| Abstract No.: | C-B3061 |
| Country: | Canada |
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| Title: | SYNAPTIC IMBALANCE, STEREOTYPIES AND IMPAIRED SOCIAL INTERACTIONS IN MICE WITH ALTERED NEUROLIGIN 2 EXPRESSION |
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| Authors/Affiliations: | 1 Rochelle Hines*; 3 Longjun Wu; 1 Dustin Hines; 3 Hendrik Steenland; 1 Regina Dahlhaus; 1 Roshni Singaraja; 2 Esther Sammler; 2 Sheriar Hormuzdi; 3 Min Zhuo;
1 University of British Columbia, Vancouver, BC, Canada; 2 University of Dundee, United Kingdom; 3 University of Toronto, ON, Canada
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| Content: | Synapse maturation is a critical step in generation of the complex networks needed for proper function of the central nervous system. The importance of tight regulation of synapse formation and maturation can be gleaned from the number of disorders arising from alterations to synapses. Excitatory synaptic transmission is driven mainly by glutamatergic synapses, whereas inhibitory synaptic transmission involves GABAergic and glycinergic signalling. A functional “balance” between excitatory and inhibitory synapses (E/I ratio) is established during development and maintained throughout life. However, the molecular machinery regulating the E/I ratio remains unclear. Neuroligin (NL) adhesion molecules are thought to be key regulators of the E/I ratio, and NL family members are differentially enriched at either excitatory (NL1,3) or inhibitory (NL2) contacts. Further, mutations in NLs have been implicated in neurodevelopmental disorders such as autism. Objective: The present experiments examine the influence of NL1 and NL2 expression on synapse morphology, E/I synaptic ratio, and behaviour. Methods: In this study we use transgenic mouse models expressing NL1 or NL2 under control of the neuron specific Thy 1 promoter. We use Western blotting, immunohistochemistry and electron microscopy to assess changes in excitatory and inhibitory synaptic protein levels, synapse morphology and density, and the E/I ratio. Electrophysiology and freely-moving EEG recordings are used to assess funcitonal changes in synaptic transmission resulting from NL expression. In addition, behavioural assessments are used to evaluate autism-related phenotypes of impaired social interaction and stereotypies, as well as some accessory features of this disorder. Results: Our analysis reveals striking differences in mice expressing NL2, not observed with expression of NL1. A change in NL2 expression results in enlarged synaptic contact size and vesicle reserve pool, and an overall reduction in the E/I synaptic ratio. Mice expressing NL2 also demonstrated spontaneous stereotyped jumping behaviour, impaired social interactions, anxiety, and enhanced incidence of spike-wave discharges, all of which are hallmarks of neurodevelopmental disorders. Conclusion: Altering NL2 expression results in changes in the E/I ratio, leading to functional changes in synaptic transmission and behavioural abnormalities. The behavioural abnormalities observed in mice expressing NL2 recapitulate multiple aspects of neurodevelopmental disorders such as autism. Taken together, these findings provide insights into the neural basis for synaptic imbalance and altered behaviour associated with autism. |
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