Colocalization of integrin receptors and reelin in dendritic spine postsynaptic densities of adult nonhuman primate cortex

Abstract

The expression of telencephalic reelin (Reln) and glutamic acid decarboxylase mRNAs and their respective cognate proteins is down-regulated in postmortem brains of schizophrenia and bipolar disorder patients. To interpret the pathophysiological significance of this finding, immunoelectron microscopic experiments are required, but these cannot be carried out in postmortem human brains. As an alternative, we carried out such experiments in the cortex of rats and nonhuman primates. We found that Reln is expressed predominantly in layer I of both cortices and is localized to bitufted (double-bouquet), horizontal, and multipolar ␥-aminobutyric acid-ergic interneurons, which secrete Reln into extracellular matrix. Reln secretion is mediated by a constitutive mechanism that depends on the expression of a specific signal peptide present in the Reln carboxy-terminal domain. Extracellular matrix Reln is found to aggregate in proximity of postsynaptic densities expressed in apical dendrite spines, which include also the ␣3 subunit of integrin receptors. Most pyramidal neurons of various cortical layers express the mouse-disabled 1 (Dab1) protein, which, after phosphorylation by a soluble tyrosine kinase, functions as an adapter protein, probably mediating a modulation of cytoskeleton protein expression. We hypothesize that the decrease of neuropil and dendritic spine density reported to exist in the neocortex of psychiatric patients may be related to a down-regulation of Relnintegrin interactions and the consequent decrease of cytoskeleton protein turnover.glutamic acid decarboxylase ͉ schizophrenia ͉ bipolar disorders ͉ long-term potentiation

Reelin glycoprotein: structure, biology and roles in health and disease

“…The overall picture emerging from these reports suggests that Reelin deficiency may be associated not only with vulnerability to developing psychosis, but also to the development of cognitive dysfunction, a clinical symptom often observed in various neuropsychiatric disorders such as bipolar disorder, 50,59 major depression, 52 autism 5 and lissencephaly. 77 This hypothesis is also supported by animal studies 19 linking Reelin-integrin interactions with synaptic plasticity. Association of ApoER2 and LDL receptor family with Reelin protein may also link certain neurodegenerative disorders such as Alzheimer's dementia 80,81 with dysregulation of Reelin signaling system.…”

“…52,53 Levels of the Reelin receptors ApoER2, VLDLR and a3b1 integrin and the adapter protein Dab-1, which are all essential to the Reelin signaling system, remain expressed in adult brain. 53 Previous work by Rodriguez et al 19 showed an association between Reelin and its receptor a3b1 integrin with synaptic structures, raising the possibility of a potential role in neurotransmission. A recent report by J Herz's laboratory 57 shows that Reelin has a direct effect on enhancement of long-term potentiation (LTP) in hippocampus, which is abolished when hippocampus slice cultures are used from VLDL-R and ApoER2 knockout mice lacking the receptors for Reelin.…”

“…[12][13][14] Reelin binding to ApoER2 and VLDLR receptors induces clustering of the latter receptors, causing dimerization/oligomerization of the adaptor protein, disabled-1 (Dab-1), on the cytosolic aspect of the plasma membrane 15 with eventual tyrosine phosphorylation of Dab-1 adapter protein, 16 facilitating the transduction of signaling pathway from the Reelin-producing cells (GABAergic neurons 17 or Cajal-Retzius cells of layer I) 18 to downstream receptor sites on cortical pyramidal cells. 19 In vivo, Reelin is processed by cleavage at two locations, that is, between repeats 2 and 3 and repeats 6 and 7, 20 resulting in three final fragments. 21 The central Reelin fragment is composed of repeats 3-6, and is necessary and sufficient for receptor binding to ApoER2 and VLDLR proteins, causing Dab-1 phosphorylation in neuronal cultures 21 and is able to rescue the reeler phenotype in embryonic brain cultures.…”

“…Furthermore, Reelin also activates serine-threonine kinases (P35/ Cdk5) and Src-tyrosine kinase family (Fyn-kinase), also leading to phosphorylation of Dab-1. [22][23][24] Phosphorylated Dab-1 can become the substrate for various kinases, leading to a number of important events such as synaptic and dendritic spine plasticity, 19 neurotransmission [22][23][24][25][26] and inhibition of the level of glycogen synthase-kinase 3b (GSK-3b), leading to modulation of pathways of cell survival and growth 23 (Figure 1). Additionally, phosphorylated Dab-1 is a substrate for polyubiquitination-dependent degradation, leading to degradation of a subpopulation of Dab-1 molecules, via the proteosome pathway.…”

Reelin mutations in mouse and man: from reeler mouse to schizophrenia, mood disorders, autism and lissencephaly

“…Phosphorylated Dab-1 may serve as a docking site for the SH2-domain of the Src-kinase family of proteins whose nuclear translocation may underlie synaptic and dendritic spine plasticity. 52 Recent reports 46,53 also implicate the reelin receptor ApoE2 protein in recruitment of the C-JunN-Terminal kinase (JNK-interacting proteins) 1 & 2 (molecular adapter proteins for JNK-signaling pathway) subserving multiple functions such as regulation of the mitogenactivated protein kinases, cell adhesion, vesicle trafficking, neurotransmission, cellular responses to environmental stress, morphogenesis and regulation of region-specific apoptosis of neurons during early brain development. 54,55 This last function may have significant implications in the etiology of a number of neurodevelopmental disorders recently connected with Reelin dysregulation (see below).…”