Bednarek E, Caroni P.
β-Adducin is required for stable assembly of new synapses and improved memory upon environmental enrichment.
Neuron. 2011 Mar 24;69(6):1132-46.
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In a groundbreaking set of studies compiled in this Neuron paper, Bednarek and Caroni explore the effects of environmental enrichment (EE) on synapse turnover and the establishment of new synapses in the hippocampus. The authors also assess the involvement of structural plasticity in EE-facilitated hippocampal memory formation, and the critical role of β-adducin in coordinating these processes. This paper stimulates new avenues of thought regarding the dynamics and plasticity of synapses and how these are regulated at the molecular level, topics that are at present scantily understood.
The elucidation of the dynamic effects of EE on synaptic plasticity in the hippocampus (CA3 and CA1) was particularly striking. Not only did EE increase complexity and density of synapses, but EE also enhanced their lability and subsequent reassembly. This enables the structural plasticity that is thought to be fundamental to aspects of long-term memory formation and recovery from brain injury and disease. EE’s effect on lability and reassembly was demonstrated using local delivery of the protein synthesis inhibitor anisomycin (which leads to a transient destabilization of synaptic complexes) and monitoring the change over time in active zone (AZ) density based on bassoon-positive puncta or synapsin-positive puncta. Relative to control animals in standard housing, the time course of AZ loss was faster in EE animals, and this enhanced lability was followed by faster synapse reassembly. Two weeks of EE exposure led to this; four weeks even more so. Remarkably, this was very rapid, with synapse disassembly nearly maximal already at six hours in the EE groups and 24 hours in the control group. Overall, these data illustrate the remarkably dynamic plasticity of the synapse, and how exposure to EE amplifies this plasticity.
Interestingly, across all groups, a subset of synapses was resistant to anisomycin-induced disassembly; hence, not all synapses are equally amenable to disassembly and plasticity. Further, with longer EE, there were more synapses and a greater percentage of them was plastic. Four weeks of EE nearly doubled CA3 synaptic density relative to standard housed animals or two weeks of EE.
Bednarek and Caroni demonstrate that β-adducin, which recruits spectrin to the fast-growing ends of actin filaments to promote actin capping and bundling and cytoskeletal stability, is a key player in regulating synaptic lability and stability with exposure to EE. Following EE, β-adducin was strongly phosphorylated in a PKC-dependent manner, and this was required for synapse disassembly. At the same time, the presence of non-phosphorylated β-adducin is required to assemble lost synapses and assemble new ones upon EE.
Generally, exposure to EE improves learning/memory and can even overcome learning deficits due to targeted mutations that compromise synaptic plasticity. However, EE did not benefit long-term memory when β-adducin was absent. In fact, EE worsened performance in the XO animals relative to XO animals in normal housing. Re-expression of β-adducin in mossy fibers rescued performance in EE XO animals. Interestingly, not all aspects of memory were impaired by EE in XO animals: Only long-term recall (24 hours) was impaired, while short-term memory (five-minute recall) improved with EE in both WT and XO mice. These findings support the idea that short- and long-term recall engage different mechanisms, with structural remodeling critical to long-term memory, at least under the conditions of heightened plasticity induced by EE.
The dramatic impairment in long-term memory in XO animals makes sense when one considers the effect of EE on synapse dynamics in the absence of β-adducin. With EE, synapses are rapidly disassembled, which normally is beneficial because the facilitated synaptic remodeling allows for enhanced plasticity. However, without β-adducin, enhanced synaptic disassembly is paired with slowed reassembly, reducing capacity in the hippocampus.
It will be important to determine if impaired regulation of β-adducin might account for the difficulties in memory formation that often accompany aging and characterize AD. If so, it would provide a novel target for intervention. It could be argued that deficits in β-adducin regulation are unlikely to be involved in age or AD-related memory difficulties, as a worsening of symptoms with an enriched lifestyle are inconsistent with the abundant literature supporting beneficial effects of enrichment on slowing cognitive decline in aging and disease progression in AD. However, modest changes in β-adducin regulation could occur with aging or AD that would cause less disruption of synaptic dynamics than a knockout. For example, dynamic synapse reassembly may slow down subtly and nonetheless interfere with synapse stabilization and long-term memory formation.
It will also be important to address the idea that, with aging and AD, the proportion of synapses that are amenable to disassembly and plasticity may change. For example, if the subset of “resistant synapses” increased with age, fewer synapses would be available for dynamic plasticity and memory encoding. Such a reduced arsenal, coupled with potential declines in the capacity for synapse reassembly (e.g., due to changes in β-adducin or related mechanisms), could contribute to impaired memory function.
This study demonstrated that EE enhances the disassembly and assembly of dynamic subpopulations of synapses, and that in conditions of EE, the stable assembly of new synapses requires the presence of β-adducin. The beneficial effects of EE on learning and memory are linked to this increased synaptic flexibility and depend on the reassembly of stable synapses. In the absence of β-adducin, the enhanced disassembly of synapses upon EE is not followed by rapid synaptic reassembly; this disrupts the capacity to store long-term memory while leaving short-term memory intact. Overall, these findings highlight the importance of structural plasticity and dynamic synaptogenesis in mediating benefits of EE on cognitive function. The findings open the field to future studies that will elucidate the mechanisms by which experience enhances synapse turnover and synaptogenesis, their roles in potentiating memory processes, and how impairment of these processes may produce memory losses in disease.