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Neurotrophin-3 from the dentate gyrus supports postsynaptic sites of mossy fiber-CA3 synapses and hippocampus-dependent cognitive functions

Abstract

At the center of the hippocampal tri-synaptic loop are synapses formed between mossy fiber (MF) terminals from granule cells in the dentate gyrus (DG) and proximal dendrites of CA3 pyramidal neurons. However, the molecular mechanism regulating the development and function of these synapses is poorly understood. In this study, we showed that neurotrophin-3 (NT3) was expressed in nearly all mature granule cells but not CA3 cells. We selectively deleted the NT3-encoding Ntf3 gene in the DG during the first two postnatal weeks to generate a Ntf3 conditional knockout (Ntf3-cKO). Ntf3-cKO mice of both sexes had normal hippocampal cytoarchitecture but displayed impairments in contextual memory, spatial reference memory, and nest building. Furthermore, male Ntf3-cKO mice exhibited anxiety-like behaviors, whereas female Ntf3-cKO showed some mild depressive symptoms. As MF-CA3 synapses are essential for encoding of contextual memory, we examined synaptic transmission at these synapses using ex vivo electrophysiological recordings. We found that Ntf3-cKO mice had impaired basal synaptic transmission due to deficits in excitatory postsynaptic currents mediated by AMPA receptors but normal presynaptic function and intrinsic excitability of CA3 pyramidal neurons. Consistent with this selective postsynaptic deficit, Ntf3-cKO mice had fewer and smaller thorny excrescences on proximal apical dendrites of CA3 neurons and lower GluR1 levels in the stratum lucidum area where MF-CA3 synapses reside but normal MF terminals, compared with control mice. Thus, our study indicates that NT3 expressed in the dentate gyrus is crucial for the postsynaptic structure and function of MF-CA3 synapses and hippocampal-dependent memory.

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Fig. 1: Deletion of the Ntf3 gene in DG granule cells.
Fig. 2: Elevated anxiety level and impaired hippocampus-dependent cognitive function in male Ntf3-cKO mice.
Fig. 3: Impaired postsynaptic function at MF-CA3 synapses in Ntf3-cKO mice.
Fig. 4: Deletion of the Ntf3 gene in DG granule cells reduces the number and size of thorny excrescences.
Fig. 5: GluA1 levels are reduced in the SL area but not the SR area of the CA3 subregion in Ntf3-cKO mice.

Data availability

Original data generated and analyzed during this study are included in this published article.

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Acknowledgements

We thank Alicia Brantley for assistance in running behavioral tests. This work was supported by the grants from the National Institutes of Health to BX (R01 MH125187, R01 DK103335, R01 DK105954, and R01 DK134650).

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JWT and BX designed research; JWT, JJA, HD, GYL, and HX performed experiments and analyzed data; and BX and JWT wrote the paper.

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Correspondence to Baoji Xu.

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Tan, JW., An, J.J., Deane, H. et al. Neurotrophin-3 from the dentate gyrus supports postsynaptic sites of mossy fiber-CA3 synapses and hippocampus-dependent cognitive functions. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-023-02404-5

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