Synaptic removal of diacylglycerol by DGKζ and PSD-95 regulates dendritic spine maintenance

Abstract

Diacylglycerol (DAG) is an important lipid signalling molecule that exerts an effect on various effector proteins including protein kinase C. A main mechanism for DAG removal is to convert it to phosphatidic acid (PA) by DAG kinases (DGKs). However, it is not well understood how DGKs are targeted to specific subcellular sites and tightly regulates DAG levels. The neuronal synapse is a prominent site of DAG production. Here, we show that DGKf is targeted to excitatory synapses through its direct interaction with the postsynaptic PDZ scaffold PSD-95. Overexpression of DGKf in cultured neurons increases the number of dendritic spines, which receive the majority of excitatory synaptic inputs, in a manner requiring its catalytic activity and PSD-95 binding. Conversely, DGKf knockdown reduces spine density. Mice deficient in DGKf expression show reduced spine density and excitatory synaptic transmission. Time-lapse imaging indicates that DGKf is required for spine maintenance but not formation. We propose that PSD-95 targets DGKf to synaptic DAG-producing receptors to tightly couple synaptic DAG production to its conversion to PA for the maintenance of spine density.

The Roles of Diacylglycerol Kinases in the Central Nervous System: Review of Genetic Studies in Mice

“…In hippocampal slices of DGKzKO mice, PA production has also been found to decrease after stimula tion, and the spine density of hippocampal CA1 pyrami dal neurons are significantly reduced, suggesting that DGKz is required to maintain dendritic spines (30). Furthermore, Schaffer collateralCA1 pyramidal syn apses in the hippocampus of DGKzKO mice showed enhanced longterm potentiation (LTP) and attenuated longterm depression (LTD) (70).…”

“…Furthermore, Schaffer collateralCA1 pyramidal syn apses in the hippocampus of DGKzKO mice showed enhanced longterm potentiation (LTP) and attenuated longterm depression (LTD) (70). In dendric spine main tenance, DGKz also plays an important role by not only affecting the PA production, but also interacting or forming a multiprotein complex with PSD95, p21 activated kinase 1 (PAK1), RASrelated C3 botulinus toxin substrate 1 (Rac1), and others (30,71). However, the behavioral analysis of cognitive function or other higher brain functions has not yet been reported and therefore, further research is needed to confirm DGKz's involvement in brain function.…”

“…To date, several overexpression or knockout (KO)mice have been generated by many research groups: DGKaKO (23), cardiacspecific overexpression of DGKa (24), DGKbKO (25), DGKdKO (26), DGKe KO (27), DGKzKO (28), and DGKiKO mice (29). From the phenotypes of these DGKKO mice, each DGK has been shown to play an important roles in regulating various neuronal functions such as cognitive functions (25,30,31) , mood (32), and resistance to excitatory stimuli (33 -35).…”

Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase activity in neurons

“…Dgkκ is a member of the DGK isozymes, master regulators of the balance between DAG and PA signaling (31). Several DGKs have been shown to be involved in structural and synaptic plasticity control (33)(34)(35)(36), but no data were available on Dgkκ neuronal function. We identified that the absence of FMRP leads to the deregulation of mGluRIdependent DGK activity, causing perturbations in the balance between its substrate, DAG, and its product, PA.…”

A Perisynaptic Ménage à Trois between Dlg,DLin-7, and Metro Controls Proper Organization of Drosophila Synaptic Junctions

“…Multivalent scaffold molecules that link transmembrane proteins to the cytoskeleton are candidate determinants of synapse stability. Recent studies imply a stabilizing role for Postsynaptic density protein-95 (PSD-95), a principal vertebrate synaptic scaffold protein, during activity-dependent maturation of glutamatergic synapses (Ehrlich et al, 2007;Steiner et al, 2008;Kim et al, 2009). The linkage of PSD-95 to ionotropic glutamate receptors (GluRs), however, makes it difficult to assess a direct involvement in synaptic structural integrity independent from activity-related effects.…”