Suzanne O. Nolan, Taylor S. Jefferson, Conner D. Reynolds, Gregory D. Smith, Andrew J. Holley and Joaquin N. Lugo*
Background: Loss of the Pten (phosphatase and tensin homolog) gene has been demonstrated to result in hyperactivation of the mammalian target of rapamycin (mTOR) pathway, a signaling pathway common to many disease etiologies, including tuberous sclerosis complex, Fragile X syndrome, and schizophrenia. Previous studies have focused on the impact of hyperactivation of the mTOR pathway in hippocampus and cortex and behaviors among those structures, but little is known about the relationship of Pten and mTOR signaling in the development and function of the cerebellum.Objective: The purpose of this investigation was to examine cerebellar levels of several molecular signaling pathways, including PI3K/AKT/mTOR signaling and markers of neuronal migration, following loss of Pten in a subset of neurons, as well as the accompanying behavior phenotype. Methods: Motor coordination and learning was measured by the sticker removal task, the accelerating rotarod, and spontaneous activity in a cylinder. Western blots were conducted on cerebellar tissue samples. Results: We demonstrated that neuron-specific deletion of Pten (NS-Pten) in mice led to deficits in motor coordination. These changes were accompanied by alterations in many different proteins, including the PI3K/AKT/mTOR signaling pathway, FMRP, glutamate receptors and neuronal migration markers. Conclusions: These data firstly support a role for hyperactivation of mTOR in the cerebellum following loss of Pten, accompanied by behavioral deficits. Moreover, the results of the current study support a broader role for Pten signaling in early neuronal migration and organization of the cerebellum, and point to a putative role for Pten for many neuropsychiatric conditions.
Motor coordination, cerebellum, mouse genetics, focal cortical dysplasia, mTOR signaling, Dab1
Department of Psychology and Neuroscience, Baylor University, Waco, TX 76798, Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, Texas College of Osteopathic Medicine, University of North Texas Health Science Center, Fort Worth, TX 76107, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90024, Department of Psychology and Neuroscience, Baylor University, Waco, TX 76798, Department of Psychology and Neuroscience, Baylor University, Waco, TX 76798