The parvalbumin/somatostatin ratio is increased in Pten mutant mice and by human PTEN ASD alleles.
Mutations in the phosphatase PTEN are strongly implicated in autism spectrum disorder (ASD). Here, we investigate the function of Pten in cortical GABAergic neurons using conditional mutagenesis in mice. Loss of Pten results in a preferential loss of SST(+) interneurons, which increases the ratio of parvalbumin/somatostatin (PV/SST) interneurons, ectopic PV(+) projections in layer I, and inhibition onto glutamatergic cortical neurons. Pten mutant mice exhibit deficits in social behavior and changes in electroencephalogram (EEG) power. Using medial ganglionic eminence (MGE) transplantation, we test for cell-autonomous functional differences between human PTEN wild-type (WT) and ASD alleles. The PTEN ASD alleles are hypomorphic in regulating cell size and the PV/SST ratio in comparison to WT PTEN. This MGE transplantation/complementation assay is efficient and is generally applicable for functional testing of ASD alleles in vivo.
Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94158, USA; Nina Ireland Laboratory of Developmental Neurobiology, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: daniel.vogt@ucsf.edu.
Daniel
D
Vogt
Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94158, USA; Center for Integrative Neuroscience, University of California, San Francisco, San Francisco, CA 94143, USA; Sloan-Swartz Center for Theoretical Neurobiology, University of California, San Francisco, San Francisco, CA 94143, USA.
Kathleen K A
KKA
Cho
Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94158, USA; Center for Integrative Neuroscience, University of California, San Francisco, San Francisco, CA 94143, USA; Sloan-Swartz Center for Theoretical Neurobiology, University of California, San Francisco, San Francisco, CA 94143, USA.
Anthony T
AT
Lee
Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94158, USA; Center for Integrative Neuroscience, University of California, San Francisco, San Francisco, CA 94143, USA; Sloan-Swartz Center for Theoretical Neurobiology, University of California, San Francisco, San Francisco, CA 94143, USA.
Vikaas S
VS
Sohal
Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94158, USA; Neuroscience Program, University of California, San Francisco, San Francisco, CA 94158, USA; Nina Ireland Laboratory of Developmental Neurobiology, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: john.rubenstein@ucsf.edu.
John L R
JLR
Rubenstein
D000483:Alleles; D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics*; D002452:Cell Count; D016923:Cell Death; D049109:Cell Proliferation; D048430:Cell Shape; D004569:Electroencephalography; D059330:GABAergic Neurons / Q000378:metabolism; D065818:Gamma Rhythm; D006801:Humans; D019426:Integrases / Q000378:metabolism; D007395:Interneurons / Q000378:metabolism; D007398:Interpersonal Relations; D008473:Median Eminence / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics*; D058953:Neural Stem Cells / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D010320:Parvalbumins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism; D015398:Signal Transduction; D013004:Somatostatin / Q000378:metabolism*
D010320:Parvalbumins; D013004:Somatostatin; D051057:Proto-Oncogene Proteins c-akt; C045073:Cre recombinase; D019426:Integrases; D051059:PTEN Phosphohydrolase