Kurzfassung

We have provided evidence for a role of plasticity-related gene 1 (PRG-1, (Brauer et al., 2003) in the maintenance of synaptic homeostasis by controlling the functional set-point at the glutamatergic junction. This signaling pathway involves lysophosphatidic acid (LPA) acting via presynaptic LPA2 receptors and PRG-1 acting from the postsynaptic side (Trimbuch et al., 2009). During the previous funding period, we assessed PRG-1 and its potential interaction partners at the PSD (Distler et al.,...We have provided evidence for a role of plasticity-related gene 1 (PRG-1, (Brauer et al., 2003) in the maintenance of synaptic homeostasis by controlling the functional set-point at the glutamatergic junction. This signaling pathway involves lysophosphatidic acid (LPA) acting via presynaptic LPA2 receptors and PRG-1 acting from the postsynaptic side (Trimbuch et al., 2009). During the previous funding period, we assessed PRG-1 and its potential interaction partners at the PSD (Distler et al., 2014), and determined a molecular pathway by which PRG-1 provides homeostatic control of both structural and functional spine plasticity in a cell-autonomous fashion (Liu et al., 2016). The role of bioactive synaptic lipid signaling in the homeostatic control of glutamatergic transmission was shown to affect neurotrophin signaling in the hippocampus (Petzold et al., 2016) and, importantly, cortical information processing (Unichenko et al., 2016). Genetic alterations in bioactive synaptic lipid signaling both in mice and man revealed that resulting changes in the homeostasis of cortical information processing may play a role in psychiatric disorders (Vogt et al., 2016).
 
In the upcoming funding period, we will 1) address the role of PRG-1/CaM binding which appears to be dynamically regulated using in vitro electrophysiology on a cellular and network level (LTP), employing pharmacological as well as specific peptide blockers, and study behavioral effects by interfering with this binding also in vivo. 2) Further, we will analyze the role of the LPA-synthesizing enzyme ATX, present at perisynaptic lamellae of astrocytes, using cellular studies of ATX-activity and its inhibition, as well as in vitro electrophysiology and behavioral studies. 3) Finally, we will assess LPA-uptake and resulting Ca2+-transients in dendritic spines using single-spine 2P-imaging with a temporal resolution in the milliseconds range (30 ms). These data will allow us to assess the kinetics of synaptic phospholipids action at the glutamatergic synapse and to arrive at a quantitative mathematical model for synaptic phospholipid function (in collaboration with the group of T. Tchumatchenko). This work will provide a new view on the homoeostatic control of synaptic signaling by bioactive lipids.
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