Neuroligin-1 Loss Is Associated with Reduced Tenacity of Excitatory Synapses

Abstract

Neuroligins (Nlgns) are postsynaptic, integral membrane cell adhesion molecules that play important roles in the formation, validation, and maturation of synapses in the mammalian central nervous system. Given their prominent roles in the life cycle of synapses, it might be expected that the loss of neuroligin family members would affect the stability of synaptic organization, and ultimately, affect the tenacity and persistence of individual synaptic junctions. Here we examined whether and to what extent the loss of Nlgn-1 affects the dynamics of several key synaptic molecules and the constancy of their contents at individual synapses over time. Fluorescently tagged versions of the postsynaptic scaffold molecule PSD-95, the AMPA-type glutamate receptor subunit GluA2 and the presynaptic vesicle molecule SV2A were expressed in primary cortical cultures from Nlgn-1 KO mice and wild-type (WT) littermates, and live imaging was used to follow the constancy of their contents at individual synapses over periods of 8–12 hours. We found that the loss of Nlgn-1 was associated with larger fluctuations in the synaptic contents of these molecules and a poorer preservation of their contents at individual synapses. Furthermore, rates of synaptic turnover were somewhat greater in neurons from Nlgn-1 knockout mice. Finally, the increased GluA2 redistribution rates observed in neurons from Nlgn-1 knockout mice were negated by suppressing spontaneous network activity. These findings suggest that the loss of Nlgn-1 is associated with some use-dependent destabilization of excitatory synapse organization, and indicate that in the absence of Nlgn-1, the tenacity of excitatory synapses might be somewhat impaired.

Metabolic Turnover of Synaptic Proteins: Kinetics, Interdependencies and Implications for Synaptic Maintenance

“…In comparison to metabolic half-lives, residency half-lives are orders of magnitude shorter (Synapsin-1: ∼1 h vs. ∼4.9 days; Bassoon: ∼3 h vs. ∼2.6d, Munc-13–1: ∼1 h vs. ∼1.3d; PSD-95: ∼3.3 h vs. ∼3.7d; residency vs. metabolic turnover half-lives, respectively [7], [71], [72], [73]); these differences become even more apparent when considering the short residency times of integral membrane proteins (e.g. [22], [24], [74]).…”

Neuroligin 2 Is Expressed in Synapses Established by Cholinergic Cells in the Mouse Brain

“…NLGNs are present postsynaptically and form a trans-synaptic signal transduction complex with presynaptic neurexins; they participate in the recruitment of synaptic proteins, and thereby play an important role in the maturation and activity-dependent regulation of synaptic contacts [3], [4], [6], [9]–[11]. Previous immunocytochemical experiments localized NLGN2 exclusively to GABAergic and a small subset of glycinergic synapses [13], [14].…”

“…Both NLGNs and neurexins recruit proteins that are involved in synaptic communication and are able to induce pre- or postsynaptic specializations [3]–[5]. Experiments with NLGN-knockout (KO) mice demonstrated that NLGNs play an important role in the maturation and proper function of synapses [6], [7] and appear to be dynamically regulated and therefore contribute to the activity dependent stabilization/destabilization of synapses [8]–[11].…”

The fate of hippocampal synapses depends on the sequence of plasticity-inducing events

“…The mechanism linking LTP to synaptic stabilization, and LTD to destabilization, is likely to involve several processes. Synaptic tenacity is known to be affected by trans-synaptic proteins 11 such as Neuroligin-1 and SynCAM-1 (Zeidan and Ziv, 2012;Körber and Stein, 2016), PSD-95 (De Roo et al, 2008;Cane et al, 2014), ubiquitin protein ligase E3A (Kim et al, 2016), ensheathment of the synapse by astrocyte processes (Bernardinelli et al, 2014) and many other local factors. It may be a combination of local physical changes and distributed network effects, such as the recurrent reactivation of a specific circuit (Wei and Koulakov, 2014;Novitskaya et al, 2016), which makes once potentiated synapses robust against depression ( Figure 5B) and pruning ( Figure 3E).…”