Membrane-Derived Phospholipids Control Synaptic Neurotransmission and Plasticity

Abstract

Synaptic communication is a dynamic process that is key to the regulation of neuronal excitability and information processing in the brain. To date, however, the molecular signals controlling synaptic dynamics have been poorly understood. Membrane-derived bioactive phospholipids are potential candidates to control short-term tuning of synaptic signaling, a plastic event essential for information processing at both the cellular and neuronal network levels in the brain. Here, we showed that phospholipids affect excitatory and inhibitory neurotransmission by different degrees, loci, and mechanisms of action. Signaling triggered by lysophosphatidic acid (LPA) evoked rapid and reversible depression of excitatory and inhibitory postsynaptic currents. At excitatory synapses, LPA-induced depression depended on LPA1/Gαi/o-protein/phospholipase C/myosin light chain kinase cascade at the presynaptic site. LPA increased myosin light chain phosphorylation, which is known to trigger actomyosin contraction, and reduced the number of synaptic vesicles docked to active zones in excitatory boutons. At inhibitory synapses, postsynaptic LPA signaling led to dephosphorylation, and internalization of the GABAAγ2 subunit through the LPA1/Gα12/13-protein/RhoA/Rho kinase/calcineurin pathway. However, LPA-induced depression of GABAergic transmission was correlated with an endocytosis-independent reduction of GABAA receptors, possibly by GABAAγ2 dephosphorylation and subsequent increased lateral diffusion. Furthermore, endogenous LPA signaling, mainly via LPA1, mediated activity-dependent inhibitory depression in a model of experimental synaptic plasticity. Finally, LPA signaling, most likely restraining the excitatory drive incoming to motoneurons, regulated performance of motor output commands, a basic brain processing task. We propose that lysophospholipids serve as potential local messengers that tune synaptic strength to precedent activity of the neuron.

Lysophospholipids and Their G-Coupled Protein Signaling in Alzheimer’s Disease: From Physiological Performance to Pathological Impairment

“…They detected presynaptic glutamate release when stimulating LPAR localized in the presynaptic terminals, whereas excessive LPA stimulation was found to cause seizures (Roza et al, 2019). These results are in line with the observation that LPA modulates the excitatory as well as the inhibitory synapses to regulate synaptic strength and neuronal activity (García- Morales et al, 2015). It has been demonstrated that LPA functions as a dual regulatory factor in modulating synaptic excitability.…”

“…High levels of LPA have been shown to lessen the size of available vesicle pools at glutamatergic pre-synaptic neurons, thus providing negative feed-back to prohibit the transmission at excitatory synaptic terminals. Nevertheless, in the presence of low concentrations of LPA, inhibitory postsynaptic receptors, namely gamma-aminobutyric acid receptor type A (GABAAR), were internalized to restrain transmission at inhibitory synaptic terminals, thereby briefly increasing the synaptic excitability (García- Morales et al, 2015;Roza et al, 2019). In line with these findings, it is believed that LPA plays a crucial role in modulating glutamatergic transmission in the nervous system.…”

“…LPARs -Neurodegeneration (Choi and Chun, 2013;Yung et al, 2015). LPA1 G i/o PLC↑, MAPK↑, PI3K/Akt↑, Rac↑ AC↓, cAMP↓ -Neuronal development (Contos et al, 2000;Fukushima et al, 2002a;Kihara et al, 2014;Suckau et al, 2019); -Neurogenesis of adult hippocampus (Fukushima et al, 2002a); -Survival and differentiation of neural progenitor cells (NPCs; Chun et al, 2002;Fukushima et al, 2002a;Yung et al, 2014); -Modulation of adult hippocampus neuroplasticity (García- Morales et al, 2015;Peñalver et al, 2017;Roza et al, 2019); -Negative feedback of microglia induced inflammation (Awada et al, 2014;Kwon et al, 2018).…”

A SLM2 Feedback Pathway Controls Cortical Network Activity and Mouse Behavior

“…Tomosyn2 controls acetyl choline release from cholinergic nerve terminals (Geerts et al., 2015) and acetylcholine (ACh) is known to induce persistent γ-oscillations in the hippocampus (Picciotto et al., 2012). LysoPLD/ATX encodes one of the major enzymes involved in synthesis of lysophospatidic acid (LPA), a molecule with a key signaling role controlling both excitatory and inhibitory synapse functions (García-Morales et al., 2015, Vogt et al., 2015). LPA has a critical role in the nervous system: knockout of LPA1 receptor causes anxiety (Santin et al., 2009), which also characterizes the Slm2 mouse, and LysoPLD/ATX is essential for brain development (Greenman et al., 2015).…”

Multidimensional Liquid Chromatography Coupled with Tandem Mass Spectrometry for Identification of Bioactive Fatty Acyl Derivatives

“…In addition to these indirect mutual effects of lipids and signaling, many lipids exert bioactive properties directly as cellular signals and 2nd messengers (for reviews, see Hannun and Obeid, 2008; García-Morales et al, 2015; Morales-Lázaro and Rosenbaum, 2015). In this study, we have focused attention on fatty acyls (for review see Divito and Cascio, 2013).…”