Implicating proteins
in synaptic plasticity

The activity of synapses, those fundamental biochemical units and cellular structures that allow nerve-impulse transmission between neurons, is not constant. Rather, synaptic strength can weaken or intensify over time in response to activity levels and other factors. Changes in activity also are associated with changes in the size and shape of synapses. This synaptic plasticity is thought to play a critical role in various forms of learning and memory, and understanding its molecular bases has become a thriving area of neuroscience research.

Synapses contain hundreds of proteins, including neurotransmitter receptors, cell-signaling molecules, scaffolding proteins and cytoskeleton components. These proteins are involved directly in synaptic activity. To understand how the brain truly works, we need to comprehend the role of proteins in synaptic plasticity.

The Journal of Biological Chemistry recently published a collection of thematic minireviews edited by Roger J. Colbran of Vanderbilt University. Titled “Molecular Mechanisms of Synaptic Plasticity,” the series includes four reviews that discuss recent advances in understanding the mechanisms that modulate synaptic protein production and function as well as the effects of these mechanisms on synaptic plasticity. 

Marc P. Lussier at the University of Quebec at Montreal, Antonio Sanz–Clemente at Northwestern University and Katherine W. Roche at the National Institute of Neurological Disorders and Stroke discuss one of the mechanisms of synaptic plasticity in the first review. The authors detail the consequences of three types of post-translational modifications — phosphorylation, ubiquitination and palmitoylation — on the stability, trafficking and synaptic expression of ionotropic glutamate N-methyl-D-aspartic acid, or NMDA, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, or AMPA, receptors, the workhorses of excitatory synapses. The review also addresses the effects of these modifications on two major forms of synaptic plasticity: long-term potentiation, or LTP, and long-term depression, or LTD.

Kevin M. Woolfrey and Mark L. Dell’Acqua at the University of Colorado provide an additional in-depth discussion of post-translational modifications. These authors discuss experimental evidence supporting the idea that the balance between phosphorylation and dephosphorylation of glutamate receptors and ion channels mediates LTP and LTD. Moreover, the dynamics of these signaling events are dictated by the association of protein kinases and protein phosphatases with postsynaptic scaffold proteins.

Next, a minireview by Erin F. Spence and Scott H. Soderling at Duke University covers the molecular processes involved in the regulation of synaptic cytoskeleton within the dendritic spines in the context of human neurodevelopmental and psychiatric disorders. This review emphasizes actin filament assembly and disassembly and its role in synaptic plasticity, because it is the most abundant cytoskeleton component in the dendritic spines.

Finally, Beatriz Alvarez–Castelao and Erin M. Schuman at the Max Planck Institute for Brain Research discuss an important mechanism of inducing long-term synaptic plasticity that involves regulation of synaptic protein synthesis and proteasome-dependent degradation. The authors present an exhaustive discussion of the evidence to date that explains where and how synaptic protein turnover occurs; which proteins are affected by these processes; and the long-term effects of these events on learning, memory and behavior.

Understanding how changes in synaptic activity are connected to modulation of protein expression and degradation, post-translational modifications and cytoskeleton dynamics is essential to determining the molecular bases of physiological and pathological processes that occur in the human brain. In addition, this knowledge could contribute to the development of novel therapies for disorders — such as Parkinson’s disease, schizophrenia and autism — that have been associated with unresponsive or overactive synapses.

Mariana Figuera-Losada Mariana Figuera-Losada is an associate scientist at Albert Einstein College of Medicine in the Bronx.