Related Experiment Video
Updated: Mar 15, 2026
Dissection of Hippocampal Dentate Gyrus from Adult Mouse
Published on: November 17, 2009
Altered Cortical Dynamics and Cognitive Function upon Haploinsufficiency of the Autism-Linked Excitatory Synaptic
Steven A Connor1, Ina Ammendrup-Johnsen2, Allen W Chan1
1Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada; Brain Research Centre and Department of Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
Abstract:
Mutations in a synaptic organizing pathway contribute to autism. Autism-associated mutations in MDGA2 (MAM domain containing glycosylphosphatidylinositol anchor 2) are thought to reduce excitatory/inhibitory transmission. However, we show that mutation of Mdga2 elevates excitatory transmission, and that MDGA2 blocks neuroligin-1 interaction with neurexins and suppresses excitatory synapse development. Mdga2(+/-) mice, modeling autism mutations, demonstrated increased asymmetric synapse density, mEPSC frequency and amplitude, and altered LTP, with no change in measures of inhibitory synapses. Behavioral assays revealed an autism-like phenotype including stereotypy, aberrant social interactions, and impaired memory. In vivo voltage-sensitive dye imaging, facilitating comparison with fMRI studies in autism, revealed widespread increases in cortical spontaneous activity and intracortical functional connectivity. These results suggest that mutations in MDGA2 contribute to altered cortical processing through the dual disadvantages of elevated excitation and hyperconnectivity, and indicate that perturbations of the NRXN-NLGN pathway in either direction from the norm increase risk for autism.
Insights
Mutations in the MDGA2 gene elevate excitatory transmission, leading to autism-like behaviors and altered brain activity in mice. This suggests disruptions in synaptic pathways increase autism risk.
Area of Science:
- Neuroscience
- Genetics
- Autism Research
Background:
- Autism-associated mutations in MDGA2 are hypothesized to reduce excitatory/inhibitory transmission.
- The precise role of MDGA2 in synaptic function and its link to autism remains incompletely understood.
Purpose of the Study:
- To investigate the functional consequences of MDGA2 mutations on synaptic transmission and neuronal activity.
- To determine if MDGA2 mutations contribute to an autism-like phenotype in a mouse model.
Main Methods:
- Utilized Mdga2(+/-) mice modeling human autism mutations.
- Assessed synaptic transmission via electrophysiology (mEPSC frequency and amplitude, LTP).
- Conducted behavioral assays and in vivo voltage-sensitive dye imaging of cortical activity.
Main Results:
- Mdga2 mutation elevated excitatory transmission, increasing asymmetric synapse density and mEPSC frequency/amplitude.
- Mdga2(+/-) mice exhibited autism-like behaviors (stereotypy, social deficits, memory impairment).
- Cortical imaging revealed increased spontaneous activity and functional connectivity, with no changes in inhibitory synapses.
Conclusions:
- MDGA2 mutations contribute to autism by elevating excitation and promoting hyperconnectivity.
- Dysregulation of the neurexin-neuroligin pathway, in either direction, increases autism risk.
More Related Videos
07:03Evaluation of Hemisphere Lateralization with Bilateral Local Field Potential Recording in Secondary Motor Cortex of Mice
Published on: July 31, 2019
07:43Immunohistochemical Visualization of Hippocampal Neuron Activity After Spatial Learning in a Mouse Model of Neurodevelopmental Disorders
Published on: May 12, 2015