International Meeting for Autism Research: Anatomical Phenotyping in a Neuroligin3 Mouse Model of Autism Using Magnetic Resonance Imaging

Anatomical Phenotyping in a Neuroligin3 Mouse Model of Autism Using Magnetic Resonance Imaging

Friday, May 21, 2010
Franklin Hall B Level 4 (Philadelphia Marriott Downtown)
11:00 AM
J. Ellegood , Mouse Imaging Centre, The Hospital for Sick Children, Toronto, ON, Canada
J. P. Lerch , Mouse Imaging Centre, The Hospital for Sick Children, Toronto, ON, Canada
R. M. Henkelman , Mouse Imaging Centre, The Hospital for Sick Children, Toronto, ON, Canada
Background: The Neuroligins and Neurexins are synaptic cell adhesion genes, and disruptions in these genes have shown up in a wide array of Autism association studies (Jamain et al. 2003; Laumonnier et al. 2004).  Mouse models with a Neuroligin3 knockout show reduced communication skills (ultrasonic vocalizations) and a lack of social novelty preference (Radyushkin et al. 2009).  A Neuroligin3 knockdown model, which displays an approximate 90% loss of Neuroligin3, has also displayed abnormal social interaction (Tabuchi et al., 2007).

Objectives: The purpose of this study was to assess differences in neuroanatomy and white matter microstructure between the Neuroligin3 mutant and wild-type mice.

Methods: Eight male Neuroligin3 mutant (Jackson Labs #008475) fixed mouse brains and 8 male wild type (B6/129 - Jackson Labs #101045) fixed mouse brains, all 108 days old, were examined.

MRI Acquisition - A 7.0 Tesla MRI scanner (Varian Inc., Palo Alto, CA) was used to acquire anatomical images of brains within skulls as well as Diffusion Tensor Images (DTI) to assess changes in the white matter. Total imaging time for a set of 3 brains imaged in parallel was ~11 h and 16 h for the two methods, respectively.
Data Analysis – We use image registration to align a neuroanatomical atlas defining 62 separate brain regions towards each scan.  Volumes of individual structures for each mouse were calculated as percentage brain volume.  Changes in white matter were determined by registering fractional anisotropy (FA) maps to the same atlas and computing average FA values per structure.  Group differences in volume or FA were calculated using t-tests, multiple comparisons controlled using the False Discovery Rate (FDR).

Results: Significant proportional volume changes were found 19 different regions, with FDRs of < 7.5%.  Some of the notable regional changes were decreases in the corpus callosum (6.5%), fornix (6.5%), dentate gyrus of the hippocampus (9.9%), stratum granulosum of the hippocampus (12.9%), internal capsule (7.3%), striatum (3.6%), and thalamus (6.8%).  Furthermore, increases were found in the medulla (6.1%), interpeduncular nucleus (13.2%), inferior cerebellar peduncle (5.9%), and forth ventricle (21.9%).  Despite the volume changes found in many white matter structures, such as the corpus callosum, internal capsule, and fornix, there were no significant FA differences detectable in the white matter of the Neuroligin3 mouse.

Conclusions: This study highlights volumetric changes in 19 different regions in the brain of the Neuroligin3 mouse.  Furthermore, volume decreases are found in major white matter structures, such as the corpus callosum (the most significant volume difference, p-value < 0.0001, FDR < 1%), and these changes may be related to those seen previously in human autism (Alexander et al. 2007), although in that study FA decreases were also found.  A change in volume without a decrease in FA seems to indicate that while there may be a loss in size of the white matter bundles, the myelination and integrity of white matter tracts seem intact.

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