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.

Keywords: Cell adhesion molecules; Neuronal activity; Proteolytic cleavage; Synaptic development; Synaptic plasticity.

FIGURE 1

Stages of excitatory synaptic development and two forms of adult synaptic plasticity. The synaptic development stage occurs in distinct steps: 1) axon elongation and targeting, 2) synaptic differentiation, and 3) synaptic refinement. Synaptic refinement is regulated by neuronal activity and includes both the maturation of active synapses and the elimination of inactive ones. In the adult, synapses undergo further activity-dependent modification primarily via two forms of synaptic plasticity: Hebbian plasticity and homeostatic plasticity. Non-activity dependent cleavage of CAMs contributes to the first two stages of synaptic development. Then, activity-dependent proteolytic cleavage of CAMs regulates synaptic maturation and adult plasticity.

FIGURE 2

The activity-dependent proteolytic cleavage of CAMs’ extracellular domains play specific, but coordinated roles in orchestrating synaptic maturation. First, activity-dependent cleavage of ICAM-5 removes the postsynaptic maturation-inhibiting signal. Thus, upon cleavage, postsynaptic maturation can begin. Second, the activity-dependent cleavage of SIRPα drives presynaptic maturation of active synapses by enabling the interaction between SIRPα ectodomain and CD47. Finally, when the synapse is mature, Neuroligin-1 is cleaved to restrict maturation and maintain the synapse at a stable state by disrupting its interaction with Neurexin.

FIGURE 3

Activity-dependent proteolytic cleavage of CAMs in the adult brain regulates homeostatic plasticity. Suppression of glutamate receptor activity at the Drosophila NMJ results in a presynaptic increase of neurotransmitter release to maintain homeostasis. This plasticity requires the cleavage of Multiplexin to form Endostatin that results in an increase in presynaptic calcium levels. Contrarily, when synaptic activity is elevated, the cleavage of Neuroligin-1 can return the synapse to a stable state by weakening the synapse. At overactive synapses, the cleavage of Neuroligin-1 decreases presynaptic release via the perturbation of Neuroligin-1/Neurexin signaling.

FIGURE 4

Improper proteolytic processing of APP in Alzheimer’s disease. Under physiological conditions, APP is cleaved via α-secretase (α) followed by γ-secretase (γ) to generate non-amyloidogenic fragments. However, when neuronal activity is altered, APP is incorrectly cleaved by β-secretase (β) and γ-secretase to generate amyloidogenic Amyloid-β (Aβ), which leads to Alzheimer’s disease.