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.
Highlights
Activity-dependent plasticity of neuronal networks refers to the adaptive changes in their properties in response to external and internal stimuli
We demonstrate that lysophosphatidic acid (LPA), an important intermediary in lipid metabolism, depresses the main excitatory and inhibitory synaptic systems by different mechanisms
Our data documents that synaptic strength and neuronal activity are modulated by products of membrane phospholipid metabolism, which suggests that bioactive phospholipids are candidates in coupling brain function to the metabolic status of the organism
Summary
Activity-dependent plasticity of neuronal networks refers to the adaptive changes in their properties in response to external and internal stimuli. Short-lived processes that modify synaptic strength occur in practically all types of synapses [1], and short-term synaptic plasticity is essential in regulating neuronal excitability and is central to information processing at both cellular and neuronal network levels [2]. The number of receptors in the surface membrane and at synaptic sites, and the size of the readily releasable pool (RRP) of synaptic vesicles (SVs), are important determinants of synaptic strength, short-term plasticity, and intersynaptic crosstalk [4,5,6,7,8]. Unmasking the feedback mechanisms that are believed to sense neuron activity and adjust synaptic strength (i.e., activity-dependent, coupled messenger synthesis and/or release) would help to explain how circuits adapt during synaptic homeostasis, experience-dependent plasticity, and/or synaptic dysfunctions that underlie cognitive decline in many neurological diseases
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