AMPA receptor inhibition by synaptically released zinc

Abstract

The vast amount of fast excitatory neurotransmission in the mammalian central nervous system is mediated by AMPA-subtype glutamate receptors (AMPARs). As a result, AMPAR-mediated synaptic transmission is implicated in nearly all aspects of brain development, function, and plasticity. Despite the central role of AMPARs in neurobiology, the fine-tuning of synaptic AMPA responses by endogenous modulators remains poorly understood. Here we provide evidence that endogenous zinc, released by single presynaptic action potentials, inhibits synaptic AMPA currents in the dorsal cochlear nucleus (DCN) and hippocampus. Exposure to loud sound reduces presynaptic zinc levels in the DCN and abolishes zinc inhibition, implicating zinc in experience-dependent AMPAR synaptic plasticity. Our results establish zinc as an activity-dependent, endogenous modulator of AMPARs that tunes fast excitatory neurotransmission and plasticity in glutamatergic synapses.AMPA receptors | zinc | ZnT3 | synaptic plasticity | auditory T he development, function, and experience-dependent plasticity of the mammalian brain depend on the refined neuronal interactions that occur in synapses. In the majority of excitatory synapses, the release of the neurotransmitter glutamate from presynaptic neurons opens transmembrane ion channels in postsynaptic neurons, the ionotropic glutamate receptors, thereby generating the flow of excitatory signaling in the brain. As a result, these receptors play a fundamental role in normal function and development of the brain, and they are also involved in many brain disorders (1).The ionotropic glutamate receptor family consists of AMPA, kainate, and NMDA receptors (NMDARs). Although kainate receptor-mediated excitatory postsynaptic responses occur in a few central synapses (2), AMPA receptors (AMPARs) and NMDARs are localized in the postsynaptic density of the vast majority of glutamatergic synapses in the brain, mediating most of excitatory neurotransmission (1). NMDAR function is regulated by a wide spectrum of endogenous allosteric neuromodulators that fine-tune synaptic responses (3-5); however, much less is known about endogenous AMPAR neuromodulators [(1, 5), but see refs. 6 and 7]. Recent structural studies revealed that the amino terminal domain (ATD) and ligand-binding domain (LBD) are tightly packed in NMDARs but not AMPARs (8-10). These structural differences explain some of the functional differences in allosteric modulation between AMPARs and NMDARs, such as why the ATD of NMDARs, unlike that of AMPARs, modulates function and contains numerous binding sites for allosteric regulators. Nonetheless, given the importance of fine-tuning both synaptic AMPAR and NMDAR responses for brain function, it is puzzling that there is not much evidence for endogenous, extracellular AMPAR modulation. The discovery and establishment of endogenous AMPAR modulators is crucial both for understanding ionotropic glutamate receptor signaling and for developing therapeutic agents for the treatment of AMPAR-related disorders, such as d...

Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration

“…S6 G and H). Continued low-level release of zinc has also been demonstrated after ZnT-3 deletion in the auditory brainstem (40), suggesting the presence of nonvesicular Zn 2+ release. In addition, it is possible that RGCs possess both Zn 2+ -dependent and Zn 2+ -independent pathways for cell death, or that some Zn 2+ accumulation may occur in RGCs via cell-autonomous mechanisms (58,59).…”

“…In addition, it is possible that RGCs possess both Zn 2+ -dependent and Zn 2+ -independent pathways for cell death, or that some Zn 2+ accumulation may occur in RGCs via cell-autonomous mechanisms (58,59). Finally, because Zn 2+ has beneficial effects, such as modulating synaptic transmission and BDNF synthesis, removing Zn 2+ could potentially have mixed positive and negative effects on RGCs (38,40,99,100).…”

“…Mobile or chelatable zinc (Zn 2+ ) is concentrated in synaptic vesicles and other intracellular organelles (30) transporters (30,(34)(35)(36). Synaptic Zn 2+ plays an essential role in modulating synaptic transmission throughout the brain (37)(38)(39)(40), including the retina, where it contributes to neuromodulation and neuroprotection (41,42). Zinc nutritional deficiency or cellular deficiency as a result of mutation in zinc transporters produces…”

Zinc transporters protein level in postmortem brain of depressed subjects and suicide victims

“…Zn 2+ binding to the GluN2A subunit of the NMDA receptor seems to play a crucial role in the Zn-dependent modulation of NMDA receptor signaling (Paoletti et al, 1997). However, recent data also provide evidence that synaptically released Zn inhibits AMPA receptors (Kalappa et al, 2015), thus further suggesting an important role of Zn homeostasis in synaptic function.…”

“…Thus, an additional aim of the present study was to examine the expression of the NMDA receptor subunit GluN2A, AMPA receptor subunit GluA1and postsynaptic density protein-95 (PSD-95). We choose these particular proteins (GluN2A, GluA1 and PSD-95) based on reports of their important role in the function of NMDA and AMPA receptors, involvement in the pathophysiology of depression and Zn action (Feyissa et al, 2009, Freudenberg et al, 2015, Kalappa et al, 2015, Popescu, 2015, Szewczyk et al, 2015). We also mesured the level of 5-HT1A receptor protein in the PFC of subjects with MDD and matched normal control subjects (cohort A).…”