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Modeling neurodevelopmental disorders : expression of neuroligin adhesion molecules in vivo Hines, Rochelle M.

Abstract

At post synaptic sites, the neuroligin (NL) family of proteins is thought to play an important role in synapse maturation, and regulation of excitatory and inhibitory synapses. Being selectively enriched at either excitatory (NL1,3) or inhibitory (NL2) synapses, NL’s have been shown to regulate the ratio of excitation to inhibition (E/I ratio), a process critical for normal brain development. In addition, NLs have been linked to neurodevelopmental disorders through genetic studies. To advance our understanding of synaptic regulation by NLs, and their potential role in synaptic dysfunciton in neurodevelopmental disorders, we have developed strains of transgenic mice which overexpress either HA tagged-NL1, or -NL2 under control of the Thy1 promoter. Detailed behavioural analysis of TgNL2 mice revealed anxiety, stereotyped jumping behaviour, and impairments in social approach and reciprocal social interactions. These animals also displayed fronto-parietal seizure activity as shown by chronic in vivo EEG recording. Synapse analysis in TgNL2 frontal cortex revealed changes in the number and morphology of synapses compared to wildtype littermates. A small change in NL2 expression results in enlarged synaptic contact size and vesicle reserve pool and an overall reduction in the E/I ratio. In addition, the frequency of miniature inhibitory synaptic currents was also found to be increased in the frontal cortex of TgNL2 mice. Behavioural assessment of TgNL1 mice revealed deficits in memory acquisition and retrieval in water maze paradigms. 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 E/I ratio towards increased excitation. Further experiments revealed impairment in the induction of long term potentiation. These data demonstrate that altered expression of members of the NL family in vivo leads to altered synapse number and morphology, which potentially underlies the profound behavioural changes. We also observed a predominant effect of NL2 expression on inhibitory synapses, with NL1 primarily influencing excitatory synapses, supporting the idea that NL’s may act to regulate the E/I ratio. In addition this data may provide insight into the pathology and symptoms of neurodevelopmental disorders such as autism thought be be caused by synaptic abnormalities.

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