- Awarded: 2015
- Award Type: Pilot
- Award #: 345915
All cells, including neurons, possess mechanisms to coordinate protein synthesis with protein degradation to maintain amino acid and protein levels within the appropriate range. Even a subtle imbalance between these processes can disrupt normal neuronal morphology and functions.
Mammalian target of rapamycin (mTOR) is a key molecule that regulates protein homeostasis by promoting protein synthesis and inhibiting autophagy, a lysosomal degradation process that maintains protein quality control via the degradation of cellular proteins and organelles to generate amino acids. David Sulzer, Guomei Tang and their colleagues at Columbia University recently discovered that mTOR is overactive in excitatory neurons in postmortem brains of individuals with autism spectrum disorder (ASD)1.
Excessive mTOR activity in ASD is associated with an increased number of dendritic spine synapses as well as a blockade in the normal net decrease of excitatory synapses, a developmental process called ‘postnatal synaptic pruning.’ Overactive mTOR is also implicated in the development of autism-related behaviors in tuberous sclerosis complex 2 heterozygous (TSC2+/-) mutant mice, including impaired social interaction and reduced preference for social novelty, along with increased dendritic spine density and impaired spine pruning. Autophagy deficiency in response to the faulty mTOR activity contributes largely, but not entirely, to the ASD synapse pathology.
This study aims to explore the involvement of mTOR-regulated translation in excitatory neurons in ASD synaptic pathology. The researchers will measure excitatory neuronal specific genome-wide gene transcription and translation in two ASD model mouse lines, TSC2+/- mice and fragile X mental retardation protein null mice (FMR1-/y) mice, using a technique called ‘ribosome profiling’2. Using the mTOR inhibitor rapamycin or its analogs, they will examine whether the neuronal translational alterations in the autism mouse models can be reversed. The research team also plans to validate the changes in neuronal translation in human postmortem brain tissue, and correlate these changes with alterations in synaptic pathology that were observed in their earlier study1.
In summary, this pilot study will investigate how translational control in excitatory neurons is involved in ASD, which will increase our understanding of the molecular underpinnings of autism.