Article

Overexpression of the cell adhesion protein neuroligin-1 induces learning deficits and impairs synaptic plasticity by altering the ratio of excitation to inhibition in the hippocampus

Department of Psychiatry, University of British Columbia, Vancouver, BC.
Hippocampus (Impact Factor: 4.3). 02/2009; 20(2):305-22. DOI: 10.1002/hipo.20630
Source: PubMed

ABSTRACT Trans-synaptic cell-adhesion molecules have been implicated in regulating CNS synaptogenesis. Among these, the Neuroligin (NL) family (NLs 1-4) of postsynaptic adhesion proteins has been shown to promote the development and specification of excitatory versus inhibitory synapses. NLs form a heterophilic complex with the presynaptic transmembrane protein Neurexin (NRX). A differential association of NLs with postsynaptic scaffolding proteins and NRX isoforms has been suggested to regulate the ratio of excitatory to inhibitory synapses (E/I ratio). Using transgenic mice, we have tested this hypothesis by overexpressing NL1 in vivo to determine whether the relative levels of these cell adhesion molecules may influence synapse maturation, long-term potentiation (LTP), and/or learning. We found that NL1-overexpressing mice show significant deficits in memory acquisition, but not in memory retrieval. Golgi and electron microscopy analysis revealed changes in synapse morphology indicative of increased maturation of excitatory synapses. In parallel, electrophysiological examination indicated a shift in the synaptic activity toward increased excitation as well as impairment in LTP induction. Our results demonstrate that altered balance in the expression of molecules necessary for synapse specification and development (such as NL1) can lead to defects in memory formation and synaptic plasticity and outline the importance of rigidly controlled synaptic maturation processes.

Full-text

Available from: Brian R Christie, Apr 29, 2015
2 Followers
 · 
98 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: IntroductionThe male sex chromosome disorder 47,XYY syndrome (XYY) is associated with increased risk for social-emotional difficulties, attention deficit (ADHD), and autism spectrum disorders (ASD). We hypothesize that increased Y chromosome gene copy number in XYY leads to overexpression of Y-linked genes related to brain development and function, thereby increasing risk for these phenotypes.Methods We measured expression in blood of two Y genes NLGN4Y and RPS4Y in 26 boys with XYY and 11 male controls and evaluated whether NLGN4Y expression correlates with anxiety, ADHD, depression, and autistic behaviors (from questionnaires) in boys with XYY.ResultsThe XYY cohort had increased risk of ASD behaviors on the Social Responsiveness Scale (SRS) and increased attention deficits on the Conners’ DSM-IV Inattention and Hyperactive scales. In contrast, there was no increase in reported symptoms of anxiety or depression by the XYY group. Peripheral expression of two Y genes in boys with XYY versus TD controls was increased two-fold in the XYY group. Results from the SRS Total and Autistic Mannerisms scales but not the attention, anxiety or depression measures correlated with peripheral expression of NLGN4Y in boys with XYY.Conclusions Males with XYY have social phenotypes that include increased risk for autism related behaviors and ADHD. Expression of NLGN4Y, a gene that may be involved in synaptic function, is increased in boys with XYY, and the level of expression correlates with overall social responsiveness and autism symptoms. Thus, further investigation of NLGN4Y as a plausible ASD risk gene in XYY is warranted.
    Genes Brain and Behavior 01/2015; 14(2). DOI:10.1111/gbb.12200 · 3.51 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In this review we examine the current understanding of how genetic deficits associated with neurodevelopmental disorders may impact synapse assembly. We then go on to discuss how the critical periods for these genetic deficits will shape the nature of future clinical interventions.Neuropsychopharmacology Reviews accepted article preview online, 03 July 2014; doi:10.1038/npp.2014.163.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2014; DOI:10.1038/npp.2014.163 · 7.83 Impact Factor
  • Source