Transgenic inhibition of synaptic transmission reveals role of CA3 output in hippocampal learning
Abstract
The hippocampus is an area of the brain involved in learning and memory. It contains parallel excitatory pathways referred to as the trisynaptic pathway (which carries information as follows: entorhinal cortex → dentate gyrus → CA3 → CA1 → entorhinal cortex) and the monosynaptic pathway (entorhinal cortex → CA1 → entorhinal cortex). We developed a generally applicable tetanus toxin–based method for transgenic mice that permits inducible and reversible inhibition of synaptic transmission and applied it to the trisynaptic pathway while preserving transmission in the monosynaptic pathway. We found that synaptic output from CA3 in the trisynaptic pathway is dispensable and the short monosynaptic pathway is sufficient for incremental spatial learning. In contrast, the full trisynaptic pathway containing CA3 is required for rapid one-trial contextual learning, for pattern completion–based memory recall, and for spatial tuning of CA1 cells.
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The disynaptic circuit can account for residual hippocampal-dependent memory and high levels of CA1 place cell firing in vivo following surgical or genetic lesions of CA3.
“Moreover, the disynaptic circuit can account for the residual hippocampal-dependent memory and high levels of CA1 place cell firing in vivo following surgical or genetic lesions of CA3 (Brun et al., 2002; Nakashiba et al., 2008).”
From Strong CA2 Pyramidal Neuron Synapses Define a Powerful Disynaptic Cortico-Hippocampal Loop (2010) · cites this paper as Nakashiba et al., 2008
This excitation may be enhanced upon lesion of CA3 due to loss of feed-forward inhibition, providing a potential explanation for elevated CA1 place cell firing in lesioned animals.
“This excitation may actually be enhanced upon lesion of CA3 due to the loss of feed-forward inhibition, providing a potential explanation for the elevated rate of CA1 neuron place cell firing in the lesioned animals (Nakashiba et al., 2008).”
From Strong CA2 Pyramidal Neuron Synapses Define a Powerful Disynaptic Cortico-Hippocampal Loop (2010) · cites this paper as Nakashiba et al., 2008
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- Authors
- Nakashiba, T., Young, J. Z., McHugh, T. J., Buhl, D. L., & Tonegawa, S.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Tonegawa, Susumu
- Venue
- Science
- Published
- 2008-02-29
- Volume
- 319
- Issue
- 5867
- Pages
- 1260-1264
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W1997595402
- Semantic Scholar
- 375a6577d24afc14154b700015dc607877160fc3
- Cited by
- 492
- References
- 35
- Citations by year
- 2026: 12 · 2025: 24 · 2024: 21 · 2023: 21 · 2022: 18 · 2021: 32 · 2020: 17 · 2019: 16 · 2018: 24 · 2017: 27 · 2016: 27 · 2015: 37 · 2014: 39 · 2013: 40 · 2012: 29
- FWCI
- 18.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (P50-MH58880, P50MH058880, R01MH078821)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- CA3, trisynaptic pathway, monosynaptic pathway, synaptic transmission inhibition, tetanus toxin, transgenic mice, spatial learning, contextual learning, pattern completion, entorhinal cortex, memory retrieval
- MeSH terms
- Action Potentials, Animals, Crosses, Genetic, Electrophysiology, Female, Hippocampus, Interneurons, Male, Metalloendopeptidases, Mice, Transgenic, Neural Pathways, Synaptic Transmission, Mental Recall, Tetanus Toxin, Pyramidal Cells, Entorhinal Cortex, Maze Learning, Dentate Gyrus, Excitatory Postsynaptic Potentials, Mice
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