Reelin central fragment supplementation improves cognitive deficits in a mouse model of Fragile X Syndrome

Morrill, Nicole K.; Joly‐Amado, Aurélie; Li, Qingyou; Prabhudeva, Sahana; Weeber, Edwin J.; Nash, Kevin

doi:10.1016/j.expneurol.2022.114170

Cited by 1 publication

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“…Others have reported benefits of Reelin supplementation in a mouse model of Angelman syndrome and in WT mice (Rogers et al, 2011, 2013) as well as in a model of maternal induced activation of schizophrenia (Ibi et al, 2020). Additionally, our laboratory has reported that administration of R3456 into HRM and a mouse model of fragile X syndrome induced recovery of known cognitive deficits (Li et al, 2023; Morrill et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

A novel Reelin construct, R36, recovered behavioural deficits in the heterozygous reeler mouse

Morrill

Joly‐Amado

et al. 2023

Eur J of Neuroscience

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Reelin, a large extracellular glycoprotein, plays a critical role in prenatal brain development and postnatally in synaptic plasticity, learning and memory. Dysregulation of Reelin signalling has been implicated in several neuropsychiatric disorders including schizophrenia, autism, depression and Alzheimer's disease. Previous studies have demonstrated that Reelin's central fragment, R3456, binds to ApoER2, inducing ApoER2 clustering and subsequent intracellular signalling. We previously reported the development of a novel luciferase complementation assay, which we used to demonstrate that R3456 can lead to ApoER2 receptor dimerization. Using this same assay, we explored various smaller fragments and combinations from R3456, and we identified a construct of repeats 3 and 6 (R36), which could still elicit equivalent receptor dimerization. The purpose of this study was to test R36 for biological effects in vitro and in vivo. We show that R36 was capable of initiating intracellular signalling in primary neuronal cultures. In addition, we demonstrate that a single intracerebroventricular injection of R36 protein into a model of Reelin deficiency, the heterozygous reeler mice, can significantly improve cognition. These data support a role for the new construct R36 to enhance the Reelin pathway, and the future possibility of exploring gene therapy approaches with R36 in diseases characterized by reduced levels of Reelin.

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