Translational control of neuronal mRNAs in autism spectrum disorders.

Translational control is a powerful homeostatic mechanism to regulate gene expression in neurons. We showed that increased translation led to enhanced excitatory(E) and inhibitory(I) synaptic transmission in CA1 pyramidal cells, which caused autism-like symptoms in mice. Genetic deletion of the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 2, 4E-BP2, induces exaggerated eIF4E-dependent synthesis of neuroligins causing an E/I imbalance and engendering autism-like behaviors. The E/I balance is restored and autism-like behaviors reversed by blocking cap-dependent translation or knocking down neuroligins. We hypothesize that 4E-BP2 regulates different pools of mRNAs in excitatory and inhibitory neurons, and this is a key mechanism regulating the E/I balance and autism-like behaviours. Now, using novel conditional-knockout 4E-BP2 transgenic mice in excitatory or inhibitory neurons of the cortex and hippocampus, and compounds modulating translation, we will study the ro le of translational control in the maintenance of the E/I balance through aberrant translation of specific mRNAs. To achieve this we will identify the translatome regulated in excitatory and inhibitory synapses of the forebrain using RNA sequencing. The proposed research can lead to the development of novel therapeutic approaches taking advantage of the selective regulation of translational control on a subset of mRNAs in mouse models of ASD.