Altered functional connectivity networks in acallosal and socially impaired BTBR mice
Agenesis of the corpus callosum (AgCC) is a congenital condition associated with wide-ranging emotional and social impairments often overlapping with the diagnostic criteria for autism. Mapping functional connectivity in the acallosal brain can help identify neural correlates of the deficits associated with this condition, and elucidate how congenital white matter alterations shape the topology of large-scale functional networks. By using resting-state BOLD functional magnetic resonance imaging (rsfMRI), here we show that acallosal BTBR T+tpr3tf/J (BTBR) mice, an idiopathic model of autism, exhibit impaired intra-hemispheric connectivity in fronto-cortical, but not in posterior sensory cortical areas. We also document profoundly altered subcortical and intra-hemispheric connectivity networks, with evidence of marked fronto-thalamic and striatal disconnectivity, along with aberrant spatial extension and strength of ipsilateral and local connectivity. Importantly, inter-hemispheric tracing of monosynaptic connections in the primary visual cortex using recombinant rabies virus confirmed the absence of direct homotopic pathways between posterior cortical areas of BTBR mice, suggesting a polysynaptic origin for the synchronous rsfMRI signal observed in these regions. Collectively, the observed long-range connectivity impairments recapitulate hallmark neuroimaging findings in autism, and are consistent with the behavioral phenotype of BTBR mice. In contrast to recent rsfMRI studies in high functioning AgCC individuals, the profound fronto-cortical and subcortical disconnectivity mapped suggest that compensatory mechanism may not necessarily restore the full connectional topology of the brain, resulting in residual connectivity alterations that serve as plausible substrates for the cognitive and emotional deficits often associated with AgCC.
KeywordsfMRI Connectivity Autism Corpus callosum BTBR Mouse retrograde tracing
The study was funded by the Istituto Italiano di Tecnologia, and supported by Italian Ministry of Health “Young investigators” GR3-2008 (MLS) and by a grant from the Simons Foundation (SFARI 314688, A.G.). We thank Dr. Angelo Bifone for critically reading the manuscript and Dr. E. Callaway for providing SADΔG-mCherry Rabies Virus and other reagents.
Conflict of interest
The authors declare that they have no conflict of interest.
All in vivo studies were conducted in accordance with the Italian law (DL 116, 1992 Ministero della Sanità, Roma) and the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Animal research protocols were also reviewed and consented to by the animal care committee of the Istituto Italiano di Tecnologia (permit 2007–2012). All surgical procedures were performed under anesthesia.
- Boly M, Tshibanda L, Vanhaudenhuyse A, Noirhomme Q, Schnakers C, Ledoux D, Boveroux P, Garweg C, Lambermont B, Phillips C, Luxen A, Moonen G, Bassetti C, Maquet P, Laureys S (2009) Functional connectivity in the default network during resting state is preserved in a vegetative but not in a brain dead patient. Hum Brain Mapp 30:2393–2400CrossRefPubMedGoogle Scholar
- Cherkassky VL, Kana RK, Keller TA, Just MA (2006) Functional connectivity in a baseline resting-state network in autism. Neuro Rep 17:1687–1690Google Scholar
- Ebisch SJ, Gallese V, Willems RM, Mantini D, Groen WB, Romani GL, Buitelaar JK, Bekkering H (2010) Altered intrinsic functional connectivity of anterior and posterior insula regions in high-functioning participants with autism spectrum disorder. Hum Brain Mapp 32:1013–1028CrossRefPubMedGoogle Scholar
- Jones-Davis DM, Yang M, Rider E, Osbun NC, da Gente GJ, Li J, Katz AM, Weber MD, Sen S, Crawley J, Sherr EH (2013) Quantitative trait loci for interhemispheric commissure development and social behaviors in the BTBR T+ tf/J mouse model of autism. PLoS One 8:e61829CrossRefPubMedPubMedCentralGoogle Scholar
- Miller VM, Gupta D, Neu N, Cotroneo A, Boulay CD, Seegal RF (2013) Novel inter-hemispheric white matter connectivity in the BTBR mouse model of autism. pp 26–33Google Scholar
- Paxinos G, Franklin K (2003) The mouse brain in stereotaxic coordinates. Academic Press, SydneyGoogle Scholar
- Rinaldi T, Perrodin C, Markram H (2008) Hyper-connectivity and hyper-plasticity in the medial prefrontal cortex in the valproic acid animal model of autism. Frontiers in Neural Circuits 2Google Scholar
- Sannino T, Gozzi A, Cerasa A, Schegga D, Manago F, Damiano M, Galbusera A, Dodero L, Tonelli D, Bifone A, Tsaftaris AS, Weinberger DR, Spalletta G, Papaleo F (2013) Sexual dimorphisms in COMT modulation of cortical anatomy and behavior in mice and humans. Cereb Cortex (ahead of print)Google Scholar
- Silverman JL, Tolu SS, Barkan CL, Crawley JN (2009) Repetitive self-grooming behavior in the BTBR mouse model of autism is blocked by the mGluR5 antagonist MPEP. NeuropsychopharmacologyGoogle Scholar
- Silverman JL, Smith DG, Rizzo SJ, Karras MN, Turner SM, Tolu SS, Bryce DK, Smith DL, Fonseca K, Ring RH, Crawley JN (2012) Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism. Sci Trans Med 4:131ra51CrossRefGoogle Scholar
- Silverman JL, Gastrell PT, Karras MN, Solomon M, Crawley JN (2013) Cognitive abilities on transitive inference using a novel touchscreen technology for mice. Cereb Cortex. doi: 10.1093/cercor/bht293
- Squillace M, Dodero L, Federici M, Migliarini S, Errico F, Napolitano F, Krashia P, Di Maio A, Galbusera A, Bifone A, Scattoni ML, Pasqualetti M, Mercuri NB, Usiello A, Gozzi A (2014) Dysfunctional dopaminergic neurotransmission in asocial BTBR mice. Trans Psychiatry (in press)Google Scholar
- Yizhar O, Fenno LE, Prigge M, Schneider F, Davidson TJ, ‘Shea DJ, Sohal VS, Goshen I, Finkelstein J, Paz JT, Stehfest K, Fudim R, Ramakrishnan C, Huguenard JR, Hegemann P, Deisseroth K (2011) Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 477:171–178Google Scholar
- Zikopoulos B, Barbas H (2013) Altered neural connectivity in excitatory and inhibitory cortical circuits in autism. Frontiers in human neuroscience 7Google Scholar