists. These tests were designed to model some aspects of psychiatric disorders such as schizophrenia, mood, and anxiety disorders. We found no differences between Reeler heterozygous mice and their wild-type littermates. However, Reelin overexpression in the mouse forebrain reduced the time spent floating in the forced-swim-test in mice subjected to chronic corticosterone treatment, reduced behavioral sensitization to cocaine, and reduced PPI deficits induced by a NMDA antagonist. In addition, we demonstrate that while stress increased NMDA NR2B-mediated synaptic transmission, known to be implicated in depression, Reelin overexpression significantly reduced it. Together, these results point to the Reelin signaling pathway as a relevant drug target for the treatment of a range of psychiatric disorders.

Cleavage within Reelin Repeat 3 Regulates the Duration and Range of the Signaling Activity of Reelin Protein

“…Incubation with Reelin-PD keeps Dab1 levels low for as long as 24 h, indicating that N-t cleavage plays a major role in inactivating the Reelin-Dab1 pathway. In recent years, up-regulation of this pathway has been suggested to be beneficial for the treatment of neuropsychiatric diseases (19,21,53,54). In particular, a single injection of Reelin protein into the ventricle has been shown to have a beneficial effect on synaptic transmission, learning, and memory (19).…”

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

“…Adult mice (two to three months of age) were given corticosterone (Sigma) in their drinking water (25 mg/l) for 3 weeks, as previously described (Gourley and Taylor, 2009;Teixeira et al, 2011). Mice were tested 1 week after the end of treatment.…”

“…The PPI apparatus and procedure were as previously described (Teixeira et al, 2011). Mice were habituated to the apparatus with a background noise of 62 dB and then exposed to six blocks of eight trial types in pseudo-random order.…”

“…Reelin expression is decreased in psychiatric disorders. In addition, reelin genetic variants are associated with these diseases, and Reelin overexpression protects against psychiatric disease-related phenotypes (Fatemi et al, 2000;Jia et al, 2010;Kim and Webster, 2009;Teixeira et al, 2011;Torrey et al, 2005). Interestingly, perinatal insults that cause behavioral deficits in the adult, such as alcohol exposure during pregnancy, maternal viral infection or exposure to Poly I:C, and serotonin dysfunction, alter the Reelin signaling pathway (Fatemi et al, 1999;Hashimoto-Torii et al, 2011;Janusonis et al, 2004).…”

The Amyloidogenic Pathway Meets the Reelin Signaling Cascade: A Cytoskeleton Bridge Between Neurodevelopment and Neurodegeneration

“…The results indicate that heterozygous reeler mice, after a stressful event, such as maternal deprivation or corticosterone injection, exhibit significantly increased depressive or schizophrenic behaviors as compared with wild type littermates [53][54]. Indeed, reeler heterozygous animals in the absence of a stressful event, display a phenotype indistinguishable from control animals [55].…”