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PMID:21808020

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Citation

Etherton, M, Földy, C, Sharma, M, Tabuchi, K, Liu, X, Shamloo, M, Malenka, RC and Südhof, TC (2011) Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function. Proc. Natl. Acad. Sci. U.S.A. 108:13764-9

Abstract

Multiple independent mutations in neuroligin genes were identified in patients with familial autism, including the R451C substitution in neuroligin-3 (NL3). Previous studies showed that NL3(R451C) knock-in mice exhibited modestly impaired social behaviors, enhanced water maze learning abilities, and increased synaptic inhibition in the somatosensory cortex, and they suggested that the behavioral changes in these mice may be caused by a general shift of synaptic transmission to inhibition. Here, we confirm that NL3(R451C) mutant mice behaviorally exhibit social interaction deficits and electrophysiologically display increased synaptic inhibition in the somatosensory cortex. Unexpectedly, however, we find that the NL3(R451C) mutation produced a strikingly different phenotype in the hippocampus. Specifically, in the hippocampal CA1 region, the NL3(R451C) mutation caused an ∼1.5-fold increase in AMPA receptor-mediated excitatory synaptic transmission, dramatically altered the kinetics of NMDA receptor-mediated synaptic responses, induced an approximately twofold up-regulation of NMDA receptors containing NR2B subunits, and enhanced long-term potentiation almost twofold. NL3 KO mice did not exhibit any of these changes. Quantitative light microscopy and EM revealed that the NL3(R451C) mutation increased dendritic branching and altered the structure of synapses in the stratum radiatum of the hippocampus. Thus, in NL3(R451C) mutant mice, a single point mutation in a synaptic cell adhesion molecule causes context-dependent changes in synaptic transmission; these changes are consistent with the broad impact of this mutation on murine and human behaviors, suggesting that NL3 controls excitatory and inhibitory synapse properties in a region- and circuit-specific manner.

Links

PubMed PMC3158170 Online version:10.1073/pnas.1111093108

Keywords

Animals; Autistic Disorder/genetics; Cell Adhesion Molecules, Neuronal/genetics; Cerebral Cortex/physiology; Hippocampus/physiology; Long-Term Potentiation/genetics; Membrane Proteins/genetics; Mice; Mice, Mutant Strains; Mutation, Missense/physiology; Nerve Tissue Proteins/genetics; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Synapses/genetics; Synapses/physiology; Synaptic Transmission/genetics

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:NLGN3

involved_in

GO:2000331: regulation of terminal button organization

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q8BYM5

P

Seeded From UniProt

complete

RAT:NLGN3

involved_in

GO:2000310: regulation of NMDA receptor activity

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q8BYM5

P

Seeded From UniProt

complete

RAT:NLGN3

involved_in

GO:0061001: regulation of dendritic spine morphogenesis

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q8BYM5

P

Seeded From UniProt

complete

RAT:NLGN3

involved_in

GO:1900271: regulation of long-term synaptic potentiation

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q8BYM5

P

Seeded From UniProt

complete

MOUSE:NLGN3

involved_in

GO:2000331: regulation of terminal button organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(UBERON:0003881)|occurs_in:(CL:0002608)

Seeded From UniProt

complete

MOUSE:NLGN3

involved_in

GO:2000311: regulation of AMPA receptor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(UBERON:0003881)

Seeded From UniProt

complete

MOUSE:NLGN3

involved_in

GO:2000310: regulation of NMDA receptor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(UBERON:0003881)

Seeded From UniProt

complete

MOUSE:NLGN3

involved_in

GO:0051966: regulation of synaptic transmission, glutamatergic

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(UBERON:0003881)

Seeded From UniProt

complete

MOUSE:NLGN3

involved_in

GO:0061001: regulation of dendritic spine morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002608)|occurs_in:(UBERON:0003881)

Seeded From UniProt

complete

MOUSE:NLGN3

involved_in

GO:0060080: inhibitory postsynaptic potential

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(UBERON:0008930)

Seeded From UniProt

complete

MOUSE:NLGN3

involved_in

GO:0060079: excitatory postsynaptic potential

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(UBERON:0003881)

Seeded From UniProt

complete

MOUSE:NLGN3

involved_in

GO:1900271: regulation of long-term synaptic potentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(UBERON:0003881)

Seeded From UniProt

complete

MOUSE:NLGN3

GO:0035176: social behavior

ECO:0000315:

P

Figure 1A, wild type mice significantly spent more time with novel stranger than familiar social object compared to mutant Nlgn3 mice.

Similar result seen is figure 1B and C

complete
CACAO 3077

MOUSE:NLGN3

GO:0035640: exploration behavior

ECO:0000315:

P

Figure 1B showed the mutant Nlgn3 mice explored unfamiliar caged mouse less then wild type.

complete
CACAO 3078

MOUSE:NLGN3

GO:0051967: negative regulation of synaptic transmission, glutamatergic

ECO:0000315:

P

Figure 2A-C showed that mutant Nlgn3 mice had large increase in excitatory mediated by AMPA receptor synaptic transmission compared to wild typed.

Similar result seen in figure 3B there was an increase NMDA/AMPA ratio in mutant mice.

complete
CACAO 3079

MOUSE:NLGN3

GO:0090394: negative regulation of excitatory postsynaptic membrane potential

ECO:0000315:

P

Figure 2A-C showed that mutant had large increase in excitatory mediated by AMPA receptor synaptic transmission compared to wild typed.

Figure S2 showing increase in mEPSC in mutant Nlgn3 mice in the hippocampus cortex compared to wild type.

This is just a suggestion: Might be helpful to add type of tissue (hippocampal neurons) column 16 in the protein 2GO database.

complete
CACAO 3080

MOUSE:NLGN3

GO:2000311: regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate selective glutamate receptor activity

ECO:0000315:

P

Figure 2A-C showed that mutant had large increase in excitatory mediated by AMPA receptor synaptic transmission compared to wild typed.

complete
CACAO 3081

MOUSE:NLGN3

GO:2000310: regulation of N-methyl-D-aspartate selective glutamate receptor activity

ECO:0000315:

P

Figure 3B shows increase in NMDA/AMPA ratio indicating that there was a greater increase in NMDA than AMPA in mutant Nlgn3 mice compared to wild type.

Mutant mice showed increase NMDA receptor response compared to control figure 4B.

complete
CACAO 3082

MOUSE:NLGN3

GO:0060080: regulation of inhibitory postsynaptic membrane potential

ECO:0000315:

P

Figure S2 showing increase in mIPSC in mutant nlgn3 mice in the somatosensory cortex compared to wild type.

This is just a suggestion: Might be helpful to add type of tissue (somatosensory neurons) column 16 in the protein 2GO database.

complete
CACAO 3083

MOUSE:NLGN3

GO:0060291: long-term synaptic potentiation

ECO:0000315:

P

Figure 3C, investigated LTP using extracellular field recording. Mutant Nlgn3 showed enhanced LTP (figure 3D) compared to control. There was a 70% increase in Nlgn3 mutant mice compared to control, figure 3E.

complete
CACAO 3084

MOUSE:NLGN3

GO:0061002: negative regulation of dendritic spine morphogenesis

ECO:0000315:

P

Figure 5A, B showed that mutant Nlgn3 has greater number of dendritic branch points of pyramidal neurons in stratum radiatum.

complete
CACAO 3085

MOUSE:NLGN3

GO:2000331: regulation of terminal button organization

ECO:0000315:

P

Figure 5G shows decrease in bouton area in mutant Nlgn3 mice compared to wild type.

complete
CACAO 3086

MOUSE:NLGN3

GO:2000809: positive regulation of synaptic vesicle clustering

ECO:0000315:

P

Figure 5H showed decrease in number of synaptic vesicles per bouton in mutant Nlgn3 mice compared to wild type.

complete
CACAO 3087

MOUSE:NLGN3

involved_in

GO:0061001: regulation of dendritic spine morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(CL:0002608)|occurs_in:(UBERON:0003881)

Seeded From UniProt

complete

MOUSE:NLGN3

involved_in

GO:2000331: regulation of terminal button organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(UBERON:0003881)|occurs_in:(CL:0002608)

Seeded From UniProt

complete

MOUSE:NLGN3

involved_in

GO:0061002: negative regulation of dendritic spine morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NLGN3

involved_in

GO:2000809: positive regulation of synaptic vesicle clustering

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NLGN3

involved_in

GO:2000331: regulation of terminal button organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NLGN3

involved_in

GO:0060291: long-term synaptic potentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NLGN3

involved_in

GO:0060080: inhibitory postsynaptic potential

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NLGN3

involved_in

GO:2000310: regulation of NMDA receptor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NLGN3

involved_in

GO:2000311: regulation of AMPA receptor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NLGN3

involved_in

GO:0090394: negative regulation of excitatory postsynaptic potential

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NLGN3

involved_in

GO:2000311: regulation of AMPA receptor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(UBERON:0003881)

Seeded From UniProt

complete

MOUSE:NLGN3

involved_in

GO:2000310: regulation of NMDA receptor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(UBERON:0003881)

Seeded From UniProt

complete

MOUSE:NLGN3

involved_in

GO:1900271: regulation of long-term synaptic potentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(UBERON:0003881)

Seeded From UniProt

complete

MOUSE:NLGN3

involved_in

GO:0060080: inhibitory postsynaptic potential

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(UBERON:0008930)

Seeded From UniProt

complete

MOUSE:NLGN3

involved_in

GO:0060079: excitatory postsynaptic potential

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(UBERON:0003881)

Seeded From UniProt

complete

MOUSE:NLGN3

involved_in

GO:0051966: regulation of synaptic transmission, glutamatergic

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(UBERON:0003881)

Seeded From UniProt

complete

MOUSE:NLGN3

involved_in

GO:0035176: social behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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