Basement membrane protein nidogen‐1 shapes hippocampal synaptic plasticity and excitability

Abstract

The basement membrane (BM) is a specialized form of extracellular matrix (ECM) underlying epithelia and endothelia and surrounding many types of mesenchymal cells. Nidogen, along with collagen IV and laminin, is a major component of BMs. Although certain ECM proteins such as laminin or reelin influence neuronal function via interactions with cell-surface receptors such as integrins, behavioral neurological impairments due to deficits of BM components have been recognized only recently. Here, alterations in neuronal network function underlying these behavioral changes are revealed. Using nidogen-1 knockout mice, with or without additional heterozygous nidogen-2 knockout (NID1(-/-)/NID2(+/+) or NID1(-/-)/NID2(+/-)), we demonstrate that nidogen is essential for normal neuronal network excitability and plasticity. In nidogen-1 knockouts, seizurelike behavior occurs, and epileptiform spiking was seen in hippocampal in vivo EEG recordings. In vitro, hippocampal field potential recordings revealed that lack of nidogen-1, while not causing conspicuous morphological changes, led to the appearance of spontaneous and evoked epileptiform activity, significant increase of the input/output ratio of synaptically evoked responses in CA1 and dentate gyrus, as well as of paired pulse accentuation, and loss of perforant-path long-term synaptic potentiation. Nidogen-1 is thus essential for normal network excitability and plasticity.

Scale Invariant Disordered Nanotopography Promotes Hippocampal Neuron Development and Maturation with Involvement of Mechanotransductive Pathways

“…In particular, collagen IV plays an important role in axon outgrowth and synaptic maturation (Fox et al, 2007; Barros et al, 2011). Another basement membrane protein found to be strongly expressed is Nidogen-1, a prominent regulator of synaptic plasticity and excitability in hippocampal neurons (Vasudevan et al, 2010). S100A4 and HSPG(Lutolf et al, 2009) are upregulated which, in a cooperative manner, are potent inducer of neurite/axon outgrowth in hippocampal neurons (Novitskaya et al, 2000; Kiryushko et al, 2006).…”

Advancing biomaterials of human origin for tissue engineering

“…For example, recombinant domain IV of perlecan, consisting of 14 immunoglobulin superfamily modules, was found to bind to entactins (entactin-1 andentactin-2),thelaminin-1/entactin-1 complex, fibronectin, fibulin-2 and heparin [374]. Entactin-1 is one of the central BM elements that play an essential role in hippocampal synaptic plasticity and excitability [375]. This entactin binds several BM macromolecules via domain-specific, well-defined interplay, and the highest-affinity cell-binding site of entactin-1 is positioned on one of the EGF repeats in the laminin γ1 chain, which is crucial for nerve guidance and for kidney development [376,377].…”

Impaired wound healing in mice lacking the basement membrane protein nidogen 1

“…In contrast, nidogen 2 deficient animals show no obvious alterations in the expression and distribution pattern of other BM components including nidogen 1 (Schymeinsky et al, 2002). Although there seems to be redundancy within the nidogen family, nidogen 1 null mice show neurological abnormalities (Dong et al, 2002;Vasudevan et al, 2009) not seen in nidogen 2 deficient mice suggesting isoform specific functions of the two nidogens.…”

“…However, different phenotypes in mice lacking either nidogen 1 or 2 (Dong et al, 2002;Murshed et al, 2000;Schymeinsky et al, 2002;Vasudevan et al, 2009) raised the question as to whether these two isoforms have also unique functions in skin physiology. Here we demonstrate that nidogen 1 plays a unique role in skin wound repair which might be of a non-structural nature.…”