Reelin supplementation recovers synaptic plasticity and cognitive deficits in a mouse model for Angelman syndrome

Abstract

The Reelin signaling pathway is implicated in processes controlling synaptic plasticity and hippocampus-dependent learning and memory. A single direct in vivo application of Reelin enhances long-term potentiation, increases dendritic spine density and improves associative and spatial learning and memory. Angelman syndrome (AS) is a neurological disorder that presents with an overall defect in synaptic function, including decreased long-term potentiation, reduced dendritic spine density, and deficits in learning and memory, making it an attractive model in which to examine the ability of Reelin to recover synaptic function and cognitive deficits. In this study, we investigated the effects of Reelin administration on synaptic plasticity and cognitive function in a mouse model of AS and demonstrated that bilateral, intraventricular injections of Reelin recover synaptic function and corresponding hippocampus-dependent associative and spatial learning and memory. Additionally, we describe alteration of the Reelin profile in tissue from both the AS mouse and post-mortem human brain.

Csmd2 interacts with Dab1 and is Required in Reelin-Mediated Neuronal Maturation

“…After 5 days of conditioned media treatment starting at the day of plating (0 days in vitro, 0 DIV), neurons cultured with Reelin-containing conditioned media displayed approximately 30% more dendritic protrusions per micrometer of dendrite compared to neurons cultured with CTRL conditioned media (Fig. 4), in line with previous reports (Niu et al, 2008;Rogers et al, 2011;Hethorn et al, 2015). However, upon knockdown of Csmd2 mRNA expression, this effect was completely negated.…”

Touchscreen learning deficits in Ube3a, Ts65Dn and Mecp2 mouse models of neurodevelopmental disorders with intellectual disabilities

“…1) Angelman syndrome is caused by a maternally-inherited deletion at chromosome 15q11-q13, in which the key mutation is in the UBE3A gene (Angelman, 1965; Williams, 2005; Maab et al, 2011), which codes for an E3 ubiquitin ligase. Ube3a heterozygous mice in which the mutation is similarly transmitted by the dam, originally generated by Jiang, Beaudet and co-workers (Jiang et al, 1998), display behavioral abnormalities including deficits in rotarod motor coordination and balance, balance beam walking, grip strength, reduced exploratory range, contextual fear conditioning, and water maze hidden platform acquisition (Jiang et al, 1998; Miura et al, 2002; van Woerden et al, 2007; Heck et al, 2008; Allensworth et al, 2011; Daily et al, 2011; Kaphzan et al, 2012; Baudry et al, 2012; Huang et al, 2013; Santini et al, 2015; Hethorn et al, 2015). 2) Down syndrome is caused by a triplication of chromosome 21, incorporating a third copy of approximately 300 genes (Holtzman and Epstein 1992; Hattori et al, 2000; Chapman et al, 2000; Gardiner et al, 2010; Dierssen, 2012; Kleschevnikov et al, 2012).…”

“…Ube3a heterozygous mice in which the mutation is similarly transmitted by the dam, originally generated by Jiang, Beaudet and co-workers, 39 display behavioral abnormalities including deficits in rotarod motor coordination and balance, balance beam walking, grip strength, reduced exploratory range, contextual fear conditioning and water maze hidden platform acquisition. 1,[39][40][41][42][43][44][45][46][47][48] (2) Down syndrome is caused by a triplication of chromosome 21, incorporating a third copy of approximately 300 genes. 15,[49][50][51][52][53] Ts65Dn mice with partial trisomy of the syntenic genes on mouse chromosome 16, originally generated by Reeves, Davisson et al, 54 display behavioral abnormalities including deficits in water maze hidden platform acquisition, novel object recognition and radial maze, and higher exploration in an open field and on an elevated plusmaze.…”

Towards targeted therapy for Angelman syndrome

“…No recovery of the motor defect was observed. [37] 4. Gene replacement therapy AS is considered a monogenic disorder despite the absence of multiple genes in cases of large chromosomal deletions in region 15q11-13.…”