Optogenetic treatment of social behavior in autism

Summary

Principal Investigator: PEYMAN GOLSHANI
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2013-07-11 - 2018-06-30
more information: NIH RePORT

Top Publications

  1. pmc Overexpression of calcium-activated potassium channels underlies cortical dysfunction in a model of PTEN-associated autism
    Pablo García-Junco-Clemente
    Departments of Neurobiology and Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095
    Proc Natl Acad Sci U S A 110:18297-302. 2013

Detail Information

Publications2

  1. pmc Overexpression of calcium-activated potassium channels underlies cortical dysfunction in a model of PTEN-associated autism
    Pablo García-Junco-Clemente
    Departments of Neurobiology and Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095
    Proc Natl Acad Sci U S A 110:18297-302. 2013
    ..These findings identify calcium-activated potassium channelopathy as a cause of cortical dysfunction in the PTEN model of autism and provide potential molecular therapeutic targets. ..

Research Grants35

  1. Functions of distinct interneuron subtypes in cortical dynamics and behavior
    Adam Kepecs; Fiscal Year: 2013
    ....
  2. Differential modes of cholinergic transmission onto cellular hippocampal targets
    JOHN JOSHUA LAWRENCE; Fiscal Year: 2013
    ....
  3. Connections of Inhibitory Cortical Neurons
    Edward M Callaway; Fiscal Year: 2013
    ....
  4. Prepubertal Stress, Windows of Risk &Sex Bias for Affective Disturbance
    C NEILL NEILL EPPERSON; Fiscal Year: 2013
    ..The Center would provide an intellectual platform with important resources to encourage established investigators, and their mentees, to consider sex and gender as crucial factors in their research. ..
  5. Functions of conditional Cx36-dependent electrical synapses in the neocortex
    Arthur U Sugden; Fiscal Year: 2013
    ....
  6. Activity-Dependent Synaptic and Circuit Plasticity
    Robert C Malenka; Fiscal Year: 2013
    ..Such information will lead to a better understanding of the causes of mental illness and eventually to the development of more efficacious treatments. ..
  7. Enduring Effects of Early-Life Serotonin Signaling
    Randy D Blakely; Fiscal Year: 2013
    ..abstract_text> ..
  8. Hippocampal inhibitory neuronal circuit organization
    Xiangmin Xu; Fiscal Year: 2013
    ..These studies should establish the operational rules of the major classes of inhibitory neurons within the hippocampal circuit. ..
  9. Epigenetic Mechanisms of Depression
    Eric J Nestler; Fiscal Year: 2013
    ..An improved understanding of the molecular basis of depression will lead to improved treatments and diagnostic tests - a high priority for the National Institutes of Health. ..
  10. Molecular Mechanisms of SOD1-linked ALS (P01)
    Joan Selverstone Valentine; Fiscal Year: 2013
    ..This project addresses this question for ALS in particular using some of the best advanced biophysical and biochemical methods available. ..
  11. INFORMATION PROCESSING IN THE NUCLEUS ACCUMBENS
    JOSEPH FRANCOIS RENE CHEER; Fiscal Year: 2013
    ....
  12. GABAergic regulation of entorhino-hippocampal excitability in epilepsy.
    Ivan Soltesz; Fiscal Year: 2013
    ..The project will determine whether aberrant inhibitory regulation of the entorhino-hippocampal circuits contributes to the generation of seizures. ..
  13. PLASTICITY OF GABAERGIC INHIBITION FOLLOWING HEAD INJURY
    Ivan Soltesz; Fiscal Year: 2013
    ..It is anticipated that defining the functional consequences of experimental post-traumatic epilepsy will aid in the future development of novel treatment strategies. ..
  14. MODULATION OF NEOCORTICAL INTERNEURONAL FUNCTION
    DAVID ALLAN PRINCE; Fiscal Year: 2013
    ..The long term goals are to identify critical abnormalities that might eventually be targets for selective agents that would used to prevent or treat human posttraumatic epilepsy. ..
  15. Sodium Channel Mutations that Cause Epilepsy
    Alan L Goldin; Fiscal Year: 2013
    ..These studies should enhance our knowledge concerning the physiological and pathological events leading to one genetic type of epilepsy. ..
  16. Alzheimer's Disease Research Center
    Douglas R Galasko; Fiscal Year: 2013
    ..It will provide an environment and core resources to enhance research, foster professional and community training, and coordinate interdisciplinary research. ..
  17. Novel Interneurons Mediating Feedforward Inhibition
    Ariel Agmon; Fiscal Year: 2013
    ..In this project we will study the crucial, but little-understood role played by specific subtypes of inhibitory neurons in shaping cortical responses to incoming information. ..
  18. Functional integration of inhibitory interneuron progenitors in the adult brain
    Robert F Hunt; Fiscal Year: 2013
    ..This study will provide detailed information about the synaptic connectivity of GABAergic progenitor cells after transplant into the adult brain. ..
  19. Hippocampal Interneuron Network Dynamics After Epileptogenesis
    PEYMAN GOLSHANI; Fiscal Year: 2013
    ....
  20. CRCNS: Gamma Rhythms and Cell Assemblies
    Nancy Kopell; Fiscal Year: 2013
    ..Finally, the specific project will also help train two graduate students and a postdoctoral fellow. ..
  21. Alcoholic liver disease: Biochemical, cellular and systemic responses to ethanol
    Laura E Nagy; Fiscal Year: 2013
    ....
  22. Stem Cell Transplantation for Epilepsy
    JANICE RAE NAEGELE; Fiscal Year: 2013
    ..4: Measure inhibitory post-synaptic currents in retrovirally-labeled populations of GCs by patch-clamp electrophysiological recordings in hippocampal slices from mice with transplants of mPSC-derived MGE-like basal forebrain cells. ..
  23. Neurotransmitter Actions in the Neocortex and Thalamus
    David A McCormick; Fiscal Year: 2013
    ....
  24. Mechanisms of Valproic Acid-Induced Neurodevelopmental and Behavioral Defects
    Elizabeth M Powell; Fiscal Year: 2013
    ....
  25. Morphogenesis and function of the cerebral cortex
    Flora M Vaccarino; Fiscal Year: 2013
    ..Both aspects may offer promising leads to correct or reverse the excitatory and inhibitory neuron imbalances that are present in the cerebral cortex of neuropsychiatric and impulse control disorders. ..
  26. INTERNEURON BASED MECHANISMS OF TEMPORAL LOBE EPILEPSY
    Paul S Buckmaster; Fiscal Year: 2013
    ..Seizures might be caused by inadequate inhibition. This project will investigate in detail how and why inhibition is abnormal in dentate gyrus of a rat model of epilepsy. ..