Stabilising influence: integrins in regulation of synaptic plasticity

Abstract

Hebbian synaptic plasticity, such as hippocampal long-term potentiation (LTP), is thought to be important for particular types of learning and memory. It involves changes in the expression and activity of a large array of proteins, including cell adhesion molecules. The integrin class of cell adhesion molecules has been extensively studied in this respect, and appear to have a defined role in consolidating both structural and functional changes brought about by LTP. With the use of integrin inhibitors, it has been possible to identify a critical time window of several minutes after LTP induction for the participation of integrins in LTP. Altering the interactions of integrins with their ligands during this time compromises structural changes involving actin polymerisation and spine enlargement that could be required for accommodating new AMPA receptors (AMPARs). After this critical window of structural remodelling and plasticity, integrins "lock-in" and stabilise the morphological changes, conferring the requisite longevity for LTP. Genetic manipulations targeting integrin subtypes have helped identify the specific integrin subunits involved in LTP and correlate alterations in plasticity with behavioural deficits. Moreover, recent studies have implicated integrins in AMPAR trafficking and glycine receptor lateral diffusion, highlighting their multifaceted functions at the synapse.

Fig. 1

Model of how integrins might consolidate LTP. (A) Synapse immediately after the induction of LTP, showing the presynaptic axon terminal (top, blue) filled with synaptic vesicles, and the postsynaptic compartment (bottom, green) with ionotrophic glutamate receptors at the cell surface and actin cytoskeleton, both of which are normally stabilised by integrin interactions with the extracellular matrix. LTP induction results in the disengagement of integrins, and disassembly of both the postsynaptic actin network and ECM. (B) Morphological changes and reassembly after LTP induction: disengagement of integrins, and depolymerisation of the postsynaptic actin network allows for the physical expansion of the postsynaptic compartment (which is associated with a concurrent expansion of the presynaptic terminal), and accommodates the insertion of AMPARs into the postsynaptic membrane. Integrin signalling then controls the polymerisation of the actin cytoskeleton. ECM is reassembled. (C) Consolidation: after a period of instability new integrins are inserted and engage with the ECM to stabilise the new synaptic morphology and function. See text for details. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)