Synaptic aberrations are commonly observed in a wide variety of neurodevelopmental disorders associated with autism, epilepsy, intellectual disability and related phenotypes. While synaptic proteomic aberrations have been identified in several models of neurodevelopmental disorders, these studies are mainly performed from whole tissue samples and few provide data on synaptic alterations in a neuron-type or synapse-type specific manner. Thus, synaptic alterations that are confined to specific types of synapses or neurons might be poorly detected using this approach due to lack of technical sensitivity. The availability of a validated technique to allow the detection of synaptic alterations in mouse models of human disorders in a neuron-type and synapse-type specific manner would accelerate our therapeutic efforts for disorders associated with synaptic aberrations. In this discovery and validation proposal, we propose to mouse models of a neurodevelopmental disorder, with known differential alterations in synaptic proteins in excitatory and inhibitory neurons, to define and validate proteomic compositions of excitatory synaptosomes in a neuron type specific manner. The success of our studies will allow great insights into the synaptic pathology neurodevelopmental disorders with synaptic aberrations. The tools, techniques and approach can be applied more globally, thus promoting great strides in cellular and molecular neuroscience.