Reelin Secreted by GABAergic Neurons Regulates Glutamate Receptor Homeostasis

Abstract

BackgroundReelin is a large secreted protein of the extracellular matrix that has been proposed to participate to the etiology of schizophrenia. During development, reelin is crucial for the correct cytoarchitecture of laminated brain structures and is produced by a subset of neurons named Cajal-Retzius. After birth, most of these cells degenerate and reelin expression persists in postnatal and adult brain. The phenotype of neurons that bind secreted reelin and whether the continuous secretion of reelin is required for physiological functions at postnatal stages remain unknown.Methodology/Principal FindingsCombining immunocytochemical and pharmacological approaches, we first report that two distinct patterns of reelin expression are present in cultured hippocampal neurons. We show that in hippocampal cultures, reelin is secreted by GABAergic neurons displaying an intense reelin immunoreactivity (IR). We demonstrate that secreted reelin binds to receptors of the lipoprotein family on neurons with a punctate reelin IR. Secondly, using calcium imaging techniques, we examined the physiological consequences of reelin secretion blockade. Blocking protein secretion rapidly and reversibly changes the subunit composition of N-methyl-D-aspartate glutamate receptors (NMDARs) to a predominance of NR2B-containing NMDARs. Addition of recombinant or endogenously secreted reelin rescues the effects of protein secretion blockade and reverts the fraction of NR2B-containing NMDARs to control levels. Therefore, the continuous secretion of reelin is necessary to control the subunit composition of NMDARs in hippocampal neurons.Conclusions/SignificanceOur data show that the heterogeneity of reelin immunoreactivity correlates with distinct functional populations: neurons synthesizing and secreting reelin and/or neurons binding reelin. Furthermore, we show that continuous reelin secretion is a strict requirement to maintain the composition of NMDARs. We propose that reelin is a trans-neuronal messenger secreted by GABAergic neurons that regulates NMDARs homeostasis in postnatal hippocampus. Defects in reelin secretion could play a major role in the development of neuropsychiatric disorders, particularly those associated with deregulation of NMDARs such as schizophrenia.

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.).…”

“…Similarly, Reelin has been shown to regulate surface mobility and synaptic residency of NMDA receptor NR2B subunits (Groc et al 2007). It is thus required for NMDA receptor maturation (Sinagra et al 2005) and for the maintenance of normal NR2A/B ratios (Campo et al 2009). …”

Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy

“…37,38 The former neurons produce and secrete Reelin; the latter are targeted by Reelin molecules released from other cells. 38 LGI1 is localized mainly in pyramidal neurons, but a detailed analysis of its distribution in the brain is missing.…”

“…37,38 The former neurons produce and secrete Reelin; the latter are targeted by Reelin molecules released from other cells. 38 LGI1 is localized mainly in pyramidal neurons, but a detailed analysis of its distribution in the brain is missing. Notably, our results show that some cortical and hippocampal neurons intensely labeled by Reelin antibodies are also heavily immunoreactive for LGI1, suggesting that these neurons Values were normalized to the serum levels of the amyloid precursor protein (APP), as reported previously.…”

Reelin signaling antagonizes β-amyloid at the synapse

“…Consistent with the findings in other laboratories, monomeric A␤ 1-42 (1°) was ineffective. A truncated form of the A␤ peptide consisting only of amino acids 25 to 35 (A␤ [25][26][27][28][29][30][31][32][33][34][35] ), which form the minimal fibrillogenic region was also able to potently suppress baseline LTP at consistently lower concentrations (100 nM; Fig. 1B, closed circles).…”