Common and rare mutations in contactin-associated protein-like 2 (CNTNAP2) are strongly linked to autism, with autosomal recessive truncating mutations resulting in autism in more than two-thirds of patients. However the alterations in functional connectivity underlying CNTNAP2-associated autism are not understood. Recently our collaborators demonstrated that a knockout mouse model of CNTNAP2 shows GABAergic interneuron migration abnormalities, robust social behavioral deficits, repetitive behaviors, communication problems, and seizures, accurately modeling the human condition. Here we propose to test the hypothesis that local and long- range functional medial prefrontal cortical connectivity is altered in the CNTNAP2 model of autism and that optogenetic interventions that correct the altered connectivity will improve social behavior. Finally, as gamma- synchronization has been hypothesized to underlie the abnormal cortical function in autism, potentially serving as a biomarker for diagnosis and gauging response to treatment, we will test the hypothesis that CNTNAP2 mice show altered gamma coherence between mPFC and amygdala, leading to altered recruitment of specific interneuron types in these structures. These hypotheses will be tested using single and paired patch clamp recordings from identified pyramidal and interneurons in combination with optogenetic stimulation or silencing of specific long-range projections, both in-vitro and in-vivo. These discoveries will guide the development of circuit-specific treatments for social behavioral deficits in ASD.
Autism spectrum disorders affect over 1% of the population and cause suffering for patients and their families. Abnormal social behavior in autism may be caused by under-connectivity of specific long- range connections in the brain. This project will determine whether abnormal social behavior in a validated model of autism can be treated by functionally correcting this under-connectivity.
|Meyer, Jochen F; Golshani, Peyman; Smirnakis, Stelios M (2018) The Effect of Single Pyramidal Neuron Firing Within Layer 2/3 and Layer 4 in Mouse V1. Front Neural Circuits 12:29|
|Einstein, Michael C; Polack, Pierre-Olivier; Tran, Duy T et al. (2017) Visually Evoked 3-5 Hz Membrane Potential Oscillations Reduce the Responsiveness of Visual Cortex Neurons in Awake Behaving Mice. J Neurosci 37:5084-5098|
|Cai, Denise J; Aharoni, Daniel; Shuman, Tristan et al. (2016) A shared neural ensemble links distinct contextual memories encoded close in time. Nature 534:115-8|
|Cantero, Gloria; Liu, Xiao-Bo; Mervis, Ronald F et al. (2016) Rescue of the Functional Alterations of Motor Cortical Circuits in Arginase Deficiency by Neonatal Gene Therapy. J Neurosci 36:6680-90|
|Bakhurin, Konstantin I; Mac, Victor; Golshani, Peyman et al. (2016) Temporal correlations among functionally specialized striatal neural ensembles in reward-conditioned mice. J Neurophysiol 115:1521-32|
|Srinivasan, Rahul; Huang, Ben S; Venugopal, Sharmila et al. (2015) Ca(2+) signaling in astrocytes from Ip3r2(-/-) mice in brain slices and during startle responses in vivo. Nat Neurosci 18:708-17|
|Peñagarikano, Olga; Lázaro, María T; Lu, Xiao-Hong et al. (2015) Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism. Sci Transl Med 7:271ra8|
|Lázaro, Maria T; Golshani, Peyman (2015) The utility of rodent models of autism spectrum disorders. Curr Opin Neurol 28:103-9|
|Garcia-Junco-Clemente, Pablo; Golshani, Peyman (2014) PTEN: A master regulator of neuronal structure, function, and plasticity. Commun Integr Biol 7:e28358|
|Mantoan Ritter, Laura; Golshani, Peyman; Takahashi, Koji et al. (2014) WONOEP appraisal: optogenetic tools to suppress seizures and explore the mechanisms of epileptogenesis. Epilepsia 55:1693-702|
Showing the most recent 10 out of 12 publications