Activity-dependent proteolytic cleavage of cell adhesion molecules regulates excitatory synaptic development and function

Abstract

Activity-dependent remodeling of neuronal connections is critical to nervous system development and function. These processes rely on the ability of synapses to detect neuronal activity and translate it into the appropriate molecular signals. One way to convert neuronal activity into downstream signaling is the proteolytic cleavage of cell adhesion molecules (CAMs). Here we review studies demonstrating the mechanisms by which proteolytic processing of CAMs direct the structural and functional remodeling of excitatory glutamatergic synapses during development and plasticity. Specifically, we examine how extracellular proteolytic cleavage of CAMs switches on or off molecular signals to 1) permit, drive, or restrict synaptic maturation during development and 2) strengthen or weaken synapses during adult plasticity. We will also examine emerging studies linking improper activity-dependent proteolytic processing of CAMs to neurological disorders such as schizophrenia, brain tumors, and Alzheimer’s disease. Together these findings suggest that the regulation of activity-dependent proteolytic cleavage of CAMs is vital to proper brain development and lifelong function.

Effect of Clozapine on DNA Methylation in Peripheral Leukocytes from Patients with Treatment-Resistant Schizophrenia

“…Similarly, in a recent analysis of differential gene expression profiles in neurons from twins with treatment-resistant SCZ who had discordant responses to clozapine using pluripotent stem (iPS) cell based technology, we found that differentially expressed genes were enriched for “cell adhesion” and “biological adhesion” [6]. Cell adhesion is essential for forming tissue and neuronal connections crucial for nervous system development [31]. Animal studies suggest that dysfunction of neuronal cell adhesion molecules, which are expressed primarily in the central nervous system where they regulate synaptic signaling, may lead to impairment of memory and learning [32,33].…”

Synaptic transmission induces site-specific changes in sialylation onN-linked glycoproteins in rat nerve terminals

“…This particular enrichment of proteases reflects the fact that glycosylation, and probably sialylation 57 , is important for protease activity 58 . For ADAMs, it is known that their enzymatic activity depends on their glycosylation and they perform activity-dependent proteolysis of synaptic cell adhesion molecules such as neuroligin-1 [59][60][61][62] . Further studies investigating the impact of sialic acids on specific N-linked glycans in ADAM proteases in synaptosomes might be of high interest to shed light on their involvement in synaptic transmission and learning and memory related processes.…”

Neuropsin in Mental Health

“…Active neuropsin cleaves the extracellular domain of L1CAM and produce a neuropsin specific 180 kDa fragment [21,28] (depicted in Figure 4). The function of this neuropsin specific L1CAM fragment has not been investigated yet, but the role of cell adhesion molecules in synaptic plasticity [29][30][31][32] suggests that neuropsin-specific L1CAM cleavage decreases synaptic adhesion and subsequent increases the flexibility of synaptic structures. Neuropsin is involved in the synaptogenesis of L1CAM expressing orphan and small synaptic boutons in pre-synaptic membranes of the Schaffer-collateral pathway in the hippocampal CA1 substructure [28].…”