Reelin deficiency exacerbates cocaine‐induced hyperlocomotion by enhancing neuronal activity in the dorsomedial striatum

Abstract

The Reln gene encodes for the extracellular glycoprotein Reelin, which regulates several brain functions from development to adulthood, including neuronal migration, dendritic growth and branching and synapse formation and plasticity. Human studies have implicated Reelin signaling in several neurodevelopmental and psychiatric disorders. Mouse studies using the heterozygous Reeler (HR) mice have shown that reduced levels of Reln expression are associated with deficits in learning and memory and increased disinhibition. Although these traits are relevant to substance use disorders, the role of Reelin in cellular and behavioral responses to addictive drugs remains largely unknown. Here, we compared HR mice to wild‐type (WT) littermate controls to investigate whether Reelin signaling contributes to the hyperlocomotor and rewarding effects of cocaine. After a single or repeated cocaine injections, HR mice showed enhanced cocaine‐induced locomotor activity compared with WT controls. This effect persisted after withdrawal. In contrast, Reelin deficiency did not induce cocaine sensitization, and did not affect the rewarding effects of cocaine measured in the conditioned place preference assay. The elevated cocaine‐induced hyperlocomotion in HR mice was associated with increased protein Fos expression in the dorsal medial striatum (DMS) compared with WT. Lastly, we performed an RNA fluorescent in situ hybridization experiment and found that Reln was highly co‐expressed with the Drd1 gene, which encodes for the dopamine receptor D1, in the DMS. These findings show that Reelin signaling contributes to the locomotor effects of cocaine and improve our understanding of the neurobiological mechanisms underlying the cellular and behavioral effects of cocaine.

Adult-specific Reelin expression alters striatal neuronal organization. Implications for neuropsychiatric disorders

“…In this study we describe a preferential expression of Reelin mRNA in a specific subpopulation of MSNs of the striatum, the D1 neurons, corroborating previous studies using FISH (de Guglielmo et al, 2022). Further, the fact that both Reelin and Dab1 expression are higher in striatonigral D1 MSNs than in striatopallidal D2 MSNs, suggests that Reelin may function in an autocrine manner in D1 MSNs.…”

“…Experiments in mice lacking D1 receptor evidence a clear role for this receptor in the psychomotor effects of cocaine. As mentioned before, our data and that of others (de Guglielmo et al, 2022) evidences a preferential expression of Reelin in D1 neurons, supporting the idea that Reelin could be somehow modulating its function and hence influencing cocaine-induced psychomotor effects which are reduced in Reelin overexpressing mice (Teixeira et al, 2011) and increased when Reelin levels are reduced (de Guglielmo et al, 2022).…”

“…It has been described that after cocaine administration, there is an specific increase in the ERK pathway in striatonigral MSNs (Bertran-Gonzalez et al, 2008), a pathway that is also activated by Reelin (Simó et al, 2007; Lee et al, 2014). Interestingly, an increased Fos activation in the dorsal medial striatum but not in the NAcc of heterozygous reeler mice after the administration of cocaine has been described (de Guglielmo et al, 2022). Increases in Fos activation are thought to be the result of the cocaine-induced upregulation in dopamine levels in the striatum (Di Chiara and Imperato, 1988) which is hypothesized that might increase the activity of MSNs by activating D1 and D2 receptors.…”

“…Besides the involvement of the striatum (including the Nucleus accumbens) and its circuitry in psychiatric disorders such as major depression, schizophrenia and obsessive-compulsive disorder (OCD), few studies addressing how Reelin influences striatal structure and circuits are available (de Guglielmo et al, 2022). Most of these studies use heterozygous reeler mice as a model, which have reduced Reelin expression also during development.…”

Adult-specific Reelin expression alters striatal neuronal organization: implications for neuropsychiatric disorders

“…Experiments in mice lacking D1 receptor indicate a clear role for this receptor in the psychomotor effects of cocaine. In this study we describe a preferential expression of Reelin mRNA in a specific subpopulation of MSNs of the striatum, the D1 neurons, corroborating previous studies using FISH (de Guglielmo et al, 2022) or genome-wide translatome (Montalban et al, 2022). The fact that the expression of both Reelin and its main downstream effector Dab1 are higher in striatonigral D1 MSNs than in striatopallidal D2 MSNs, suggests that Reelin may function in an autocrine manner in D1 MSNs and could be somehow modulating its function and hence influencing cocaine-induced psychomotor effects which are reduced in Reelin overexpressing mice (Teixeira et al, 2011) and increased when Reelin levels are reduced (de Guglielmo et al, 2022).…”