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Membrane-derived phospholipids control synaptic neurotransmission and plasticity.

García-Morales V, Montero F, González-Forero D, Rodríguez-Bey G, Gómez-Pérez L, Medialdea-Wandossell MJ, Domínguez-Vías G, García-Verdugo JM, Moreno-López B - PLoS Biol. (2015)

Bottom Line: 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.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.We propose that lysophospholipids serve as potential local messengers that tune synaptic strength to precedent activity of the neuron.

View Article: PubMed Central - PubMed

Affiliation: Grupo de Neurodegeneración y Neuroreparación (GRUNEDERE), Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain.

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.

No MeSH data available.


Related in: MedlinePlus

Involvement of LPA1 in activity-dependent STD at inhibitory signaling.(A) Same as in Fig 6E, but GABA pulses were performed before and after 4 min addition to the bath of Glut (30 μM) and Gly (1 μM) and after successive washing (cRNA: n = 4 SMNs; siRNAlpa1: n = 5 SMNs). *p < 0.05, one-way RM-ANOVA relative to the control (before) condition. (B) Same as in Fig 6G but performed from SMNs cultures receiving indicated pretreatments and incubated for 4 min with aCSF alone or with Glut/Gly to stimulate NMDARs. *p < 0.05, one-way ANOVA on Ranks relative to control (untreated) condition. Experiments were carried out in the presence of TTX, d-tubocurarine, strychnine, and NBQX. Plots data can be found in S1 Data.
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pbio.1002153.g008: Involvement of LPA1 in activity-dependent STD at inhibitory signaling.(A) Same as in Fig 6E, but GABA pulses were performed before and after 4 min addition to the bath of Glut (30 μM) and Gly (1 μM) and after successive washing (cRNA: n = 4 SMNs; siRNAlpa1: n = 5 SMNs). *p < 0.05, one-way RM-ANOVA relative to the control (before) condition. (B) Same as in Fig 6G but performed from SMNs cultures receiving indicated pretreatments and incubated for 4 min with aCSF alone or with Glut/Gly to stimulate NMDARs. *p < 0.05, one-way ANOVA on Ranks relative to control (untreated) condition. Experiments were carried out in the presence of TTX, d-tubocurarine, strychnine, and NBQX. Plots data can be found in S1 Data.

Mentions: LPA1 couples with and activates three G proteins: Gα12/13, Gαi/o, and Gαq/11 [10]. Previous findings [8] and pharmacological data (S1 Text) did not support Gα12/13 involvement. Alternatively, preincubation for 2 h with the Gαi/o specific inhibitor pertussis toxin (PTX), but not with the noncatalytic B oligomer of PTX (bPTX), prevented (s-)LPA-induced STD and PPR increase (Fig 4E, 4G, and 4H; S8A, S8D, and S8E Fig). Cascade downstream of lysophospholipids included PLC activation; the PLC inhibitor U73122, but not its inactive analog U73343, reversed—to a control-like state—the changes in amplitude and PPR provoked by (s-)LPA (Fig 4F–4H; S8B, S8D, and S8E Fig). Finally, the Gαq/11 inhibitor YM-254890 did not interfere with s-LPA effects on eEPSCsAMPA (S8C–S8E Fig). Altogether, these findings indicate that LPA signaling controls excitatory inputs via presynaptic Gαi/o-protein-coupled LPA1 and PLC (Fig 4I).


Membrane-derived phospholipids control synaptic neurotransmission and plasticity.

García-Morales V, Montero F, González-Forero D, Rodríguez-Bey G, Gómez-Pérez L, Medialdea-Wandossell MJ, Domínguez-Vías G, García-Verdugo JM, Moreno-López B - PLoS Biol. (2015)

Involvement of LPA1 in activity-dependent STD at inhibitory signaling.(A) Same as in Fig 6E, but GABA pulses were performed before and after 4 min addition to the bath of Glut (30 μM) and Gly (1 μM) and after successive washing (cRNA: n = 4 SMNs; siRNAlpa1: n = 5 SMNs). *p < 0.05, one-way RM-ANOVA relative to the control (before) condition. (B) Same as in Fig 6G but performed from SMNs cultures receiving indicated pretreatments and incubated for 4 min with aCSF alone or with Glut/Gly to stimulate NMDARs. *p < 0.05, one-way ANOVA on Ranks relative to control (untreated) condition. Experiments were carried out in the presence of TTX, d-tubocurarine, strychnine, and NBQX. Plots data can be found in S1 Data.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4440815&req=5

pbio.1002153.g008: Involvement of LPA1 in activity-dependent STD at inhibitory signaling.(A) Same as in Fig 6E, but GABA pulses were performed before and after 4 min addition to the bath of Glut (30 μM) and Gly (1 μM) and after successive washing (cRNA: n = 4 SMNs; siRNAlpa1: n = 5 SMNs). *p < 0.05, one-way RM-ANOVA relative to the control (before) condition. (B) Same as in Fig 6G but performed from SMNs cultures receiving indicated pretreatments and incubated for 4 min with aCSF alone or with Glut/Gly to stimulate NMDARs. *p < 0.05, one-way ANOVA on Ranks relative to control (untreated) condition. Experiments were carried out in the presence of TTX, d-tubocurarine, strychnine, and NBQX. Plots data can be found in S1 Data.
Mentions: LPA1 couples with and activates three G proteins: Gα12/13, Gαi/o, and Gαq/11 [10]. Previous findings [8] and pharmacological data (S1 Text) did not support Gα12/13 involvement. Alternatively, preincubation for 2 h with the Gαi/o specific inhibitor pertussis toxin (PTX), but not with the noncatalytic B oligomer of PTX (bPTX), prevented (s-)LPA-induced STD and PPR increase (Fig 4E, 4G, and 4H; S8A, S8D, and S8E Fig). Cascade downstream of lysophospholipids included PLC activation; the PLC inhibitor U73122, but not its inactive analog U73343, reversed—to a control-like state—the changes in amplitude and PPR provoked by (s-)LPA (Fig 4F–4H; S8B, S8D, and S8E Fig). Finally, the Gαq/11 inhibitor YM-254890 did not interfere with s-LPA effects on eEPSCsAMPA (S8C–S8E Fig). Altogether, these findings indicate that LPA signaling controls excitatory inputs via presynaptic Gαi/o-protein-coupled LPA1 and PLC (Fig 4I).

Bottom Line: 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.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.We propose that lysophospholipids serve as potential local messengers that tune synaptic strength to precedent activity of the neuron.

View Article: PubMed Central - PubMed

Affiliation: Grupo de Neurodegeneración y Neuroreparación (GRUNEDERE), Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain.

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.

No MeSH data available.


Related in: MedlinePlus