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Intrinsic Excitability Defects in Specific Subtypes of Medial Prefrontal Cortex Pyramidal Neurons in a Mouse Model of Autism

Saturday, May 17, 2014
Atrium Ballroom (Marriott Marquis Atlanta)
A. C. Brumback1 and V. S. Sohal2, (1)Child Neurology, University of California, San Francisco, San Francisco, CA, (2)Psychiatry, University of California, San Francisco, San Francisco, CA
Background: 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 underconnectivity 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. 

Objectives:  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. 

Methods:  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.  

Results:  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 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.

Conclusions:  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.

See more of: Animal Models
See more of: Animal Models