Autism is a severe neurodevelopmental disorder characterized by impairments in social interaction and communication. Rates of autism have exploded over the past decade and it is now estimated that 1 out of every 166 children exhibit some form of autism. The neuropathological cause of autism remains elusive, though a strong genetic contribution is evident from the 60%-92% concordance between monozygotic twins versus 0-10% in dizogtic twins. Research in human populations indicates that the number of loci associated with autism exceeds 15. Of specific relevance to this proposal is the phosphatase and tensin homologe (Pten). This oncogene regulates the growth of post-mitotic neurons. The PTEN signaling pathway is emerging as one of two major pathways that regulate the susceptibility to autism spectrum disorders. Mice with a cortical Pten deletion exhibit many of the characteristics associated with autism, including macrocephaly, deficits in social interactions, impaired social learning, hyperactivity, and increased anxiety-like behavior. Many of these deficits are reversible with chronic treatment of the mTOR inhibitor, rapamycin. In this proposal, we employ mice in which the Pten gene is deleted specifically from the cortex by CRE-mediated excision beginning some 6-8 weeks after birth. We recently demonstrated that cortical layer 2/3 pyramidal neurons experience a unique growth of their apical dendrites following PTEN deletion. This growth expands the apical dendritic tree by upwards of 1mm and adds hundreds of new dendritic spines. Our goal is to fully characterize any changes in basic physiology and sensory information processing in these growing neurons. To this end we use 2-photon laser scanning microscopy to guide the placement of in vivo whole cell patch recordings from growing neurons in the mouse primary visual cortex. We also use 2-photon imaging to image network activity in the cortex of knockout and wildtype mice. Results from these studies may provide targets for the development of rationally based therapeutics for autism spectrum disorders.
The PTEN signaling pathway is emerging as one of two major pathways that regulate the susceptibility to autism spectrum disorders. We earlier characterized robust changes in dendritic structure in conditional knockout mice. Here we measure changes in physiology and sensory processing in these growing neurons using in vivo whole cell patch recordings and 2-photon in vivo imaging of network activity.
|Garcia-Junco-Clemente, Pablo; Chow, David K; Tring, Elaine et al. (2013) Overexpression of calcium-activated potassium channels underlies cortical dysfunction in a model of PTEN-associated autism. Proc Natl Acad Sci U S A 110:18297-302|