Effect of Pb Exposure on Synaptic Scaling Through Regulation of AMPA Receptor Surface Trafficking

Abstract

Homeostatic synaptic plasticity (HSP) helps to stabilize the neuronal network activity, which is essential for optimal information coding. Synaptic scaling is a form of homeostatic plasticity that stabilizes neuronal firing in response to activity blockade. Lead (Pb) is a ubiquitous environmental neuro-toxicant and can impair the input-specific Hebbian type synaptic plasticity, but whether Pb exerts effects in HSP remains unknown. We previously reported that blocking L-type calcium channel induces synaptic scaling, which stimulates the synthesis of all-trans retinoic acid (RA) and the expression of GluA2-lacking α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. Given Pb is a potent blocker of calcium channel, we hypothesized Pb may participate in synaptic scaling accompanied by RA synthesis and AMPA receptor trafficking. In this study, cultured hippocampal neurons were treated with Pb (1 μM 5 min, 15 min, 4 h, 24 h, and 10 μM 24 h) alone or in combination with tetrodotoxin (TTX, 1 μM, 24 h). The results showed that Pb alone, either at 1 μM or 10 μM, cannot induce synaptic scaling. But Pb participated in synaptic scaling when concurrent with TTX (10 μM Pb + 1 μM TTX, 24 h). Further results showed that surface heteromeric GluA1 and GluA2 AMPA receptors were increased in TTX+ Pb-induced synaptic scaling. In addition, RA was proved not to participate in TTX+ Pb-mediated synaptic scaling. Taken together, our work supported that TTX+ Pb could induce synaptic scaling and enhance synaptic accumulation of AMPAR GluA1 and GluA2 during synaptic up scaling. Our study would help for elucidation of the Pb-induced neuronal network instability mechanism.

Interleukin-10 Facilitates Glutamatergic Synaptic Transmission and Homeostatic Plasticity in Cultured Hippocampal Neurons

“…In our experiments with DIV 13–15 neuroglial culture, treatment with TTX for 24 h resulted in a significant reduction in mEPSC frequency. At the same time we did not find any significant changes in the mEPSC amplitude of 24 h TTX treated neurons which can be also observed in other studies using neuronal cultures of similar age and/or similar duration for TTX treatment [23,24]. Next, we found that the short-term application of IL-10 to established HSP, similar to its effect on basal glutamatergic synaptic transmission, significantly increased mEPSC frequency partially compensating for the reduction of mEPSC frequency induced with 24 h TTX treatment.…”

Probiotic Lactobacillus rhamnosus GR-1 supplementation attenuates Pb-induced learning and memory deficits by reshaping the gut microbiota

“…Our previous studies showed that Pb exposure could inhibit synaptic transmission in cultured hippocampal neurons ( 18 , 26 ). We next wondered whether G-CSF treatment restores excitatory and inhibitory synaptic transmission in cultured hippocampal neurons.…”

Molecular Mechanisms of Environmental Metal Neurotoxicity: A Focus on the Interactions of Metals with Synapse Structure and Function

“…This result was further confirmed showing that the expression of GluA1, GluA2, GluA3, and GluA4 AMPAR subunits is decreased by Pb exposure in cortical neurons, but with a more pronounced decrease in GluA2 expression [ 71 ]. Other results showed that GluA1 and GluA2 expressions are increased in tetrodotoxin-Pb induced synaptic scaling [ 72 ].…”

“…Although the glutamatergic receptors might not be the primary target of Mn neurotoxicity, they might play a role in Mn accumulation in the central nervous system. Mn can permeate the plasma membrane through the NMDAR [ 72 ] ( Figure 1 ). The entry of Mn into the brain is accelerated by the activation of NMDAR (but not AMPAR) in glutamatergic neurons [ 88 ].…”