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A tough read but very intersting and a positive/hopeful outcome

Posted by on May. 21, 2011 at 10:43 PM
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  Histopathologic characterization of the BTBR mouse model of autistic-like behavior reveals selective changes in neurodevelopmental proteins and adult hippocampal neurogenesis



The inbred mouse strain, BTBR T+ tf/J (BTBR) exhibits behavioral deficits which mimic the core deficits of autism. Neuroanatomically, the BTBR strain is also characterized by a complete absence of the corpus callosum.

The goal of this study was to identify novel molecular and cellular changes in the BTBR mouse focusing on, neuronal, synaptic, glial and plasticity markers in the limbic system as a model for identifying putative molecular and cellular substrates associated with autistic behaviors. .

Methods: Forebrains of 8 to 10 week old male BTBR and aged matched C57Bl/6J controls were evaluated by immunohistochemistry using free floating and paraffin embedded sections.

Twenty antibodies directed to antigens specific to neurons, synapses and glia were used. Nissl, Timm's and acetylcholinesterase (AchE) stains were performed to assess cytoarchitecture, mossy fibers and cholinergic fiber density, respectively.

In the hippocampus, quantitative stereological estimates for the mitotic marker bromodeoxyuridine were performed to determine hippocampal progenitor proliferation, survival and differentiation and BDNF mRNA was quantified by in situ hybridization. Quantitative image analysis was performed for NG2, doublecortin, NeuroD, GAD67 and PSA-NCAM.

Results: In midline structures including the region of the absent corpus callosum of BTBR mice, myelin markers myelin basic protein (MBP) and 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) were reduced and oligodendrocyte precursor NG2 was increased.

MBP and CNPase were expressed in small ectopic white matter bundles within the cingulate cortex. Microglia and astrocytes showed no evidence of gliosis, yet orientations of glial fibers were altered in specific white matter areas.

In the hippocampus, evidence of reduced neurogenesis included significant reductions in the number of doublecortin, PSA-NCAM, and NeuroD immunoreactive cells in the subgranular zone of the dentate gyrus and a marked reduction in the number of BrdU positive progenitors Furthermore, a significant and profound reduction in BDNF mRNA in the BTBR dentate gyrus was observed. No significant differences were observed in the expression of acetylcholinesterase, mossy fiber synapses, and immunoreactivities for MAP2, parvalbumin, GAD65 and GAD67.

Conclusions: We documented modest and selective alterations in glia, neurons and synapses in BTBR forebrain, along with reduced adult hippocampal neurogenesis.

Of all markers examined, the most distinctive changes were observed in the neurodevelopmental proteins NG2, PSA-NCAM, NeuroD and doublecortin. Our results are consistent with aberrant development of the nervous system in BTBR mice and may reveal novel substrates to link callosal abnormalities and autistic behaviors.

The changes that we observed in the BTBR mice suggest potential novel therapeutic strategies for intervention in autism spectrum disorders.

Author: Diane StephensonSharon O'NeillSapna NarayanAadhya TiwariElizabeth ArnoldHarry SamarooFu DuRobert RingBrian CampbellMathew PletcherVidita VaidyaDaniel Morton
Credits/Source: Molecular Autism 2011, 2:7

by on May. 21, 2011 at 10:43 PM
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