Reelin Regulates Postnatal Neurogenesis and Enhances Spine Hypertrophy and Long-Term Potentiation

Abstract

Reelin, an extracellular protein essential for neural migration and lamination, is also expressed in the adult brain. To unravel the function of this protein in the adult forebrain, we generated transgenic mice that overexpress Reelin under the control of the CaMKII␣ promoter. Overexpression of Reelin increased adult neurogenesis and impaired the migration and positioning of adult-generated neurons. In the hippocampus, the overexpression of Reelin resulted in an increase in synaptic contacts and hypertrophy of dendritic spines. Induction of long-term potentiation (LTP) in alert-behaving mice showed that Reelin overexpression evokes a dramatic increase in LTP responses. Hippocampal field EPSP during a classical conditioning paradigm was also increased in these mice. Our results indicate that Reelin levels in the adult brain regulate neurogenesis and migration, as well as the structural and functional properties of synapses. These observations suggest that Reelin controls developmental processes that remain active in the adult brain.

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

“…These findings explain the profound effect of Reelin on glutamatergic neurotransmission and synaptic plasticity ex corpore (Weeber et al 2002;Beffert et al 2005;Beffert et al 2006b;Qiu et al 2006;Campo et al 2009) and in vivo (Pujadas et al 2010) (E Weeber, pers. comm.).…”

“…The latter may, however, not be entirely dependent on Apoer2 and Vldlr (Chameau et al 2009) and may also involve interactions with APP (Hoe et al 2009). Reelin signaling also regulates dendritic spine morphology (Costa et al 2001;Niu et al 2008;Pujadas et al 2010), which likely involves regulation of actin dynamics and the participation of n-cofilin (Chai et al 2009;Rust et al 2010). It activates LIM kinase (LIMK), which inhibits the actin-depolymerizing activity of n-cofilin.…”

“…Increased tyrosine phosphorylation of the NMDA receptor increases ion gating and reduces its endocytosis, thereby increasing NMDA receptor activity overall (Salter and Kalia 2004;Snyder et al 2005). Intriguingly, differential splicing of this exon is regulated in a circadian, activitydriven manner , suggesting that periodic variation of NMDA receptor activity by Reelin is physiologically significant for synapse function, learning, and memory Weeber et al 2002;Beffert et al 2005;D'Arcangelo 2005;Beffert et al 2006b;Pujadas et al 2010).…”

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).…”

Reelin supplementation enhances cognitive ability, synaptic plasticity, and dendritic spine density

“…Organotypic hippocampal cultures of mutant Reeler mice have decreased spine density, which is rescued with recombinant Reelin application in a lipoprotein-dependent manner (Niu et al 2008). Conversely, transgenic mice that overexpress Reelin present with hypertrophy of dendritic spines in the hippocampus (Pujadas et al 2010). Wildtype organotypic hippocampal cultures chronically treated with Reelin (.5 d) results in increases of dendritic spine density and increased AMPA receptor insertion.…”