Vogt, Johannes | Kepser, Lara-Jane - C 17

We have shown that bioactive phospholipids such as lysophosphatidic acids (LPA) play important roles in synaptic neurotransmission and plasticity (1-5). LPA is a short-lived mediator with a half-time in the subminute range, but a potent signaling molecule acting via specific G-protein coupled receptors, LPA-R_1-6. LPA-levels are tightly regulated by specific phosphatases (LPP_1-3) suggesting that LPA synthesis and action are locally restricted. LPA is synthesized by the enzyme autotaxin (ATX) from the lipid precursor lysophosphatidyl choline (LPC). LPC is derived from the peripheral lipid metabolism and is actively transported into the CNS present at perisynaptic astrocytic processes In the cortex, ATX is expressed by astrocytes and is located at glutamatergic synapses where it fuels LPA levels by conversion of LPC into LPA (6, 7). However, in contrast to blood plasma, LPC is only present at very low concentrations in the CSF, indicating that LPC-levels are a limiting factor for LPA-synthesis in the CNS.  At glutamatergic synapses, LPA is a powerful modulator of presynaptic glutamate release by activation of presynaptic LPA2 receptors, which regulate glutamate release probabilities and hereby neuronal excitability. Our recent data show, that LPA regulates the excitation-inhibition (E/I) balance in cortical networks and controls cortical sensory information processing in mice and humans in a similar way(8, 9). 

While LPA effects are mediated by presynaptic LPA₂-receptors (LPA₂), plasticity-related gene-1 (PRG-1/LPPR4), a regulatory molecule located at the postsynaptic density of excitatory synapses, controls synaptic LPA-levels by transmembrane transport into intracellular compartments (3, 9). Hereby, PRG-1 regulates presynaptic LPA₂ signaling and controls the functional set-point at the glutamatergic synapse. Alteration of this postsynaptic regulatory mechanism by PRG-1 results in higher local LPA levels, which lead to increased glutamatergic release probabilities, higher neuronal excitability and consequently to a shift in cortical network E/I-balance towards higher excitability (3, 9). 

Our previous data show that altered E/I-balance affected memory formation and led an endophyotype of psychiatric disorders in mice and humans(8). Moreover, since the LPA-precursor LPC is secreted by the liver and underlies metabolic alterations, our data show the changes in peripheral energy metabolism may rapidly affect brain lipid levels and thereby cortical excitability(10). In disease conditions however, synaptic lipid signaling is critically involved in stroke pathophysiology (11). Our recent data suggest that synaptic LPA synthesis in regions with high neuronal density like the hippocampus may provide a niche supporting adult neurogenesis. In fact, our data show that local LPA-synthesis in the hippocampal dentate gyrus plays a regulatory role in adult neurogenesis leading to improved survival and circuit integration of newborn neurons. 

• Department of Molecular and Translational Neuroscience, Institute of Anatomy II, University Hospital of Cologne
• Center of Molecular Medicine Cologne (CMMC)