Altered neuroligin expression is involved in social deficits in a mouse model of the fragile X syndrome.
The fragile X syndrome (FXS) is the most common form of inherited mental retardation. Caused by a transcriptional silencing of the fragile X mental retardation protein (FMRP), a mRNA binding protein itself, misregulated translation is thought to be the leading cause of the fragile X syndrome. Interestingly, recent results indicated several neuroligin interacting proteins to be affected by this misregulation, including neurexin1 and PSD95, which have also been implicated in autism spectrum disorders. Using co-immunoprecipitation assays and RT-PCR, FMRP is shown to interact with neuroligin1- and 2-mRNA, while no interaction with neuroligin3-mRNA is observed. In line with FMRP's role in translation regulation, Western blot as well as immunohistochemistry analysis reveal changes in protein expression levels suggesting impaired synaptic function. As increasing evidence indicates neuroligin expression to be critical for synapse maturation and function, consequences of impaired neuroligin1 expression in FXS are assessed by overexpressing HA-neuroligin1 in FMR1-/- mice, a model for FXS. Behavioural assessments demonstrate that enhanced neuroligin1 expression improves social behaviour in FMR1-/- mice, whereas no positive effect on learning and memory is seen. These results provide for the first time evidence for an involvement of a neuroligin-neurexin protein network in core symptoms of FXS.
Dahlhaus
Regina
R
Brain Research Centre, Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada V6T 1Z3. rdahlhaus@hotmail.com
El-Husseini
Alaa
A
D000374:Aggression / Q000502:physiology; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein; D005106:Exploratory Behavior / Q000502:physiology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000150:complications* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D051528:Guanylate Kinases; D006624:Hippocampus / Q000378:metabolism; D047468:Immunoprecipitation / Q000379:methods; D007398:Interpersonal Relations; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D018782:Maze Learning / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009483:Neuropsychological Tests; D010320:Parvalbumins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D021641:Recognition, Psychology / Q000502:physiology; D012920:Social Behavior Disorders / Q000209:etiology*; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D014785:Vision, Ocular / Q000235:genetics; D050994:Voltage-Dependent Anion Channels
D002352:Carrier Proteins; D015816:Cell Adhesion Molecules, Neuronal; D000076122:Disks Large Homolog 4 Protein; D051860:Fragile X Messenger Ribonucleoprotein 1; D051528:Guanylate Kinases; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010320:Parvalbumins; D012333:RNA, Messenger; D050598:Vesicular Glutamate Transport Protein 1; D050994:Voltage-Dependent Anion Channels; C501447:Dlg4 protein, mouse; C497684:Fmr1 protein, mouse; C493465:Slc17a7 protein, mouse; C073441:gephyrin; C093438:neuroligin 1; C098003:neuroligin 2