ProSAP2 is a multidomain scaffold protein located in the post-synaptic density (PSD) of excitatory synapses. It is hypothesized to functionally couple membrane-bound glutamate receptors, the actin cytoskeleton and second messenger signaling pathways [1]. ProSAP2 exchange is activity-dependent, such that it is stable in the absence of activity and dynamic in the presence of electrical [2] or chemical [see preliminary data] stimulation, thereby suggesting that the dynamic properties of ProSAP2 are coupled to its function. This proposal tests the hypothesis that activity converts ProSAP2 from an inactive oligomerized form to a dynamic activated state that is responsive to NMDAR-mediated plasticity. Live-cell time-lapse confocal microscopy and Fluorescence Recovery After Photobleaching (FRAP) will be used here to assess the dynamic exchange properties of ProSAP2 in response to pharmacological manipulations. Experiments will be performed using dissociated hippocampal cultures infected with a EGFP-ProSAP2 lentiviral constuct in a specialized temperature controlled imaging chamber. This project specifically aims to define the features of synaptic activity that regulate ProSAP2 dynamics, and then to assess whether SAM domain oligomerization regulates the exchange properties of ProSAP family members. Taken together, the experiments described here will test whether the dynamic state of ProSAP2 is coupled to synaptic plasticity. Relevance: Autism is a prevalent developmental disorder, characterized by deficits in social interaction and communication. Though twin studies suggest a strong genetic component, mapping studies have failed to identify a single gene underling this complex social disorder, rather they have implicated several interacting synaptic proteins that are involved in cell adhesion and cytoskeletal architecture. This project explores the synaptic mechanisms regulating the dynamics of ProSAP2 [3], a particulariy interesting protein implicated in Autism Spectrum Disorders.
| Arons, Magali H; Thynne, Charlotte J; Grabrucker, Andreas M et al. (2012) Autism-associated mutations in ProSAP2/Shank3 impair synaptic transmission and neurexin-neuroligin-mediated transsynaptic signaling. J Neurosci 32:14966-78 |
| Grabrucker, Andreas M; Rowan, Magali; Garner, Craig C (2011) Brain-Delivery of Zinc-Ions as Potential Treatment for Neurological Diseases: Mini Review. Drug Deliv Lett 1:13-23 |
