The biochemistry of memory: The 26year journey of a 'new and specific hypothesis'

Abstract

This Special Issue of Neurobiology of Learning and Memory dedicated to Dr. Richard Thompson to celebrate his 80th birthday and his numerous contributions to the field of learning and memory gave us the opportunity to revisit the hypothesis we proposed more than 25years ago regarding the biochemistry of learning and memory. This review summarizes our early 1980s hypothesis and then describes how it was tested and modified over the years following its introduction. We then discuss the current status of the hypothesis and provide some examples of how it has led to unexpected insights into the memory problems that accompany a broad range of neuropsychiatric disorders.

Figure 1

Theta stimulation increases dendritic spine actin polymerization, and activities of actin regulatory proteins, in adult hippocampus. Photomicrographs (A-C) show in situ phalloidin labeling of filamentous (F) actin (A,B) and immunolabeling for cofilin (C) and phosphorylated-cofilin (D) in the apical CA1 dendritic field of an adult hippocampal slice. As shown in panels A and B, the incidence of dendritic spines (seen as small white punctae) containing dense F-actin, is low in control tissue (con) and increased by theta burst stimulation (TBS) of afferents to this field: Quantification shows this increase is rapid (<2 min) and lasts for over an hour in acute hippocampal slice tissue (Kramar et al., 2006; Rex et al., 2009). (C,D) Immunofluorescence images show that the actin regulatory protein cofilin (both phosphorylated and unphosphorylated forms detected in C) is abundant in the great proportion of dendritic spines (small punctae) within hippocampal field CA1, whereas in control tissue, the phosphorylated (inactivated) form (detected in D) is present in a small minority of the spine-like profiles in a similar sized sample field; arrows indicate representative labeled spines(deconvolved with field immunofluorescence images shown in C and D). E) Numbers of spines immunopositive for phospho (p)-cofilin are significantly increased within 2 and decline by 15 min after TBS (results in C-E are from Chen at al. 2007).

Figure 2

Signaling pathways regulating dendritic spine actin remodeling with the induction of LTP by theta burst stimulation (TBS). Schematic of signaling pathways linking three classes of synaptic to regulation of the actin cytoskeleton. Neurotransmitter receptors (glutamate-receptors), integrins, and modulatory receptors including the A1 adenosine receptor, estrogen receptor beta (ERB) and the TrkB receptor for BDNF) are all activated by LTP-inducing theta burst stimulation and, in turn influence signaling cascades that influence the state of filamentous (F) actin within dendritic spines. As illustrated our studies have shown that the modulatory and integrin receptors regulate signaling through two pathways. The first, through the RhoA GTPase drives new actin polymerization whereas the second, through Cdc42/Rac>PAK, mediates stabilization of the new actin filaments. The downstream effectors of the latter pathway are not known but are likely to involve actin nucleating factors such as cortactin and Arp2/3, both of these are concentrated within dendritic spines and are influenced by TBS in adult tissue (grey lettering denotes elements which may influence these processes but have not been tested).

Figure 3

Schematic representation of the links between BDNF, calpain, and synaptic modifications underlying long-term potentiation. Patterns of electrical activity producing LTP trigger the release of BDNF, resulting in activation of TrkB tyrosine kinase, followed by stimulation of ERK. ERK phosphorylates m-calpain, facilitating its activation possibly through binding to membrane-associated PIP2. Activated calpain can produce various modifications of synaptic structure and function by several mechanisms: i) by truncating FAK, calpain can modify adhesion properties of dendritic spines, possibly influencing presynaptic terminals; ii) by regulating elements of the actin cytoskeleton, calpain can participate in the enlargement of dendritic spines; iii) by truncating spectrin and disrupting the accumulation machinery, calpain can facilitate the insertion of AMPA receptors in postsynaptic densities; iv) finally, by regulating local protein synthesis, calpain can participate in the stabilization of the synaptic reorganization taking place after LTP induction.