PI: Mirella Dapretto, Ph.D., Assistant Professor
Psychiatry and Biobehavioral Sciences
David Geffen School of Medicine at UCLA

Abstract and Specific Aims

Converging evidence across a number of recent investigations suggests that a dysfunctional mirror neuron system (MNS) may underlie the core deficits observed in autism spectrum disorders (ASD). In a previous functional MRI (fMRI) study, we found that high-functioning children with ASD showed no significant MNS activation during observation and imitation of emotional expressions, with MNS activity being inversely related to symptom severity in the social domain. In another recent fMRI study, we also found that ASD children could recruit normative neural networks to infer a speaker’s communicative intent if explicit instructions were provided to direct their attention to the critical information provided by the speaker’s facial expression and/or tone of voice. Here we seek to expand on these earlier findings to address the fundamental question of whether we can elicit reliable MNS activity in children with ASD by manipulating their attention via task instructions (Study 1) or through behavioral interventions (Study 2). Specifically, in the proposed studies we will again examine MNS functioning in children with ASD as they observe and imitate facial expressions. However, in Study 1 we will now explicitly direct the ASD children’s attention to the emotions being portrayed, asking them to identify how a person might feel by thinking about how they themselves feel when they make such expressions. In Study 2, we will study of second group of ASD children who previously participated in behavioral interventions and we will relate MNS activity to treatment type and post-treatment gains on key behavioral measures (e.g., imitation, joint attention).

PI: Yi Sun, Ph.D., Assistant Professor
Psychiatry and Biobehavioral Sciences
David Geffen School of Medicine at UCLA

Abstract and Specific Aims

Autism is a common neurodevelopmental disorder of complex genetic etiology. Rett syndrome is an X-linked neurodevelopmental disease caused by mutations in the Mecp2 gene that encodes a methyl-CpG binding protein. Rett syndrome has phenotypic and genetic overlap with autism, however it is unclear what cellular processes link together these two diseases. Since the identification of neuroligin 3 and 4 being autism disease genes, it has been postulated that abnormal synaptogenesis and/or synaptic dysfunction are involved in the autistic trait of both diseases. Starting in 2005, a number of reports pointed out more comprehensive similarities between autism and Rett: 1) both autism-related mutations in neuroligin and RTT mutations in Mecp2 cause an imbalance between excitation/inhibition (E/I), which is critical for neuronal function; and 2) disease mutations in either gene lead to smaller neuronal cell size and reduced dendritic volume. Importantly, ever since 2005, three other reports (one in Science, one in Nature, and one in Proceedings of the National Academy of Sciences) demonstrated that small non-coding RNAs, namely microRNAs (MiRNAs), could play critical roles in regulating both neuronal morphology and synaptic function. These findings supported our initial hypothesis that miRNAs could be major target genes for MeCP2 that are involved in regulating neuronal morphology, synaptogenesis, and synaptic function. The objective of this proposal is to profile potential changes in miRNA as well as mRNA expression due to MeCP2 deficiency by using mouse ES cell derived highly enriched Mecp2+/y and Mecp2-/y GABAergic neurons.

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