Mice lacking the synaptic adhesion molecule Neph2/Kirrel3 display moderate hyperactivity and defective novel object preference.

Published on Jul 28, 2015in Frontiers in Cellular Neuroscience3.921
· DOI :10.3389/FNCEL.2015.00283
Su Yeon Choi5
Estimated H-index: 5
Kihoon Han17
Estimated H-index: 17
(KU: Korea University)
+ 8 AuthorsEunjoon Kim73
Estimated H-index: 73
Synaptic adhesion molecules regulate diverse aspects of neuronal synapse development, including synapse specificity, formation, and maturation. Neph2, also known as Kirrel3, is an immunoglobulin superfamily adhesion molecule implicated in intellectual disability, neurocognitive delay associated with Jacobsen syndrome, and autism spectrum disorders. We here report mice lacking Neph2 (Neph2–/– mice) display moderate hyperactivity in a familiar but not novel environment and novel object recognition deficit with normal performances in Morris water maze spatial learning and memory, contextual fear conditioning and extinction, and pattern separation tests. These mice show normal levels of anxiety-like behaviors, social interaction, and repetitive behaviors. At the synapse level, Neph2–/– dentate gyrus granule cells exhibit unaltered dendritic spine density and spontaneous excitatory synaptic transmission. These results suggest that Neph2 is important for normal locomotor activity and object recognition memory.
📖 Papers frequently viewed together
93 Citations
10 Citations
9 Citations
#1Shaul Yogev (HHMI: Howard Hughes Medical Institute)H-Index: 10
#2Kang ShenH-Index: 60
Precise connectivity in neuronal circuits is a prerequisite for proper brain function. The dauntingly complex environment encountered by axons and dendrites, even after navigation to their target area, prompts the question of how specificity of synaptic connections arises during development. We review developmental strategies and molecular mechanisms that are used by neurons to ensure their precise matching of pre- and postsynaptic elements. The emerging theme is that each circuit uses a combina...
95 CitationsSource
#1Joris de Wit (Katholieke Universiteit Leuven)H-Index: 25
#2Anirvan Ghosh (Hoffmann-La Roche)H-Index: 74
The function of neural circuits depends on the precise connectivity between populations of neurons. Increasing evidence indicates that disruptions in excitatory or inhibitory synapse formation or function lead to excitation/inhibition (E/I) imbalances and contribute to neurodevelopmental and psychiatric disorders. Leucine-rich repeat (LRR)-containing surface proteins have emerged as key organizers of excitatory and inhibitory synapses. Distinct LRR proteins are expressed in different cell types ...
72 CitationsSource
#1Ji Won Um (Yonsei University)H-Index: 23
#2Jaewon Ko (Yonsei University)H-Index: 39
Abstract The synapse is the most elementary operating unit in neurons, creating neural circuits that underlie all brain functions. Synaptic adhesion molecules initiate neuronal synapse connections, promote their stabilization and refinement, and control long-term synaptic plasticity. Leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) have previously been implicated as essential elements in central nervous system (CNS) development. Recent studies have demonstrated...
120 CitationsSource
#1Hideto Takahashi (UBC: University of British Columbia)H-Index: 17
#2Ann Marie Craig (UBC: University of British Columbia)H-Index: 61
Synapse development requires differentiation of presynaptic neurotransmitter release sites and postsynaptic receptive apparatus coordinated by synapse organizing proteins. In addition to the well-characterized neurexins, recent studies identified presynaptic type IIa receptor-type protein tyrosine phosphatases (RPTPs) as mediators of presynaptic differentiation and triggers of postsynaptic differentiation, thus extending the roles of RPTPs from axon outgrowth and guidance. Similarly to neurexins...
175 CitationsSource
#1Yoo Sung Song (KAIST)H-Index: 11
#2Eunjoon Kim (KAIST)H-Index: 73
Synaptic adhesion molecules control neuronal synapse development. In this issue of Neuron, Siddiqui et al. (2013) and de Wit et al. (2013) demonstrate that LRRTM4, a postsynaptic adhesion molecule, trans-synaptically interacts with presynaptic heparan sulfate proteoglycans (HSPGs) to promote synapse development.
15 CitationsSource
#1Ye Cheng (UCSF: University of California, San Francisco)H-Index: 1
#2Jeffrey Francis Quinn (UCSF: University of California, San Francisco)H-Index: 1
Last. Lauren A. Weiss (UCSF: University of California, San Francisco)H-Index: 36
view all 3 authors...
To date, genome-wide single nucleotide polymorphism (SNP) and copy number variant (CNV) association studies of autism spectrum disorders (ASDs) have led to promising signals but not to easily interpretable or translatable results. Our own genome-wide association study (GWAS) showed significant association to an intergenic SNP near Semaphorin 5A (SEMA5A) and provided evidence for reduced expression of the same gene. In a novel GWAS follow-up approach, we map an expression regulatory pathway for a...
41 CitationsSource
#1Janet E. A. Prince (McGill University)H-Index: 3
#2Alexandra C. Brignall (McGill University)H-Index: 3
Last. Jean-François CloutierH-Index: 23
view all 5 authors...
The accessory olfactory system controls social and sexual interactions in mice that are crucial for survival. Vomeronasal sensory neurons (VSNs) form synapses with dendrites of second order neurons in glomeruli of the accessory olfactory bulb (AOB). Axons of VSNs expressing the same vomeronasal receptor coalesce into multiple glomeruli within spatially conserved regions of the AOB. Here we examine the role of the Kirrel family of transmembrane proteins in the coalescence of VSN axons within the ...
43 CitationsSource
#1Andrea Guerin (U of T: University of Toronto)H-Index: 5
#1Andrea Guerin (U of T: University of Toronto)H-Index: 7
Last. David Chitayat (Ontario Power Generation)H-Index: 86
view all 8 authors...
Jacobsen syndrome (JS) is a rare contiguous gene disorder characterized by a deletion within the distal part of the long arm of chromosome 11 ranging in size from 7 to 20 Mb. The clinical findings include characteristic dysmorphic features, growth and psychomotor delays and developmental anomalies involving the brain, eyes, heart, kidneys, immune, hematologic, endocrine, and gastrointestinal systems. The majority of cases are due to a terminal deletion of 11q; however interstitial deletions have...
37 CitationsSource
#1Dilja D. Krueger (MPG: Max Planck Society)H-Index: 17
#2Liam P. Tuffy (MPG: Max Planck Society)H-Index: 12
Last. Nils Brose (MPG: Max Planck Society)H-Index: 95
view all 4 authors...
Neurexins (NXs) and neuroligins (NLs) are transsynaptically interacting cell adhesion proteins that play a key role in the formation, maturation, activity-dependent validation, and maintenance of synapses. As complex alternative splicing processes in nerve cells generate a large number of NX and NLs variants, it has been proposed that a combinatorial interaction code generated by these variants may determine synapse identity and network connectivity during brain development. The functional impor...
167 CitationsSource
#1Michael E. Talkowski (Harvard University)H-Index: 52
#2Jill A. Rosenfeld (PerkinElmer)H-Index: 69
Last. James F. GusellaH-Index: 140
view all 35 authors...
Balanced chromosomal abnormalities (BCAs) represent a relatively untapped reservoir of single-gene disruptions in neurodevelopmental disorders (NDDs). We sequenced BCAs in patients with autism or related NDDs, revealing disruption of 33 loci in four general categories: (1) genes previously associated with abnormal neurodevelopment (e.g., AUTS2, FOXP1, and CDKL5), (2) single-gene contributors to microdeletion syndromes (MBD5, SATB2, EHMT1, and SNURF-SNRPN), (3) novel risk loci (e.g., CHD8, KIRREL...
465 CitationsSource
Cited By18
#1Hyo-Jeong Yong (KU: Korea University)
#2Jong Ik Hwang (KU: Korea University)H-Index: 21
Last. Seong Jae Young (KU: Korea University)
view all 3 authors...
Neurogenesis and functional brain activity require complex associations of inherently programmed secretory elements that are regulated precisely and temporally. Family with sequence similarity 19 A1 (FAM19A1) is a secreted protein primarily expressed in subsets of terminally differentiated neuronal precursor cells and fully mature neurons in specific brain substructures. Several recent studies have demonstrated the importance of FAM19A1 in brain physiology; however, additional information is nee...
#1Tanya Gandhi (LSU: Louisiana State University)
#2Charles C. Lee (LSU: Louisiana State University)H-Index: 29
Last. Charles C. Lee (LSU: Louisiana State University)H-Index: 13
view all 2 authors...
Autism spectrum disorder (ASD) is comprised of several conditions characterized by alterations in social interaction, communication and repetitive behaviors. Genetic and environmental factors contribute to the heterogeneous development of ASD behaviors. Several rodent models display ASD-like phenotypes, including repetitive behaviors. In this review, we discuss the potential neural mechanisms involved in repetitive behaviors in rodent models of ASD and related neuropsychiatric disorders. We revi...
1 CitationsSource
#1Xiao-Qin Zhang (NBU: Ningbo University)H-Index: 3
#2He-Jia Jiang (NBU: Ningbo University)H-Index: 1
Last. Haowei Shen (NBU: Ningbo University)H-Index: 26
view all 13 authors...
Abstract Juvenile social isolation (SI) and neglect have a negative impact on neurodevelopment persistently, which is associated with cognitive dysfunction in neurodevelopmental disorders. Given the critical role of metabotropic glutamate receptors (mGluRs) in synaptic homeostasis of the prefrontal cortex (PFC), pharmacological intervention on mGluRs has been attempted in order to improve cognitive dysfunction in animal models of neurodevelopmental disorder, as well as in clinical trials. Here w...
2 CitationsSource
#1Matthew R. Taylor (UofU: University of Utah)H-Index: 4
#2E. Anne Martin (UofU: University of Utah)H-Index: 5
Last. Megan E. Williams (UofU: University of Utah)H-Index: 14
view all 7 authors...
Missense variants in Kirrel3 are repeatedly identified as risk factors for autism spectrum disorder and intellectual disability but it has not been reported if or how these variants disrupt Kirrel3 function. Previously, we studied Kirrel3 loss-of-function using knockout mice and showed that Kirrel3 is a synaptic adhesion molecule necessary to form one specific type of hippocampal synapse in vivo. Here, we developed an in vitro, gain-of-function assay for Kirrel3 using neuron cultures prepared fr...
3 CitationsSource
#1Danlu Liu (MU: University of Missouri)H-Index: 2
#2William I. Baskett (MU: University of Missouri)H-Index: 3
Last. Chi-Ren Shyu (MU: University of Missouri)H-Index: 25
view all 4 authors...
Finding small homogeneous subgroup cohorts in large heterogeneous populations is a critical process for hypothesis development in biomedical research. Concurrent computational approaches are still lacking in robust answers to the question “what hypotheses are likely to be novel and to produce clinically relevant results with well thought-out study designs?” We have developed a novel subgroup discovery method which employs a deep exploratory mining process to slice and dice thousands of potential...
3 CitationsSource
#1Kyung Ah Han (DGIST: Daegu Gyeongbuk Institute of Science and Technology)H-Index: 8
#2Jinhu Kim (DGIST: Daegu Gyeongbuk Institute of Science and Technology)H-Index: 3
Last. Ji Won Um (DGIST: Daegu Gyeongbuk Institute of Science and Technology)H-Index: 8
view all 7 authors...
Members of the Slitrk (Slit- and Trk-like protein) family of synaptic cell-adhesion molecules control excitatory and inhibitory synapse development through isoform-dependent extracellular interactions with leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs). However, how Slitrks participate in activation of intracellular signaling pathways in postsynaptic neurons remains largely unknown. Here we report that, among the six members of the Slitrk family, only Slitrk2...
4 CitationsSource
#1Solène ConradH-Index: 1
#1Solène ConradH-Index: 3
Last. Mathilde Nizon (University of Nantes)H-Index: 8
view all 12 authors...
This report presents two families with interstitial 11q24.2q24.3 deletion, associated with malformations, hematologic features, and typical facial dysmorphism, observed in Jacobsen syndrome (JS), except for intellectual disability (ID). The smallest 700 Kb deletion contains only two genes FLI1 and ETS1, and a long noncoding RNA, SENCR, narrowing the minimal critical region for some features of JS. Consistent with recent literature, it adds supplemental data to confirm the crucial role of FLI1 an...
4 CitationsSource
#1Linus A. Völker (University of Cologne)H-Index: 10
#2Barbara A. Maar (University of Cologne)H-Index: 1
Last. Martin Hoehne (University of Cologne)H-Index: 8
view all 13 authors...
: Adhesion molecules of the immunoglobulin superfamily (IgSF) are essential for neuronal synapse development across evolution and control various aspects of synapse formation and maturation. Neph2, also known as Kirrel3, is an IgSF adhesion molecule implicated in synapse formation, synaptic transmission and ultrastructure. In humans, defects in the NEPH2 gene have been associated with neurodevelopmental disorders such as Jacobsen syndrome, intellectual disability, and autism-spectrum disorders. ...
10 CitationsSource
#1Chunmei Jin (KU: Korea University)H-Index: 7
#2Hyojin Kang (Korea Institute of Science and Technology Information)H-Index: 23
Last. Kihoon Han (KU: Korea University)H-Index: 17
view all 8 authors...
Variants of the SHANK3 (SH3 and multiple ankyrin repeat domains 3) gene, encoding excitatory postsynaptic core scaffolding proteins, are causally associated with numerous neurodevelopmental and neuropsychiatric disorders, including autism spectrum disorders (ASDs), bipolar disorder, intellectual disability, and schizophrenia (SCZ). Although detailed synaptic changes of various Shank3 mutant mice have been well-characterized, broader downstream molecular changes, including both direct and indirec...
12 CitationsSource
#1Dongseok Park (DGIST: Daegu Gyeongbuk Institute of Science and Technology)H-Index: 4
#2Sungwon Bae (DGIST: Daegu Gyeongbuk Institute of Science and Technology)H-Index: 2
Last. Jaewon Ko (DGIST: Daegu Gyeongbuk Institute of Science and Technology)H-Index: 39
view all 4 authors...
: Synapses and neural circuits form with exquisite specificity during brain development to allow the precise and appropriate flow of neural information. Although this property of synapses and neural circuits has been extensively investigated for more than a century, molecular mechanisms underlying this property are only recently being unveiled. Recent studies highlight several classes of cell-surface proteins as organizing hubs in building structural and functional architectures of specific syna...
6 CitationsSource