Neuroligin-1 mediates presynaptic maturation through brain-derived neurotrophic factor signaling

Abstract

Background Maturation is a process that allows synapses to acquire full functionality, optimizing their activity to diverse neural circuits, and defects in synaptic maturation may contribute to neurodevelopmental disorders. Neuroligin-1 (NL1) is a postsynaptic cell adhesion molecule essential for synapse maturation, a role typically attributed to binding to pre-synaptic ligands, the neurexins. However, the pathways underlying the action of NL1 in synaptic maturation are incompletely understood, and some of its previously observed effects seem reminiscent of those described for the neurotrophin brain-derived neurotrophic factor (BDNF). Here, we show that maturational increases in active zone stability and synaptic vesicle recycling rely on the joint action of NL1 and brain-derived neurotrophic factor (BDNF). Results Applying BDNF to hippocampal neurons in primary cultures or organotypical slice cultures mimicked the effects of overexpressing NL1 on both structural and functional maturation. Overexpressing a NL1 mutant deficient in neurexin binding still induced presynaptic maturation. Like NL1, BDNF increased synaptic vesicle recycling and the augmentation of transmitter release by phorbol esters, both hallmarks of presynaptic maturation. Mimicking the effects of NL1, BDNF also increased the half-life of the active zone marker bassoon at synapses, reflecting increased active zone stability. Overexpressing NL1 increased the expression and synaptic accumulation of BDNF. Inhibiting BDNF signaling pharmacologically or genetically prevented the effects of NL1 on presynaptic maturation. Applying BDNF to NL1-knockout mouse cultures rescued defective presynaptic maturation, indicating that BDNF acts downstream of NL1 and can restore presynaptic maturation at late stages of network development. Conclusions Our data introduce BDNF as a novel and essential component in a transsynaptic pathway linking NL1-mediated cell adhesion, neurotrophin action, and presynaptic maturation. Our findings connect synaptic cell adhesion and neurotrophin signaling and may provide a therapeutic approach to neurodevelopmental disorders by targeting synapse maturation.

Advancements in the study of synaptic plasticity and mitochondrial autophagy relationship

“…Neuroligin-1 (NL1), as a member of the neurexin family, is a cell adhesion molecule located on the postsynaptic neuron membrane, predominantly expressed in excitatory synapses (Luo et al, 2020), and is involved in excitatory synaptic formation and activity (Xia et al, 2019). NL1 interacts with PSD-95 through its PDZ domain and regulates synaptic plasticity by increasing the recruitment of NMDARs and the release of presynaptic NMDA through interaction with NMDARs (Guo, Zhao, et al, 2018;Petkova-Tuffy et al, 2021).…”

“…Neuroligin‐1 (NL1), as a member of the neurexin family, is a cell adhesion molecule located on the postsynaptic neuron membrane, predominantly expressed in excitatory synapses (Luo et al., 2020), and is involved in excitatory synaptic formation and activity (Xia et al., 2019). NL1 interacts with PSD‐95 through its PDZ domain and regulates synaptic plasticity by increasing the recruitment of NMDARs and the release of presynaptic NMDA through interaction with NMDARs (Guo, Zhao, et al., 2018; Petkova‐Tuffy et al., 2021). Exposure to maltol aluminum can lead to a decrease in the expression levels of NMDAR1 and NMDAR2B proteins in the rat hippocampus, as well as a decrease in LTP, hindering the development of excitatory synapses and synaptic plasticity (Yang et al., 2017).…”

Is Autism a PIN1 Deficiency Syndrome? A Proposed Etiological Role for Glyphosate

“…BDNF is an important player in WNT signaling, and its expression has been shown to be essential for synapse maturation in the hippocampus mediated by neuroligin [270]. Downregulation of BDNF leads to decreased levels of Bcl2 through impaired Akt signaling, with a resulting increase in apoptosis in neurons, a mechanism that has been proposed as potentially being responsible for the pathogenesis of autism [271].…”

An Imbalance in the Pro/mature BDNF Ratio Occurs in Multiple Brain Regions During Normal Ageing in Wild-Type Mice

“…These synaptic alterations are mediated through its interaction with the neurotrophin receptor p75NTR at some hippocampal synapses, but not all (Garad et al 2021 ). By contrast, the mature isoform, mBDNF, strengthens hippocampal synapses following excitatory plasticity (Kellner et al 2014 ; Petkova-Tuffy et al 2021 ; Rauti et al 2020 ). These neurotrophic effects are mediated through its interaction with TrkB and activation of associated down-stream pathways (Niculescu et al 2018 ).…”