Reelin, an extracellular matrix protein linked to early onset psychiatric diseases, drives postnatal development of the prefrontal cortex via GluN2B-NMDARs and the mTOR pathway

Abstract

Defective brain extracellular matrix (ECM) is a factor of vulnerability in various psychiatric diseases such as schizophrenia, depression and autism. The glycoprotein reelin is an essential building block of the brain ECM that modulates neuronal development and participates to the functions of adult central synapses. The reelin gene (RELN) is a strong candidate in psychiatric diseases of early onset, but its synaptic and behavioral functions in juvenile brain circuits remain unresolved. Here, we found that in juvenile reelin-haploinsufficient heterozygous reeler mice (HRM), abnormal fear memory erasure is concomitant to reduced dendritic spine density and anomalous long-term potentiation in the prefrontal cortex. In juvenile HRM, a single in vivo injection with ketamine or Ro25-6981 to inhibit GluN2B-N-methyl-𝒟-aspartate receptors (NMDARs) restored normal spine density, synaptic plasticity and converted fear memory to an erasure-resilient state typical of adult rodents. The functional and behavioral rescue by ketamine was prevented by rapamycin, an inhibitor of the mammalian target of rapamycin pathway. Finally, we show that fear memory erasure persists until adolescence in HRM and that a single exposure to ketamine during the juvenile period reinstates normal fear memory in adolescent mice. Our results show that reelin is essential for successful structural, functional and behavioral development of juvenile prefrontal circuits and that this developmental period provides a critical window for therapeutic rehabilitation with GluN2B-NMDAR antagonists.

Collagen-derived matricryptins promote inhibitory nerve terminal formation in the developing neocortex

“…We observed a mean of ∼40 seizures in col19a1 −/− mutants over 5 d (37.7 ± 5.4 [mean ± SEM] seizure-like events, n = 9, versus 5.8 ± 4.8 in controls, n = 6). Although this number seems high, it is comparable to other mouse models of schizophrenia (e.g., 51.5 ± 2.5 seizure events in reln rl/+ heterozygotes, n = 2; Iafrati et al, 2014).…”

“…Mice with a spontaneous mutation in the reln gene (reln rl/rl ; also called reeler mutant mice) were identified more than 60 years ago (Falconer, 1951). Recent studies have demonstrated that mice lacking a single copy of reln (reln rl/+ ) display traits associated with complex brain disorders (Iafrati et al, 2014).…”

Dab1 Is Required for Synaptic Plasticity and Associative Learning

“…We previously reported that reduced Reelin signaling in juvenile heterozygous reeler or Dab1 KO mice leads to a reduction in dendritic spine density in the hippocampus (Niu et al, 2008). Recent findings further demonstrated that spinogenesis and long-term synaptic plasticity are impaired in the prefrontal cortex of juvenile heterozygous reeler mice (Iafrati et al, 2013). Based on these findings, we predict that there is a postnatal window during which Reelin signaling promotes spinogenesis.…”

“…Spontaneous mutant mice lacking Reelin (reeler) or Dab1 (scrambler), and Dab1 knock-out (KO) mice present with widespread defects in cellular layer formation Howell et al, 1997Howell et al, , 2000Sheldon et al, 1997). A developmental delay in dendrite and axon branching, as well as spine formation and synaptogenesis, has been also reported in the hippocampus of Reelin and Dab1 mutant mice Niu et al, 2004Niu et al, , 2008Borrell et al, 2007).…”

“…Receptor binding leads to the activation of Src family kinases (SFKs) and tyrosine phosphorylation of Dab1 Howell et al, 1999). Phosphorylated Dab1 propagates Reelin signaling, regulating neuronal migration through the recruitment of Crk/CrkL Park and Curran, 2008), Rap1, cadherins, and integrin ␣5␤1 (Franco et al, 2011;Jossin and Cooper, 2011;Sekine et al, 2012).…”