title: Altered synchrony and connectivity in neuronal networks expressing an autism-related mutation of neuroligin 3.
abstract: The neuroligin (NL) gene family codes for brain specific cell adhesion molecules that play an important role in synaptic connectivity. Recent studies have identified NL mutations linked to patients with autism spectrum disorders (ASD). Cognitive deficits seen in autistic patients are hypothesized to arise from altered synchronicity both within and between brain regions. Here we show how the expression of autism-associated neuroligin mutation R471C-NL3 affects synchrony in dissociated cultures of rat hippocampal neurons. Spontaneous network activity patterns of cultures expressing wild type and mutant NL3 were measured by optical techniques. Firing events were quantified and compared by cross-correlation analysis. Our results suggest that NL3 overexpression enhances synchrony of spontaneous activity patterns, however, this ability is reduced with the R471C-NL3 mutation. We investigated the structural basis of this phenomenon using fractal dimension analysis to characterize the arrangement of axon trajectories. R471C-NL3 cultures were associated with lower fractal dimensions and higher lacunarity values, indicating a decrease in the complexity of axonal architecture. Transfection of R471C-NL3 into a subpopulation of cells in a network resulted in neuronal degeneration. This degeneration likely affected the inhibitory population of neurons, as there were half as many (P<0.01, n=12) glutamate decarboxylase (GAD) 65 expressing cells in R471C-NL3 cultures compared to wild type NL3 and control cultures. Electrophysiological recordings showed a reduction of inhibitory activity in networks carrying the mutation in comparison to networks overexpressing wild-type NL3. Together, these data support the hypothesis that the autism-associated NL3 mutation affects information processing in neuronal networks by altering network architecture and synchrony.
authors.affiliation: Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, ABT2N4N1, Canada.
authors.forename: R C
authors.initials: RC
authors.lastname: Gutierrez
authors.forename: J
authors.initials: J
authors.lastname: Hung
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: A C
authors.initials: AC
authors.lastname: Kertesz
authors.forename: F J
authors.initials: FJ
authors.lastname: Espina
authors.forename: M A
authors.initials: MA
authors.lastname: Colicos
mesh_terms: D000200:Action Potentials / Q000235:genetics / Q000502:physiology; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal; D002478:Cells, Cultured; D018920:Coculture Techniques; D017709:Fractals; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics / Q000503:physiopathology; D009415:Nerve Net / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009457:Neuroglia / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000235:genetics* / Q000502:physiology*; D014162:Transfection
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C098004:neuroligin 3; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2; D002118:Calcium