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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    719—Genetic Models of Autism in Animals

    Wednesday, November 13, 2013, 8:00 am - 12:00 noon

    719.12: Intrinsic excitability defects in specific subtypes of medial prefrontal cortex pyramidal neurons in a mouse model of autism

    Location: Halls B-H

    *A. C. BRUMBACK1, V. S. SOHAL2;
    1Pediatric Neurol., 2Psychiatry, Univ. of California, San Francisco, San Francisco, CA

    Abstract Body: Autism, like many neuropsychiatric disorders, involves abnormal electrical activity in the brain. A leading hypothesis is that this abnormal activity results from an imbalance between neuronal excitation and inhibition. One main hypothesis for the proposed imbalance is that there is long-range hypoconnectivity but local hyperconnectivity in cortical microcircuits.
    Many of the major output neurons of cortex are located in Layer 5 (L5), and our lab recently showed that L5 of medial prefrontal cortex (mPFC) contains at least two distinct subpopulations of pyramidal neurons: “Type A” cells project subcortically, have prominent hyperpolarization-activated currents (Ih), thick-tufted apical dendrites, and express dopamine D2 receptors, whereas “Type B” neurons project to the contralateral cortex, have small Ih currents, thin-tufted apical dendrites, and lack D2 receptors. We hypothesize that in autism, the proposed pathological changes do not come about via global changes in the overall level of cortical excitation or inhibition, but rather reflect an imbalance of activity between these two subtypes of cortical pyramidal neurons.
    We performed whole cell current clamp recordings from mPFC L5 Type A and B cells in acute brain slices from adult mice exposed to valproate or saline in utero at embryonic day 10.5. We found that in the prenatal valproate exposure mouse model of autism (“VPA mice”), there is a defect in action potential generation in the cortically projecting (Type B) mPFC neurons but not the subcortically projecting (Type A) cells. In addition, we found that in VPA mice, Type A but not Type B cells had decreased frequency of action potentials in response to injected current. By elucidating how these subtype-specific cellular alterations relate to synaptic, EEG, and behavioral abnormalities, our studies may lead to new ways of understanding neuronal circuit dysfunction in autism.

    Lay Language Summary: Our research shows that in autism, specific types of brain cells are less active than in the normal brain. Specifically, the neurons that allow the two halves of the brain to communicate with each other do not work properly. In addition, in the autistic brain, the neurons that allow the surface layers of the brain to communicate with deeper regions are abnormal.
    Autism is a common neuropsychiatric disorder that affects up to 1 in 100 people. It is a lifelong condition that begins in early childhood. Individuals with autism are disabled in interacting with other people using words and body language. People with autism also have restricted, repetitive interests and behaviors. Autism is a brain disorder, but surprisingly little is known about how the nerves of the autistic brain work differently than the nerves of the typically developing brain. Our research suggests that in the autistic brain, there are changes in certain groups of neurons that affect the way the brain functions. These cellular defects could be a target for drug therapy in autism.
    We tested the hypothesis that in autism, neurons in specific brain circuits have abnormal electrical activity. We used a drug exposure model of autism to study this in rodents. Prenatal mice were exposed to the anticonvulsant valproic acid in utero. Work by other groups has shown that when these drug-exposed mice grow up to be adults, they exhibit the core features of autism (deficits in social communication, and restricted, repetitive interests and behaviors). We measured the electrical activity of neurons in the prefrontal cortex region of the brains of these mice, and found that the neurons that communicate with the opposite side of the brain do not produce normal electrical signals. In addition, our results show other neurons in the same region that communicate with deeper structures of the brain respond abnormally to stimulation.
    Previous work using functional imaging and electroencephalography (EEG) has demonstrated that in the autistic brain, the prefrontal cortex is not connected normally to the rest of the brain. Our results are the first to demonstrate that there are defects in specific brain circuits at the level of individual neurons.
    Future work will help understand how defects in these specific neuronal circuits may cause the disabilities in social communication of autism and ultimately may lead to new therapies for the core features of this prevalent neuropsychiatric disorder.