title: White matter loss in a mouse model of periventricular leukomalacia is rescued by trophic factors.
abstract: Periventricular leukomalacia (PVL) is the most frequent cause of cerebral palsy and other intellectual disabilities, and currently there is no treatment. In PVL, glutamate excitotoxicity (GME) leads to abnormal oligodendrocytes (OLs), myelin deficiency, and ventriculomegaly. We have previously identified that the combination of transferrin and insulin growth factors (TSC1) promotes endogenous OL regeneration and remyelination in the postnatal and adult rodent brain. Here, we produced a periventricular white matter lesion with a single intracerebral injection of N-methyl-d-aspartate (NMDA). Comparing lesions produced by NMDA alone and those produced by NMDA + TSC1 we found that: NMDA affected survival and reduced migration of OL progenitors (OLPs). In contrast, mice injected with NMDA + TSC1 proliferated twice as much indicating that TSC1 supported regeneration of the OLP population after the insult. Olig2-mRNA expression showed 52% OLP survival in mice receiving a NMDA injection and increased to 78% when TSC1 + NMDA were injected simultaneously and ventricular size was reduced by TSC1. Furthermore, in striatal slices TSC1 reduced the inward currents induced by NMDA in medium-sized spiny neurons, demonstrating neuroprotection. Thus, white matter loss after excitotoxicity can be partially rescued as TSC1 conferred neuroprotection to preexisting OLP and regeneration via OLP proliferation. Furthermore, we showed that early TSC1 administration maximizes neuroprotection.
authors: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry, University of California Los Angeles, Los Angeles, CA 90095, USA. aespinosa@mednet.ucla.edu.
authors: Araceli
authors: A
authors: Espinosa-Jeffrey
authors: University Center for Biological and Agricultural Sciences, University of Guadalajara, Guadalajara 44100, Mexico. barajasmercado@yahoo.com.mx.
authors: Socorro A R
authors: SA
authors: Barajas
authors: University Center for Biological and Agricultural Sciences, University of Guadalajara, Guadalajara 44100, Mexico. aracafar@yahoo.com.mx.
authors: Alfonso R
authors: AR
authors: Arrazola
authors: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry, University of California Los Angeles, Los Angeles, CA 90095, USA. at.miyori@gmail.com.
authors: Alana
authors: A
authors: Taniguchi
authors: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry, University of California Los Angeles, Los Angeles, CA 90095, USA. zhaoyang17@yahoo.com.
authors: Paul M
authors: PM
authors: Zhao
authors: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry, University of California Los Angeles, Los Angeles, CA 90095, USA. payambokhoor@ucla.edu.
authors: Payam
authors: P
authors: Bokhoor
authors: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry, University of California Los Angeles, Los Angeles, CA 90095, USA. sholley@mednet.ucla.edu.
authors: Sandra M
authors: SM
authors: Holley
authors: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry, University of California Los Angeles, Los Angeles, CA 90095, USA. dpdejarme@gmail.com.
authors: Don P
authors: DP
authors: Dejarme
authors: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry, University of California Los Angeles, Los Angeles, CA 90095, USA. aznhistrymaker@gmail.com.
authors: Brian
authors: B
authors: Chu
authors: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry, University of California Los Angeles, Los Angeles, CA 90095, USA. ccepeda@mednet.ucla.edu.
authors: Carlos
authors: C
authors: Cepeda
authors: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry, University of California Los Angeles, Los Angeles, CA 90095, USA. mlevine@mednet.ucla.edu.
authors: Michael S
authors: MS
authors: Levine
authors: French Institute of Health and Medical Research (INSERM), U676, Robert Debré Hospital, Paris 75019, France. pierre.gressens@inserm.fr.
authors: Pierre
authors: P
authors: Gressens
authors: University Center for Biological and Agricultural Sciences, University of Guadalajara, Guadalajara 44100, Mexico.
authors: Alfredo
authors: A
authors: Feria-Velasco
authors: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry, University of California Los Angeles, Los Angeles, CA 90095, USA. jdevellis@mednet.ucla.edu.
authors: Jean
authors: J
authors: de Vellis