Abstract
Consolidated memories influence later learning and cognitive processes when new information is overlapped with previous events. To reveal which cellular and molecular factors are associated with this proactive interference, we challenged mice with odor–reward associative learning followed by a reversal-learning task. The results showed that genetical ablation of ErbB4 in parvalbumin (PV)-positive interneurons improved performance in reversal-learning phase, with no alteration in learning phase, supporting that PV interneuron ErbB4 is required for proactive interference. Mechanistically, olfactory learning promoted PV interneuron excitatory synaptic plasticity and direct binding of ErbB4 with presynaptic Neurexin1β (NRXN1β) and postsynaptic scaffold PSD-95 in the prefrontal cortex. Interrupting ErbB4–NRXN1β interaction impaired network activity-driven excitatory inputs and excitatory synaptic transmission onto PV interneurons. Neuronal activity-induced ErbB4-PSD-95 association facilitated transsynaptic binding of ErbB4–NRXN1β and excitatory synapse formation in ErbB4-positive interneurons. Furthermore, ErbB4–NRXN1β binding was responsible for the activity-regulated activation of ErbB4 and extracellular signal-regulated kinase (ERK) 1/2 in PV interneurons, as well as synaptic plasticity-related expression of brain-derived neurotrophic factor (BDNF). Correlatedly, blocking ErbB4–NRXN1β coupling in the medial prefrontal cortex of adult mice facilitated reversal learning of an olfactory associative task. These findings provide novel insight into the physiological role of PV interneuron ErbB4 signaling in cognitive processes and reveal an associative learning-related transsynaptic NRXN1β-ErbB4-PSD-95 complex that affects the ERK1/2-BDNF pathway and underlies local inhibitory circuit plasticity and proactive interference.
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Acknowledgements
We would like to thank Prof. Lin Mei at Case Western Reserve University and Prof. Yanmei Tao at Hangzhou Normal University for helpful discussions on experimental design. We also thank Prof. Lin Mei for kindly providing PV-Cre mice, floxed Erbb4 mice, and NRXN1βNTF plasmids.
Funding
This work was supported by grants from the National Natural Science Foundation of China (81673418 and 81473185) and a project founded by the Jiangsu 333 program (BRA2018059).
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Design of experiments: YX and XYH. Investigation and data acquisition: YX, MLW, HT, CG, FG, BH, RW. Data analysis: YX, MLW, CG, and BH. Writing-original draft: YX. Conception, revision of manuscript, and funding: XYH. All authors approved the final manuscript before submission.
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Xu, Y., Wang, ML., Tao, H. et al. ErbB4 in parvalbumin-positive interneurons mediates proactive interference in olfactory associative reversal learning. Neuropsychopharmacol. 47, 1292–1303 (2022). https://doi.org/10.1038/s41386-021-01205-0
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DOI: https://doi.org/10.1038/s41386-021-01205-0
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