Increased excitatory synaptic transmission of dentate granule neurons in mice lacking PSD-95-interacting adhesion molecule Neph2/Kirrel3 during the early postnatal period

Junyeop D. Roh, Su Yeon Choi, Yi Sul Cho, Tae Yong Choi, Jong Sil Park, Tyler Cutforth, Woosuk Chung, Hanwool Park, Dongsoo Lee, Myeong Heui Kim, Yeunkum Lee, Seojung Mo, Jeong Seop Rhee, Hyun Kim, Jaewon Ko, Se Young Choi, Yong Chul Bae, Kang Shen, Eunjoon Kim, Kihoon Han

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11 Citations (Scopus)

Abstract

Copy number variants and point mutations of NEPH2 (also called KIRREL3) gene encoding an immunoglobulin (Ig) superfamily adhesion molecule have been linked to autism spectrum disorders, intellectual disability and neurocognitive delay associated with Jacobsen syndrome, but the physiological roles of Neph2 in the mammalian brain remain largely unknown. Neph2 is highly expressed in the dentate granule (DG) neurons of the hippocampus and is localized in both dendrites and axons. It was recently shown that Neph2 is required for the formation of mossy fiber filopodia, the axon terminal structure of DG neurons forming synapses with GABAergic neurons of CA3. In contrast, however, it is unknown whether Neph2 also has any roles in the postsynaptic compartments of DG neurons. We here report that, through its C-terminal PDZ domain-binding motif, Neph2 directly interacts with postsynaptic density (PSD)-95, an abundant excitatory postsynaptic scaffolding protein. Moreover, Neph2 protein is detected in the brain PSD fraction and interacts with PSD-95 in synaptosomal lysates. Functionally, loss of Neph2 in mice leads to age-specific defects in the synaptic connectivity of DG neurons. Specifically, Neph2−/− mice show significantly increased spontaneous excitatory synaptic events in DG neurons at postnatal week 2 when the endogenous Neph2 protein expression peaks, but show normal excitatory synaptic transmission at postnatal week 3. The evoked excitatory synaptic transmission and synaptic plasticity of medial perforant pathway (MPP)-DG synapses are also normal in Neph2−/− mice at postnatal week 3, further confirming the age-specific synaptic defects. Together, our results provide some evidence for the postsynaptic function of Neph2 in DG neurons during the early postnatal period, which might be implicated in neurodevelopmental and cognitive disorders caused by NEPH2 mutations.

Original languageEnglish
Article number81
JournalFrontiers in Molecular Neuroscience
Volume10
DOIs
Publication statusPublished - 2017 Mar 22

Bibliographical note

Funding Information:
This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government Ministry of Science, ICT and Future Planning (MISP; NRF-2015R1C1A1A01052794 to KH) and (NRF-2012M3A9B6055378 to HK), the grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health and Welfare, South Korea (HI16C0090 to KH) and the Institute for Basic Science (IBS-R002-D1 to EK).

Publisher Copyright:
© 2017 Roh, Choi, Cho, Choi, Park, Cutforth, Chung, Park, Lee, Kim, Lee, Mo, Rhee, Kim, Ko, Choi, Bae, Shen, Kim and Han.

Keywords

  • Dentate granule neuron
  • Excitatory synapse
  • Kirrel3
  • Neph2
  • PSD-95

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

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