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A stabilising influence: Integrins in regulation of synaptic plasticity

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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.

Introduction

The activity-dependent modification of synaptic efficacy, termed synaptic plasticity, underpins the capacity of neuronal networks to adapt to changes in external stimuli, and to process and transmit information. Many forms of plasticity have been described, from short-term (ranging from milliseconds to several minutes) (Zucker and Regehr, 2002) to long-term (ranging from hours to years) (Citri and Malenka, 2008), all of which involve changes in synaptic efficacy in a discrete number of synapses. The two most extensively studied forms of long-term plasticity, LTP and long-term depression (LTD), which are thought to represent the cellular correlate of learning and memory, can have different mechanisms of expression depending on the neuronal circuits in which they operate (Citri and Malenka, 2008). Other forms of plasticity act on a much broader regulatory scale. For example, homeostatic synaptic plasticity serves as a negative feedback mechanism in response to global changes in neuronal network activity, resulting in a compensatory and uniform scaling of all synaptic strengths (Pozo and Goda, 2010, Turrigiano, 2008).

The mechanisms by which neurons translate transient changes in stimuli into long-term changes in synaptic efficacy are varied, and can include alterations in presynaptic release probability and postsynaptic responsiveness. Regardless, they usually always involve progressive steps engaging a discrete collection of proteins and signalling events. For example, LTP is commonly divided into two phases: an early phase lasting 1–2 h (E-LTP), which relies on posttranslational modifications and glutamate receptor trafficking, and a later phase (L-LTP), which is dependent on transcription and translation (Abraham and Williams, 2008). Induction of E-LTP requires NMDA receptor (NMDAR) activation and elevation of [Ca2+]i, followed by protein kinase activation, AMPAR phosphorylation and insertion into the postsynaptic membrane; in some cases, E-LTP may also accompany increased presynaptic glutamate release probability. L-LTP appears to entail structural changes requiring local protein synthesis, protease activation and proteolytic cleavage, actin polymerisation and growth of spines, in conjunction with synthesis and insertion of adhesion molecules to stabilise synaptic contacts (Citri and Malenka, 2008, Abraham and Williams, 2008).

Many cell adhesion molecules (CAMs) have a well established role in the development and maintenance of synaptic structures. Moreover, it is now well appreciated that they also have an important role in the activity-dependent functional changes in synaptic efficacy in the mature brain. CAMs that have been demonstrated to play key roles in synaptic plasticity include neurexins and neuroligins (Dahlhaus et al., 2010), Ephs and ephrins, immunoglobulin superfamily adhesion molecules, cadherins (Dalva et al., 2007) and integrins (Dityatev et al., 2010).

The purpose of this article is to review the literature to date on the regulation of synaptic plasticity by the integrins. This class of CAMs are heterodimers consisting of one of eighteen α and one of eight β subunits, which associate into 24 different combinations, and interact with extracellular matrix proteins or counter receptors on adjacent cells. The integrins are bidirectional, allosteric signalling molecules capable of activating intracellular signalling pathways in response to changes in the extracellular environment (outside-in signalling) or altering cell adhesion as a consequence of intracellularly generated stimuli (inside-out signalling). They have well established roles in a large variety of cellular processes including cell survival, cell proliferation, cell motility, transcription and cytoskeletal organisation (Berrier and Yamada, 2007, Hynes, 2002, Legate et al., 2009). Given their involvement in many basic cellular processes, it is not surprising that most integrin subunits are broadly expressed in many tissues. Although none of the subunits is neural specific, a subset is also expressed in the brain at moderate levels, and a few are enriched at synapses (Table 1). Accumulating evidence suggests that the integrins play important roles in synaptic plasticity, particularly in LTP consolidation (Chan et al., 2003, Chan et al., 2006, Huang et al., 2006, Staubli et al., 1998), albeit other functions have also been described (Charrier et al., 2010, Chavis and Westbrook, 2001, Cingolani and Goda, 2008, Cingolani et al., 2008).

Section snippets

RGD peptides

The well established function of integrins in cell–cell and cell–matrix adhesion provided the impetus for investigating whether these CAMs play a role in the synaptic structural changes associated with LTP (Lee et al., 1980). Early studies made use of peptides containing the Arg-Gly-Asp (RGD) sequence found in extracellular matrix proteins, such as fibronectin, and recognised by many integrin subtypes, including those present in neurons (Ruoslahti, 1996). Application of RGD peptides to acute

Conclusions and future directions

Integrins have a wide range of roles in a variety of cellular systems (Berrier and Yamada, 2007, Hynes, 2002, Legate et al., 2009). In this review, we have outlined an important function for integrins in regulating the ability of neurons to adjust synaptic strength in response to activity. In particular, we have focused on the role of integrins in Hebbian plasticity, such as LTP. Taken together, it appears that ITGβ1, ITGα3, ITGα5 and ITGα8 all have important roles in the stabilisation of LTP,

Acknowledgements

Research in the authors’ laboratory is supported by the Medical Research Council and by grants from the Royal Society International Joint Projects scheme and the European Union Seventh Framework Programme under grant agreement no. HEALTH-F2-2009-241498 (“EUROSPIN” project).

References (43)

  • K. Pozo et al.

    Unraveling mechanisms of homeostatic synaptic plasticity

    Neuron

    (2010)
  • U. Staubli et al.

    An inhibitor of integrin receptors blocks long-term potentiation

    Behav. Neural Biol.

    (1990)
  • G.G. Turrigiano

    The self-tuning neuron: synaptic scaling of excitatory synapses

    Cell

    (2008)
  • B.A. Bahr et al.

    Arg-Gly-Asp-Ser-selective adhesion and the stabilization of long-term potentiation: pharmacological studies and the characterization of a candidate matrix receptor

    J. Neurosci.

    (1997)
  • J.A. Bernard-Trifilo et al.

    Integrin signaling cascades are operational in adult hippocampal synapses and modulate NMDA receptor physiology

    J. Neurochem.

    (2005)
  • A.L. Berrier et al.

    Cell–matrix adhesion

    J. Cell. Physiol.

    (2007)
  • X. Bi et al.

    Polarized distribution of alpha5 integrin in dendrites of hippocampal and cortical neurons

    J. Comp. Neurol.

    (2001)
  • C.D. Buckley et al.

    RGD peptides induce apoptosis by direct caspase-3 activation

    Nature

    (1999)
  • J.D. Cahoy et al.

    A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function

    J. Neurosci.

    (2008)
  • C.S. Chan et al.

    Alpha8-integrins are required for hippocampal long-term potentiation but not for hippocampal-dependent learning

    Genes Brain Behav.

    (2010)
  • C.S. Chan et al.

    Alpha3-integrins are required for hippocampal long-term potentiation and working memory

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