Hyejung Won^1,2*, Hye-Ryeon Lee^3*, Heon Yung Gee^4*, Won Mah^1,2*, Jae-Ick Kim^3*, Jiseok Lee^1,2, Seungmin Ha^1,2, Changuk Chung^1,2, Eun Suk Jung⁴, Yi Sul Cho⁵, Sae-Geun Park¹, Jung-Soo Lee⁴, Kyungmin Lee⁶, Daesoo Kim¹, Yong Chul Bae⁵, Bong-Kiun Kaang^3,7, Min Goo Lee⁴ & Eunjoon Kim^1,2,8,9

¹Department of Biological Sciences, KAIST, Daejeon 305-701, Korea. ²National Creative Research Initiative Center for Synaptogenesis, KAIST, Daejeon 305-701, Korea. ³National Creative Research Initiative Center for Memory, Department of Biological Sciences, College of Natural Sciences, Seoul National University, Gwanangno 599, Gwanak-gu, Seoul 151-747, Korea. ⁴Department of Pharmacology, Brain Korea 21 Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 120-752, Korea. ⁵Department of Oral Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu 700-412, Korea. ⁶Department of Anatomy, School of Medicine, Brain Science & Engineering Institute, Kyungpook National University, Daegu 700-412, Korea. ⁷Department of Brain and Cognitive Sciences, Seoul National University, Seoul 151-747, Korea. ⁸Graduate School of Nanoscience and Technology (World Class University), KAIST, Daejeon 305-701, Korea. ⁹Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon 305-811, Korea.
*These authors contributed equally to this work.

Correspondence to: Bong-Kiun Kaang or Min Goo Lee or Eunjoon Kim

Autism spectrum disorder (ASD) is a group of conditions characterized by impaired social interaction and communication, and restricted and repetitive behaviours. ASD is a highly heritable disorder involving various genetic determinants¹. Shank2 (also known as ProSAP1) is a multi-domain scaffolding protein and signalling adaptor enriched at excitatory neuronal synapses^2-4, and mutations in the human SHANK2 gene have recently been associated with ASD and intellectual disablility5. Although ASD-associated genes are being increasingly identified and studied using various approaches, including mouse genetics^6-16, further efforts are required to delineate important causal mechanisms with the potential for therapeutic application. Here we show that Shank2-mutant (Shank^2-/-) mice carrying a mutation identical to the ASD-associated microdeletion in the human SHANK2 gene exhibit ASD-like behaviours including reduced social interaction, reduced social communication by ultrasonic vocalizations, and repetitive jumping. These mice show a marked decrease in NMDA (N-methyl-d-aspartate) glutamate receptor (NMDAR) function. Direct stimulation of NMDARs with d-cycloserine, a partial agonist of NMDARs, normalizes NMDAR function and improves social interaction in Shank^2-/- mice. Furthermore, treatment of Shank^2-/- mice with a positive allosteric modulator of metabotropic glutamate receptor 5 (mGluR5), which enhances NMDAR function via mGluR5 activation¹⁷, also normalizes NMDAR function and markedly enhances social interaction. These results suggest that reduced NMDAR function may contribute to the development of ASD-like phenotypes in Shank^2-/- mice, and mGluR modulation of NMDARs offers a potential strategy to treat ASD.