International Meeting for Autism Research: Changes In Proteolytic Processing Lead to Increased Pro-Brain-Derived Neurotrophic Factor Levels In Fusiform Gyrus of Subjects with Autism

Changes In Proteolytic Processing Lead to Increased Pro-Brain-Derived Neurotrophic Factor Levels In Fusiform Gyrus of Subjects with Autism

Thursday, May 12, 2011
Elizabeth Ballroom E-F and Lirenta Foyer Level 2 (Manchester Grand Hyatt)
3:00 PM
M. Fahnestock1,2, K. L. Garcia1, G. Yu1, B. Michalski1, D. J. Garzon1, V. S. Chiu3, E. Tongiorgi4 and P. Szatmari5, (1)Psychiatry & Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada, (2)Dept. of Biology, McMaster University, Hlamilton, ON, Canada, (3)Biology, McMaster University, Hamilton, ON, Canada, (4)BRAIN Center for Neuroscience, Department of Life Sciences, University of Trieste, Trieste, Italy, (5)Offord Centre for Child Studies, McMaster University, Hamilton, ON, Canada

Recent genetic studies suggest defects in synaptic development and plasticity may lead to autism.  Brain-derived neurotrophic factor (BDNF) is secreted at synapses in an activity-dependent fashion and plays a critical role in synaptogenesis, differentiation of excitatory and inhibitory circuits, synaptic function and plasticity.  BDNF is synthesized as a large precursor, proBDNF, which can be processed into either a truncated form or into mature BDNF, which is neurotrophic.  ProBDNF and mature BDNF have opposing activities and roles in the brain, but truncated BDNF has unknown biological activity.  Previous studies reported increased BDNF-immunoreactive protein in autism, although neither the mechanism of this increase nor the responsible BDNF protein isoform was investigated.


The purpose of this study was to compare BDNF mRNA and protein isoforms in post mortem brain tissue from autism and control subjects. 


Fusiform gyrus is a cortical area that has been implicated in the impairments in face recognition and perception of autism.  We assayed BDNF mRNA using real-time RT-PCR in fusiform gyrus from nine subjects with autism and fourteen control samples.  We assayed BDNF-immunoreactive protein by ELISA and BDNF protein isoforms by Western blotting in fusiform gyrus from nine subjects with autism and nine controls.


BDNF mRNA levels were unchanged in the autism group compared to controls.  However, BDNF-like immunoreactive protein, as measured by ELISA, was increased in autism samples compared to controls, in agreement with previous studies.  Western blotting revealed increased proBDNF, reduced truncated BDNF and a trend towards increased mature BDNF levels in autism samples compared to controls. 


Our data demonstrate that increased levels of BDNF-immunoreactive protein in autism are not transcriptionally driven.  In contrast, increased proBDNF and reduced truncated BDNF implicate defective processing of proBDNF to its truncated form.  This leads to distortion of the balance between the three isoforms of BDNF which could lead to changes in connectivity and synaptic plasticity and hence behavior.  Our results focus attention on defective proteolytic maturation as a possible new mechanism for altered synaptic plasticity leading to autism.


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