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The Journal of Neuroscience, June 11, 2008, 28(24):6055-6067; doi:10.1523/JNEUROSCI.0032-08.2008

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Cellular/Molecular
Synaptic Imbalance, Stereotypies, and Impaired Social Interactions in Mice with Altered Neuroligin 2 Expression

Rochelle M. Hines,^1 * Longjun Wu,^2 * Dustin J. Hines,¹ Hendrik Steenland,² Souraya Mansour,¹ Regina Dahlhaus,¹ Roshni R. Singaraja,³ Xiaoyan Cao,² Esther Sammler,⁴ Sheriar G. Hormuzdi,⁴ Min Zhuo,² and Alaa El-Husseini¹

¹Department of Psychiatry, Brain Research Centre, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada V6T 2B5, ²Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8, ³Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4, and ⁴Department of Neurology, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom

Correspondence should be addressed to Rochelle M. Hines, 2255 Wesbrook Mall, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3. Email: rbruneau{at}interchange.ubc.ca

The level of excitation in the brain is kept under control through inhibitory signals mainly exerted by GABA neurons. However, the molecular machinery that regulates the balance between excitation and inhibition (E/I) remains unclear. Candidate molecules implicated in this process are neuroligin (NL) adhesion molecules, which are differentially enriched at either excitatory or inhibitory contacts. In this study, we use transgenic mouse models expressing NL1 or NL2 to examine whether enhanced expression of specific NLs results in synaptic imbalance and altered neuronal excitability and animal behavior. Our analysis reveals several abnormalities selectively manifested in transgenic mice with enhanced expression of NL2 but not NL1. A small change in NL2 expression results in enlarged synaptic contact size and vesicle reserve pool in frontal cortex synapses and an overall reduction in the E/I ratio. The frequency of miniature inhibitory synaptic currents was also found to be increased in the frontal cortex of transgenic NL2 mice. These animals also manifested stereotyped jumping behavior, anxiety, impaired social interactions, and enhanced incidence of spike-wave discharges, as depicted by EEG analysis in freely moving animals. These findings may provide the neural basis for E/I imbalance and altered behavior associated with neurodevelopmental disorders.

Key words: neuroligin; transgenic; synapse; excitatory/inhibitory ratio; neurodevelopmental disorder; autism

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Received Jan. 4, 2008; revised April 29, 2008; accepted April 30, 2008.

Correspondence should be addressed to Rochelle M. Hines, 2255 Wesbrook Mall, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3. Email: rbruneau{at}interchange.ubc.ca

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