Invited Review
Learning and memory: An emergent property of cell motility

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Highlights

Abstract

In this review, we develop the argument that the molecular/cellular mechanisms underlying learning and memory are an adaptation of the mechanisms used by all cells to regulate cell motility. Neuronal plasticity and more specifically synaptic plasticity are widely recognized as the processes by which information is stored in neuronal networks engaged during the acquisition of information. Evidence accumulated over the last 25 years regarding the molecular events underlying synaptic plasticity at excitatory synapses has shown the remarkable convergence between those events and those taking place in cells undergoing migration in response to extracellular signals. We further develop the thesis that the calcium-dependent protease, calpain, which we postulated over 25 years ago to play a critical role in learning and memory, plays a central role in the regulation of both cell motility and synaptic plasticity. The findings discussed in this review illustrate the general principle that fundamental cell biological processes are used for a wide range of functions at the level of organisms.

Introduction

Learning and memory is a property of all living organisms, and thus it must have appeared very early during evolution. Consequently, the underlying cellular mechanism(s), or at least some primitive form(s) of it, must also have appeared very early during evolution. While learning and memory has been reported in unicellular organisms, it is only in more complex organisms that learning and memory has been extensively studied at the molecular and cellular levels. Indeed, some forms of learning and memory have been found in invertebrates as well as in early vertebrates (Benfenati, 2007). It is generally assumed that learning and memory is due to the plasticity of the nervous system, a notion going back to James, Tanzi and Cajal, over a century ago (see Berlucchi & Buchtel, 2009 for a review). This concept has been further expanded to that of synaptic plasticity, and the search for the mechanisms of learning and memory at the molecular level has thus focused on those mechanisms that can account for activity-dependent modifications of synaptic strength. In this review we will argue that learning and memory is an emerging property of cell motility, a process that also evolved very early in unicellular organisms, and was further developed in multicellular organisms. Nevertheless, the basic machinery used by unicellular organisms to navigate through the environment remained present in every cell of complex organisms and was adapted to serve a variety of functions related to cell division, contraction, extension, movement and cell–cell interactions. As we will discuss, this basic machinery is extremely complex and involves a multitude of molecular components that have evolved and intermingled with other cellular components regulating other cell functions, including cell signaling, transcription and translation. Interestingly, the majority of proteins present in mammalian postsynaptic densities contributes to generic cellular functions, including protein synthesis and degradation, vesicular trafficking and regulation of actin cytoskeleton, and is found in most organisms from yeasts to invertebrates and vertebrates (Emes et al., 2008). In neurons, the cell motility machinery is used during various phases of developmental growth and expansion, and, we will argue, for producing long-lasting changes in structure and function in certain subcellular compartments, such as dendritic spines in adult organisms. We will first review the basic mechanisms involved in cell motility, focusing on the role of actin polymerization, and of the plasma membrane, which provides for the dynamic integration of major components regulating motility. We will then discuss the specific adaptation of the machinery to neurons, both during development when neurons are actively growing and establishing synaptic connections, as well as in the adult when motility is restricted to specific subcellular compartments. This will be followed by a brief review of the features of and mechanisms underlying synaptic plasticity in adult brain, with an emphasis on long-term potentiation (LTP) of synaptic transmission at hippocampal synapses, a phenomenon widely recognized as one of the mechanisms underlying memory formation in mammalian brain. We will develop the argument that many of the molecular events involved in LTP induction and consolidation are adaptations of the events underlying cell motility. We will conclude our review by discussing how the understanding of this commonality between learning and memory and cell motility might shed new light on the understanding of several disorders associated with learning and memory impairments.

Section snippets

Regulation of cell motility

Since numerous reviews have been written on the subject of cell motility (Allard and Mogilner, 2013, Levayer and Lecuit, 2012, Rottner and Stradal, 2011), we will provide a simplified version of the complex mechanisms that are involved in the regulation of cell motility. In particular, we will focus on actin filaments and the role of specific areas of the plasma membrane in the control of cell movement. Actin filaments are formed by polymerization of globular actin, G-actin, the most abundant

Axonal elongation

In addition to cell migration, neurons have a unique specialization requiring extensive motile mechanisms, which is related to neurite extension and axonal growth during the development of the nervous system. While the exact mechanisms involving axonal growth are still not completely understood, a certain number of features have been identified. In particular, it is now clear that axon elongation is the result of cytoskeletal dynamics involving tubulin and actin polymerization at the tip of the

General features of LTP

Synaptic transmission underlies every aspect of brain function, and neuronal plasticity is by and large due to the existence of synaptic plasticity. In general, synaptic plasticity refers to activity-dependent modifications of the strength of synaptic transmission. Such modifications may include changes in synapse number and strength. In 1973, Bliss and Lømo made the important discovery that a brief high-frequency electrical stimulation of the perforant pathway in rabbit hippocampus produced a

Role of cytoskeleton regulation in LTP consolidation

While the events underlying LTP induction are now well understood, recent findings have indicated that actin polymerization plays a critical role in LTP consolidation. These findings have greatly extended ideas that were developed earlier regarding the potential functions of the actin cytoskeleton in dendritic spines (Crick, 1982, Halpain, 2000, Matus et al., 1982). LTP induction by theta burst stimulation (TBS) of the Schafer collateral pathway results in rapid actin polymerization in

Implications for learning and memory disorders

We recently discussed how the understanding of the molecular/cellular mechanisms of synaptic plasticity, and by extension of learning and memory, could help us understand the causes of learning and memory impairments observed in a wide range of human disorders (Baudry, Bi, Gall, & Lynch, 2011). In particular, we reviewed recent findings indicating that mental retardation associated with Fragile X syndrome could be accounted for by a failure of TBS to activate Rac and PAK (Chen et al., 2010).

Conclusion

Actin polymerization and increasingly complex mechanisms of cell motility were early events in life evolution, and were then used over and over by cells to perform a multitude of functions. With the apparition of neurons, the cellular mechanisms underlying cell motility were adapted to not only underlie neuronal migration, axonal elongation and spine formation, but also to produce rapid activity-dependent modifications of synaptic contacts, the cellular mechanism of synaptic plasticity and of

Acknowledgments

This work was supported by grants P01NS045260-01 from NINDS (PI: Dr. C.M. Gall), and Grant R01NS057128 from NINDS to M.B. X.B. is also supported by funds from the Daljit and Elaine Sarkaria Chair. We wish to thank Drs. G. Lynch and C. Gall for numerous discussions and ideas discussed in the review. We also want to acknowledge the work of all the students, postdocs and technicians who have worked in our laboratories over the years.

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