Defining cells and circuits affected in autism spectrum disorders
Autism is a genetically determined spectrum of disorders that result in the aberrant development and function of the nervous system. Researchers have identified several genes that contribute to autism, but there has been little progress in pinpointing the brain cell types and circuits that are affected by mutations in these genes.
Nathaniel Heintz, Paul Greengard and their colleagues at The Rockefeller University are testing a hypothesis that they can identify cells preferentially affected by mutations in autism-linked genes by analyzing their molecular profiles in mouse models of autism.
The researchers previously developed a new approach to molecular profiling, called translating ribosome affinity purification, or TRAP. The technique allows messenger RNA molecules to be captured in the process of being translated into proteins, yielding a global snapshot of the proteins that are being expressed in a given cell type. The team plans to use TRAP to identify changes in the protein profiles of brain cells in mouse models of three chromosomal defects associated with autism: 15q duplication, and 16p deletion and duplication syndromes.
The researchers then plan to compare how these chromosomal defects affect protein expression among the different cell types in the brain, including neurons in the frontal cortex, striatum and cerebellum. Heintz and Greengard hope their powerful new profiling approach will help them to identify the neural cell types and circuits that play key roles in autism, and to shed light on the molecular pathways that are disrupted in these critical cell types.
Epigenetic modifications alter gene expression without changing the nucleotide sequence. For example, the cytosine (C) nucleotide can be modified to become 5-hydroxymethylcytosine (hmC). In 2009, Heintz and his colleagues reported high levels of hmC in the genomes of mammalian neurons, but not in those of several other tissues. The researchers are studying hmC levels in certain types of neurons to determine how many cytosines are modified in this way and how the presence of hmC in a gene affects the expression of that gene. These epigenetic modifications may be involved in autism spectrum disorders.