Learning is correlated with the assembly of new synapses, but the roles of synaptogenesis processes in memory are poorly understood. I will discuss recent evidence that learning-related synapse rearrangements have critical roles for the efficiency and precision of learning and memory in the adult. First, I will show how synapse disassembly and the establishment of new synapses are both critically important for augmented long-term learning and memory upon environmental enrichment. Enrichment enhanced the disassembly and assembly of dynamic subpopulations of synapses. Upon enrichment, stable assembly of new synapses depended on the presence of β-Adducin, disassembly involved β-Adducin phosphorylation through PKC, and both were required for augmented learning. In the absence of β-Adducin enrichment still led to an increase in spine structures, but the assembly of synapses at those spines and learning were compromised. Virus-mediated re-expression of β-Adducin in hippocampal granule cells of β-Adducin -/- mice rescued new synapse assembly and learning upon enrichment. Second, I will show how a learning-related doubling in the numbers of hippocampal mossy fiber synapses that promote feedforward inhibition is critically important for the precision of hippocampus-dependent memories. One-trial and incremental learning led to robust, circuit-specific, long-lasting and reversible increases in the numbers of filopodial synapses onto fast-spiking interneurons that trigger feedforward inhibition in both hippocampus and cerebellum. For contextual fear conditioning and Morris water-maze learning, increased feedforward inhibition connectivity by hippocampal mossy fibers had a critical role for the precision of the memory and the learned behavior. In the absence of mossy fiber LTP in Rab3a-/- mice, c-Fos ensemble re-organization and feedforward inhibition growth were both absent in CA3 upon learning, and the memory was imprecise. By contrast, in the absence of β-Adducin c-Fos re-organization was normal, but feedforward inhibition growth was abolished. In parallel, c-Fos ensembles in CA3 were greatly enlarged, and the memory was imprecise. Feedforward inhibition growth and memory precision were both rescued by re-expression of β-Adducin specifically in hippocampal mossy fibers. Finally, I will discuss how the pronounced alterations in the numbers of defined synapses revealed by these studies provide structural readouts to investigate the specific contributions of individual systems to learning.
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