The &lt;em&gt;Reeler&lt;/em&gt; Mouse: A Translational Model of Human Neurological Conditions or Simply a Good Tool for Better Understanding Neurodevelopment?

Lossi, Laura; Granato, Alberto; Merighi, Adalberto

doi:10.20944/preprints201910.0120.v1

Cited by 5 publications

References 180 publications

(234 reference statements)

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Reelin deficiency contributes to long-term behavioral abnormalities induced by chronic adolescent exposure to Δ9-tetrahydrocannabinol in mice

Iemolo

Nur

Montilla‐Perez

et al. 2020

Preprint

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Heavy and frequent use of cannabis during adolescence increases the risk of developing psychiatric disorders. However, the neurobiological mechanisms underlying this vulnerability remain largely unknown. Here, we explore whether adolescent vulnerability to long-term behavioral effects of cannabis is modulated by Reelin, a gene implicated in the development of the brain and of psychiatric disorders. To this aim, heterozygous Reeler (HR) mice, that express reduced level of Reelin, were chronically exposed during adolescence to high doses (10mg/kg) of Δ9-tetrahydrocannabinol (THC), a major psychoactive component of cannabis. Mice were tested in early adulthood with multiple behavioral assays, including working memory, social interaction, locomotor activity, anxiety-like responses, stress reactivity, and pre-pulse inhibition. Compared to wild-type (WT), HR mice treated with THC showed, impaired social behaviors, elevated disinhibitory phenotypes and increased responsiveness to aversive situations, in a sex-specific manner. Independent of THC exposure, HR mice also spent more time exploring unfamiliar objects, indicating that Reelin modulates novelty seeking behavior. To identify the neuronal ensemble underlying this elevated novelty seeking in HR mice, we mapped the regional brain expression of the immediate early gene, Fos, in mice exposed to novel objects. HR mice exhibited reduced neuronal activation in the lateral septum, a subcortical brain structure implicated in emotions, cognition and reward processes. Overall, these findings show that (1) Reelin deficiency influences behavioral abnormalities caused by heavy consumption of THC during adolescence, and (2) that Reelin plays a role in the neurobiological mechanisms underlying disinhibitory behaviors, such as novelty seeking.

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Reelin deficiency contributes to long-term behavioral abnormalities induced by chronic adolescent exposure to Δ9-tetrahydrocannabinol in mice

Iemolo

Nur

Montilla‐Perez

et al. 2020

Preprint

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Lateral Septal Circuits Govern Schizophrenia-Like Effects of Ketamine on Social Behavior

Wang

Peterson

Balasubramanian

et al. 2023

Preprint

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Schizophrenia is marked by poor social functioning that can have a severe impact on quality of life and independence, but the underlying neural circuity is not well understood. Here we used a translational model of subanesthetic ketamine mice to delineate neural pathways in the brain linked to social deficits in schizophrenia. Mice treated with chronic ketamine exhibit profound social and sensorimotor deficits as previously reported. Using three-dimensional c-Fos immunolabeling and volume imaging (iDISCO), we show that ketamine treatment resulted in hypoactivation of the lateral septum (LS) in response to social stimuli. Chemogenetic activation of the LS rescued social deficits after ketamine treatment, while chemogenetic inhibition of previously active populations in the LS (i.e. social engram neurons) recapitulated social deficits in ketamine-naive mice. We then examined the translatome of LS engram neurons and found that ketamine treatment dysregulated genes implicated in neuronal excitability and apoptosis, which may contribute to LS hypoactivation. A number of ketamine-induced differentially expressed genes (DEGs), including those involved in mitochondrial function and neuroinflammatory pathways, were shared with human schizophrenia and mouse models of neurodevelopmental disorders. Chemogenetic activation of LS engram neurons induced downstream activity in the ventral part of the basolateral amygdala, subparafascicular nucleus of the thalamus, intercalated amygdalar nucleus, olfactory areas, and dentate gyrus, and may also reduce connectivity of the LS with the piriform cortex and caudate-putamen. In sum, schizophrenia-like social deficits may emerge via changes in the intrinsic excitability of a discrete subpopulation of LS neurons that serve as a central hub to coordinate social behavior via downstream projections to reward, fear extinction, motor and sensory processing regions of the brain.

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Safety of Anti-Reelin Therapeutic Approaches for Chronic Inflammatory Diseases

Calvier,

Alexander,

Marckx

et al. 2024

Cells

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Reelin, a large extracellular glycoprotein, plays critical roles in neuronal development and synaptic plasticity in the central nervous system (CNS). Recent studies have revealed non-neuronal functions of plasma Reelin in inflammation by promoting endothelial–leukocyte adhesion through its canonical pathway in endothelial cells (via ApoER2 acting on NF-κB), as well as in vascular tone regulation and thrombosis. In this study, we have investigated the safety and efficacy of selectively depleting plasma Reelin as a potential therapeutic strategy for chronic inflammatory diseases. We found that Reelin expression remains stable throughout adulthood and that peripheral anti-Reelin antibody treatment with CR-50 efficiently depletes plasma Reelin without affecting its levels or functionality within the CNS. Notably, this approach preserves essential neuronal functions and synaptic plasticity. Furthermore, in mice induced with experimental autoimmune encephalomyelitis (EAE), selective modulation of endothelial responses by anti-Reelin antibodies reduces pathological leukocyte infiltration without completely abolishing diapedesis. Finally, long-term Reelin depletion under metabolic stress induced by a Western diet did not negatively impact the heart, kidney, or liver, suggesting a favorable safety profile. These findings underscore the promising role of peripheral anti-Reelin therapeutic strategies for autoimmune diseases and conditions where endothelial function is compromised, offering a novel approach that may avoid the immunosuppressive side effects associated with conventional anti-inflammatory therapies.

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The <em>Reeler</em> Mouse: A Translational Model of Human Neurological Conditions or Simply a Good Tool for Better Understanding Neurodevelopment?

Cited by 5 publications

References 180 publications

Reelin deficiency contributes to long-term behavioral abnormalities induced by chronic adolescent exposure to Δ9-tetrahydrocannabinol in mice

Reelin deficiency contributes to long-term behavioral abnormalities induced by chronic adolescent exposure to Δ9-tetrahydrocannabinol in mice

Lateral Septal Circuits Govern Schizophrenia-Like Effects of Ketamine on Social Behavior

Safety of Anti-Reelin Therapeutic Approaches for Chronic Inflammatory Diseases

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