title: Increased Excitatory Synaptic Transmission of Dentate Granule Neurons in Mice Lacking PSD-95-Interacting Adhesion Molecule Neph2/Kirrel3 during the Early Postnatal Period.
abstract: Copy number variants and point mutations ofNEPH2(also calledKIRREL3) 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 inNeph2-/-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 byNEPH2mutations.
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST) Daejeon, South Korea.
authors.forename: Junyeop D
authors.initials: JD
authors.lastname: Roh
authors.affiliation: Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS) Daejeon, South Korea.
authors.forename: Su-Yeon
authors.initials: SY
authors.lastname: Choi
authors.affiliation: Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University Daegu, South Korea.
authors.forename: Yi Sul
authors.initials: YS
authors.lastname: Cho
authors.affiliation: Department of Physiology, Dental Research Institute, Seoul National University School of Dentistry Seoul, South Korea.
authors.forename: Tae-Yong
authors.initials: TY
authors.lastname: Choi
authors.affiliation: Department of Physiology, Dental Research Institute, Seoul National University School of Dentistry Seoul, South Korea.
authors.forename: Jong-Sil
authors.initials: JS
authors.lastname: Park
authors.affiliation: Department of Neurology, Columbia University Medical Center New York, NY, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Cutforth
authors.affiliation: Department of Anesthesiology and Pain Medicine, College of Medicine, Chungnam National University Daejeon, South Korea.
authors.forename: Woosuk
authors.initials: W
authors.lastname: Chung
authors.affiliation: Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS) Daejeon, South Korea.
authors.forename: Hanwool
authors.initials: H
authors.lastname: Park
authors.affiliation: Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS) Daejeon, South Korea.
authors.forename: Dongsoo
authors.initials: D
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST) Daejeon, South Korea.
authors.forename: Myeong-Heui
authors.initials: MH
authors.lastname: Kim
authors.affiliation: Department of Neuroscience, College of Medicine, Korea University Seoul, South Korea.
authors.forename: Yeunkum
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Anatomy, College of Medicine, Korea University Seoul, South Korea.
authors.forename: Seojung
authors.initials: S
authors.lastname: Mo
authors.affiliation: Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine Göttingen, Germany.
authors.forename: Jeong-Seop
authors.initials: JS
authors.lastname: Rhee
authors.affiliation: Department of Anatomy, College of Medicine, Korea University Seoul, South Korea.
authors.forename: Hyun
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST) Daegu, South Korea.
authors.forename: Jaewon
authors.initials: J
authors.lastname: Ko
authors.affiliation: Department of Physiology, Dental Research Institute, Seoul National University School of Dentistry Seoul, South Korea.
authors.forename: Se-Young
authors.initials: SY
authors.lastname: Choi
authors.affiliation: Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University Daegu, South Korea.
authors.forename: Yong Chul
authors.initials: YC
authors.lastname: Bae
authors.affiliation: Department of Biology, Howard Hughes Medical Institute, Stanford University Stanford, CA, USA.
authors.forename: Kang
authors.initials: K
authors.lastname: Shen
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST)Daejeon, South Korea; Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS)Daejeon, South Korea.
authors.forename: Eunjoon
authors.initials: E
authors.lastname: Kim
authors.affiliation: Department of Neuroscience, College of Medicine, Korea University Seoul, South Korea.
authors.forename: Kihoon
authors.initials: K
authors.lastname: Han
keywords: Kirrel3; Neph2; PSD-95; dentate granule neuron; excitatory synapse