107
J Physiol 588.1 (2010) pp 107–116
SYMPOSIUM REVIEW
Excitatory amino acid involvement in dendritic spine formation, maintenance and remodelling R. Anne McKinney Department of Pharmacology and Therapeutics, Bellini Life Science Building, Room 167, McGill University, 3649 Promenade Sir-William-Osler, Montreal, H3G 0B1, Canada
In the central nervous system, most excitatory synapses occur on dendritic spines, which are small protrusions from the dendritic tree. In the mature cortex and hippocampus, dendritic spines are heterogeneous in shape. It has been shown that the shapes of the spine can affect synapse stability and synaptic function. Dendritic spines are highly motile structures that can undergo actin-dependent shape changes, which occur over a time scale ranging from seconds to tens of minutes or even days. The formation, remodelling and elimination of excitatory synapses on dendritic spines represent ways of refining the microcircuitry in the brain. Here I review the current knowledge on the effects of modulation of AMPA and NMDA ionotropic glutamate receptors on dendritic spine formation, motility and remodelling. (Received 19 July 2009; accepted after revision 17 November 2009; first published online 23 November 2009) Corresponding author R. A. McKinney: Department of Pharmacology and Therapeutics, Bellini Life Science Building, Room 167, McGill University, 3649 Promenade Sir-William-Osler, Montreal, H3G 0B1, Canada. Email:
[email protected] L-Glutamate
is the major excitatory neurotransmitter in the vertebrate central nervous system (CNS), acting through both ionotropic and metabotropic receptors. It has been well documented to play a major role in basal excitatory synaptic transmission and in more recent years, it has been shown to be important in many forms of synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD), which are thought to underlie learning and memory (Rumpel et al. 2005; Morris, 2006; Pastalkova et al. 2006; Whitlock et al. 2006). The main subtypes of glutamate receptors expressed at glutamatergic synapses are α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N -methyl-D-asparate (NMDA) receptors. The activation of AMPA-type glutamate receptors provides most of the synaptic currents mediating excitatory postsynaptic potentials (EPSPs). NMDA receptor subtypes can initiate lasting changes in the strength of excitatory synaptic transmission that is thought to underlie learning and memory (Malenka & Nicoll, 1993; Huang & Pallas, 2001) and plays a major role in
This review was presented at a symposium on Neurophysiology of inhibitory & excitatory amino acid receptors which took place at the 11th International Congress on Amino Acids, Peptides and Proteins, Vienna, on 3 August 2009. C 2010 The Author. Journal compilation C 2010 The Physiological Society
the refinement and the pruning of synaptic circuits (L¨uthi et al. 2001; Adesnik et al. 2008). In the mature CNS, the majority of excitatory synapses occur on dendritic spines, which are small, approximately 1 μm in length, protrusions of the dendritic tree (Yuste & Bonhoeffer, 2004). Dendritic spines receive excitatory glutamatergic input directly from apposing presynaptic terminals (Bourne & Harris, 2008). Dendritic spines are
R. Anne McKinney (McGill University, Montreal, Canada) received her BSc (Hons) in Biomedical Sciences and her DPhil in Neuroscience from the University of Ulster, Coleraine, Northern Ireland, in 1992. She completed her postdoctoral fellowship and had her first independent research group in the Department of Neurophysiology, Brain Research Institute, University of Zurich, Switzerland. She is currently an Associate Professor in the Department of Pharmacology and Therapeutics, McGill University. Her principle research interest is the mechanisms involved in development, maintenance and plasticity of excitatory synapses in the CNS, during physiological and pathological conditions such as epilepsy and autism. She has won many awards for her work including in 1999 the Pfizer Research Prize in Basic Neuroscience and in 2009 the Hugh and Helene McPherson Memorial Award.
DOI: 10.1113/jphysiol.2009.178905
108
R. A. McKinney
heterogeneous in shape and size, in particular in the mammalian cortex and hippocampus (Fig.1), and have been classified as mushroom, thin and stubby spines, based on the length of their neck and the size of their spine head (Jones & Powell, 1969; Peters & Kaiserman-Abramof, 1970; Harris et al. 1992). Occupying a small region of the dendritic spine membrane directly opposing the contacting presynaptic terminal is the postsynaptic density (PSD), an electron-dense protein matrix which contains glutamate receptors and various membrane proteins which are anchored to cytoskeletal scaffolding molecules (Okabe, 2007; Sheng & Hoogenraad, 2007; Newpher & Ehlers, 2009). Within the PSD, most excitatory synaptic transmission occurs through NMDA and AMPA receptors. Different glutamate receptors have been shown through electron microscopy studies to be predominately located in different regions of the postsynaptic membrane (Baude et al. 1995; Kharazia et al. 1996; Nusser et al. 1998; Takumi et al. 1999a; Perez-Otano et al. 2006; Masugi-Tokita et al. 2007). For example, AMPA receptors are at the edge of the PSD, whereas NMDA receptors are often centrally located within the PSD (Kharazia & Weinberg, 1997). Furthermore, subcellular immunogold labelling of NMDA and AMPA receptor subunits provides high resolution electron microscopy visualization of the presence of extrasynaptic sites on spines, dendrites and soma, and within intracellular compartments (Baude et al. 1995; He et al. 1998; Nusser et al. 1998; Petralia & Wenthold, 1999; Takumi et al. 1999b). Considerable progress has been made recently in correlating dendritic spine morphology with the strength of the synapses formed on those spines. Differences in size
Figure 1. Diversity of spine shape A, three-dimensional tertiary portion of the dendritic tree of a CA1 pyramidal cell from a green fluorescent protein-expressing mouse brain. Dendritic spines are classified into three main types: short, stubby spines (
