Activity dependent CAM cleavage and neurotransmission

Abstract

Spatially localized proteolysis represents an elegant means by which neuronal activity dependent changes in synaptic structure, and thus experience dependent learning and memory, can be achieved. In vitro and in vivo studies suggest that matrix metalloproteinase and adamalysin activity is concentrated at the cell surface, and emerging evidence suggests that increased peri-synaptic expression, release and/or activation of these proteinases occurs with enhanced excitatory neurotransmission. Synaptically expressed cell adhesion molecules (CAMs) could therefore represent important targets for neuronal activity-dependent proteolysis. Several CAM subtypes are expressed at the synapse, and their cleavage can influence the efficacy of synaptic transmission through a variety of non-mutually exclusive mechanisms. In the following review, we discuss mechanisms that regulate neuronal activity-dependent synaptic CAM shedding, including those that may be calcium dependent. We also highlight CAM targets of activity-dependent proteolysis including neuroligin and intercellular adhesion molecule-5 (ICAM-5). We include discussion focused on potential consequences of synaptic CAM shedding, with an emphasis on interactions between soluble CAM cleavage products and specific pre- and post-synaptic receptors.

Keywords: CAM; MMP; adhesion; dendritic spine; glutamate; metalloproteases.

FIGURE 1

Synaptically localized CAM cleavage. Pre and post synaptic components (black outline) and glial components (green outline) of the synapse are shown. MMPs can be released from neurons and/or glia to cleave peri-synaptic CAMs, thus generating CAM N-terminal fragments with the potential to stimulate intregrin dependent signaling. Though not the focus of this review, cleavage generated CAM intracellular domains (ICDs) may also influence synaptic transmission.

FIGURE 2

Post-synaptic mechanisms by which MMP activity could enhance glutamatergic transmission. There are several non-mutually exclusive possibilities by which MMP activity could influence excitatory neurotransmission. Shown (top) is a dendritic segment with representative spines. As the schematic suggests with arrows to show potential changes, existing spine expansion, new spine formation, synaptic unsilencing, and formation of spine head protrusions represent post synaptic changes that might contribute to MMP and/or integrin dependent changes in the post synaptic element.