Learning-related feedforward inhibitory connectivity growth required for memory precision

Nature. 2011 May 26;473(7348):514-8. doi: 10.1038/nature09946. Epub 2011 May 1.


In the adult brain, new synapses are formed and pre-existing ones are lost, but the function of this structural plasticity has remained unclear. Learning of new skills is correlated with formation of new synapses. These may directly encode new memories, but they may also have more general roles in memory encoding and retrieval processes. Here we investigated how mossy fibre terminal complexes at the entry of hippocampal and cerebellar circuits rearrange upon learning in mice, and what is the functional role of the rearrangements. We show that one-trial and incremental learning lead to robust, circuit-specific, long-lasting and reversible increases in the numbers of filopodial synapses onto fast-spiking interneurons that trigger feedforward inhibition. The increase in feedforward inhibition connectivity involved a majority of the presynaptic terminals, restricted the numbers of c-Fos-expressing postsynaptic neurons at memory retrieval, and correlated temporally with the quality of the memory. We then show that for contextual fear conditioning and Morris water maze learning, increased feedforward inhibition connectivity by hippocampal mossy fibres has a critical role for the precision of the memory and the learned behaviour. In the absence of mossy fibre long-term potentiation in Rab3a(-/-) mice, c-Fos ensemble reorganization and feedforward inhibition growth were both absent in CA3 upon learning, and the memory was imprecise. By contrast, in the absence of adducin 2 (Add2; also known as β-adducin) c-Fos reorganization 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 Add2 specifically in hippocampal mossy fibres. These results establish a causal relationship between learning-related increases in the numbers of defined synapses and the precision of learning and memory in the adult. The results further relate plasticity and feedforward inhibition growth at hippocampal mossy fibres to the precision of hippocampus-dependent memories.

MeSH terms

  • Action Potentials
  • Animals
  • Cerebellum / physiology
  • Conditioning, Psychological / physiology
  • Cytoskeletal Proteins
  • Fear / physiology
  • Feedback, Physiological / physiology*
  • Hippocampus / cytology*
  • Hippocampus / physiology*
  • Maze Learning / physiology
  • Memory / physiology*
  • Mice
  • Microfilament Proteins / deficiency
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism
  • Models, Neurological
  • Mossy Fibers, Hippocampal / physiology
  • Neural Inhibition / physiology*
  • Neuronal Plasticity / physiology
  • Proto-Oncogene Proteins c-fos / metabolism
  • Pseudopodia / metabolism
  • Pyramidal Cells / cytology
  • Pyramidal Cells / metabolism
  • Synapses / metabolism


  • Add2 protein, mouse
  • Cytoskeletal Proteins
  • Microfilament Proteins
  • Proto-Oncogene Proteins c-fos