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Learning-related feedforward inhibitory connectivity growth required for memory precision

Abstract

In the adult brain, new synapses are formed and pre-existing ones are lost, but the function of this structural plasticity has remained unclear1,2,3,4,5. Learning of new skills is correlated with formation of new synapses6,7,8. These may directly encode new memories, but they may also have more general roles in memory encoding and retrieval processes2. 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−/− mice9, 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)10 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.

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Figure 1: Learning-related feedforward inhibition connectivity growth in the hippocampus.
Figure 2: Specificity of learning-related feedforward inhibition growth.
Figure 3: Correlation between feedforward inhibition growth and quality of hippocampal learning and memory.
Figure 4: Relationship between induction of c-Fos in CA3 pyramidal neurons and behavioural memory precision upon contextual fear conditioning.
Figure 5: Critical role of mossy fibre Add2 for feedforward inhibition growth at LMTs and hippocampal memory precision.

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Acknowledgements

We thank S. Arber and B. Roska for valuable comments on the manuscript. We are grateful to J. Pielage for sharing with us his findings on the function of Add2 in synapse stability, and to G. Courtine for advice on the c-Fos labelling protocol. The Friedrich Miescher Institut is part of the Novartis Research Foundation.

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Authors

Contributions

S.R. devised, carried out and analysed all experiments except for those of Fig. 2a–c, part of Fig. 2d, Fig. 5a, e–g and Supplementary Fig. 4; C.V. carried out the experiments of Fig. 2a–c, part of Fig. 2d and Supplementary Fig. 4; E.B. devised and carried out the behavioural and rescue experiments on Add2−/− mice; C.G. carried out the immuno-electron microscopy experiments; B.S. provided advice in planning and interpreting the fear conditioning experiments; P.S. provided advice on the cerebellar experiments; P.C. helped devise the experiments and wrote the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Pico Caroni.

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The authors declare no competing financial interests.

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Ruediger, S., Vittori, C., Bednarek, E. et al. Learning-related feedforward inhibitory connectivity growth required for memory precision. Nature 473, 514–518 (2011). https://doi.org/10.1038/nature09946

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