Heparan sulfate (HS) is a constituent of the cell surface and extracellular matrix and plays critical roles in various biological processes. This proposal will investigate our novel hypothesis that deficiency in neuronal cell surface HS can be a cause of social interaction deficits as seen in autistic spectrum disorders. This hypothesis is based on the following experimental and clinical observations: (1) HS is concentrated in synapses, regulates the maturation of synapses, and is involved in the expression of hippocampal synaptic plasticity. (2) Hereditary Multiple Exostosis (HME) is an autosomal dominant bone disorder that is caused by defective HS synthesis due to mutations of the GlcNAc/GIcA co-polymerase EXT1. Interestingly, there have been clinical reports indicating that HME patients associate autistic traits. Some of these cases carry only point mutations of EXT1, suggesting that mutations of EXT1 per se could cause autistic disorders. (3) Our analysis of EXT1 conditional knockout mice suggests that these mice have abnormal social behavior. (4) We found that the GluR1 subunit of AMPA-type glutamate receptors binds heparin, and that surface expression of AMPA receptors is drastically reduced in EXT1-deficient neurons in vitro. Abnormalities in the glutamate receptor system have been implicated as a potential cause of autism spectrum disorders. Based on these observations, we hypothesize that neuronal HS deficiency causes abnormal glutamatergic synaptic transmission, which in turn results in the development of autistic traits. In this project, we aim at demonstrating that genetic disruption of HS synthesis results in social interaction deficits and impaired glutamate receptor function of the animal.
In Aim 1, we will perform detailed behavioral analysis on conditional EXT1 knockout mice to determine whether there is a correlation between HS deficiency and social and behavioral phenotypes.
In Aim 2, using biochemical and electrophysiological approaches, we will examine whether the expression of functional glutamate receptors is impaired in EXT1-deficient neurons in vivo. Together, these aims should effectively answer whether there is a causative linkage between neuronal HS deficiency and the expression of autistic traits. If our hypothesis proves correct, this project will pave a way toward a new direction of autism research. ? ? ?
| Irie, Fumitoshi; Badie-Mahdavi, Hedieh; Yamaguchi, Yu (2012) Autism-like socio-communicative deficits and stereotypies in mice lacking heparan sulfate. Proc Natl Acad Sci U S A 109:5052-6 |
