Reelin Regulates the Maturation of Dendritic Spines, Synaptogenesis and Glial Ensheathment of Newborn Granule Cells

Abstract

The Reelin pathway is essential for both neural migration and for the development and maturation of synaptic connections. However, its role in adult synaptic formation and remodeling is still being investigated. Here, we investigated the impact of the Reelin/Dab1 pathway on the synaptogenesis of newborn granule cells (GCs) in the young-adult mouse hippocampus. We show that neither Reelin overexpression nor the inactivation of its intracellular adapter, Dab1, substantially alters dendritic spine numbers in these neurons. In contrast, 3D-electron microscopy (focused ion beam milling/scanning electron microscope) revealed that dysregulation of the Reelin/Dab1 pathway leads to both transient and permanent changes in the types and morphology of dendritic spines, mainly altering mushroom, filopodial, and branched GC spines. We also found that the Reelin/Dab1 pathway controls synaptic configuration of presynaptic boutons in the dentate gyrus, with its dysregulation leading to a substantial decrease in multi-synaptic bouton innervation. Lastly, we show that the Reelin/Dab1 pathway controls astroglial ensheathment of synapses. Thus, the Reelin pathway is a key regulator of adult-generated GC integration, by controlling dendritic spine types and shapes, their synaptic innervation patterns, and glial ensheathment. These findings may help to better understanding of hippocampal circuit alterations in neurological disorders in which the Reelin pathway is implicated.Significance StatementThe extracellular protein Reelin has an important role in neurological diseases, including epilepsy, Alzheimer's disease and psychiatric diseases, targeting hippocampal circuits. Here we address the role of Reelin in the development of synaptic contacts in adult-generated granule cells (GCs), a neuronal population that is crucial for learning and memory and implicated in neurological and psychiatric diseases. We found that the Reelin pathway controls the shapes, sizes, and types of dendritic spines, the complexity of multisynaptic innervations and the degree of the perisynaptic astroglial ensheathment that controls synaptic homeostasis. These findings show a pivotal role of Reelin in GC synaptogenesis and provide a foundation for structural circuit alterations caused by Reelin deregulation that may occur in neurological and psychiatric disorders.

A Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1, Mapping to SCA37, Causes Spinocerebellar Ataxia

“…31,36,37 In young-adult mouse hippocampus, the reelin-DAB1 pathway regulates the maturation of dendritic spines, synaptogenesis, and glial ensheathment of newborn granule cells. 38 In humans, a homozygous deletion of VLDLR (MIM: 192977), which encodes a receptor for reelin, originates an autosomal-recessive nonprogressive cerebellar ataxia and mental impairment (MIM: 224050). 39 The presence of cerebellar symptoms is a common feature when the reelin-DAB1 pathway is impaired; however, the cerebellar atrophy exhibited by the affected individuals in this study is very mild in comparison with the recessive phenotypes referred above.…”

ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease

“…In turn, PI3kinase initiates a signaling pathway that induces phosphorylation of LIM kinase-1 (LIMK-1), which in turn phosphorylates cofilin at an inhibitory site, blocking the actin-depolymerizing activity of cofilin [62, 63]. As a result, actin polymerization and dendritic spine growth exhibit a net increase in the presence of Reelin, and mice that overexpress Reelin have higher spine density and increased spine complexity [64, 65]. …”

3d Synaptic Organization of the Rat Ca1 and Alterations Induced by Cocaine Self-Administration

“…However, it has been well established via electron microscopy that dendritic shafts also form synapses and not all dendritic spines represent postsynaptic targets 23,24,25 . Thus, electron microscopy with serial section reconstruction is the gold standard method for studying the normal synaptic organization and its possible alterations.…”