1. Presynaptic AMPA Receptors in Health and Disease
Letizia Zanetti, Maria Regoni, Elena Ratti, Flavia Valtorta, Jenny Sassone Cells. 2021 Aug 31;10(9):2260. doi: 10.3390/cells10092260.
AMPA receptors (AMPARs) are ionotropic glutamate receptors that play a major role in excitatory neurotransmission. AMPARs are located at both presynaptic and postsynaptic plasma membranes. A huge number of studies investigated the role of postsynaptic AMPARs in the normal and abnormal functioning of the mammalian central nervous system (CNS). These studies highlighted that changes in the functional properties or abundance of postsynaptic AMPARs are major mechanisms underlying synaptic plasticity phenomena, providing molecular explanations for the processes of learning and memory. Conversely, the role of AMPARs at presynaptic terminals is as yet poorly clarified. Accruing evidence demonstrates that presynaptic AMPARs can modulate the release of various neurotransmitters. Recent studies also suggest that presynaptic AMPARs may possess double ionotropic-metabotropic features and that they are involved in the local regulation of actin dynamics in both dendritic and axonal compartments. In addition, evidence suggests a key role of presynaptic AMPARs in axonal pathology, in regulation of pain transmission and in the physiology of the auditory system. Thus, it appears that presynaptic AMPARs play an important modulatory role in nerve terminal activity, making them attractive as novel pharmacological targets for a variety of pathological conditions.
2. Activation of postsynaptic Ca(2+) stores modulates glutamate receptor cycling in hippocampal neurons
Brady J Maher, Roger L Mackinnon 2nd, Jihong Bai, Edwin R Chapman, Paul T Kelly J Neurophysiol. 2005 Jan;93(1):178-88. doi: 10.1152/jn.00651.2004.
We show that activation of postsynaptic inositol 1,4,5-tris-phosphate receptors (IP(3)Rs) with the IP(3)R agonist adenophostin A (AdA) produces large increases in AMPA receptor (AMPAR) excitatory postsynaptic current (EPSC) amplitudes at hippocampal CA1 synapses. Co-perfusion of the Ca(2+) chelator bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid strongly inhibited AdA-enhanced increases in EPSC amplitudes. We examined the role of AMPAR insertion/anchoring in basal synaptic transmission. Perfusion of an inhibitor of synaptotagmin-soluble n-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor SNARE-mediated exocytosis depressed basal EPSC amplitudes, whereas a peptide that inhibits GluR2/3 interactions with postsynaptic density-95 (PDZ) domain proteins glutamate receptor interacting protein (GRIP)/protein interacting with C-kinase-1 (PICK1) enhanced basal synaptic transmission. These results suggest that constitutive trafficking and anchoring of AMPARs help maintain basal synaptic transmission. The regulation of postsynaptic AMPAR trafficking involves synaptotagmin-SNARE-mediated vesicle exocytosis and interactions between AMPARs and the PDZ domains in GRIP/PICK1. We show that inhibitors of synaptotagmin-SNARE-mediated exocytosis, or interactions between AMPARs and GRIP/PICK1, attenuated AdA-enhanced increases in EPSC amplitudes. These results suggest that IP(3)R-mediated Ca(2+) release can enhance AMPAR EPSC amplitudes through mechanisms that involve AMPAR-PDZ interactions and/or synaptotagmin-SNARE-mediated receptor trafficking.
3. Hippocampal AMPA autoreceptors positively coupled to NMDA autoreceptors traffic in a constitutive manner and undergo adaptative changes following enriched environment training
Maria Summa, Silvia Di Prisco, Massimo Grilli, Mario Marchi, Anna Pittaluga Neuropharmacology. 2011 Dec;61(8):1282-90. doi: 10.1016/j.neuropharm.2011.07.032. Epub 2011 Jul 30.
α-Amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) autoreceptors exist on glutamate hippocampal terminals. Aimed at investigating whether these autoreceptors traffic constitutively, (S)AMPA-evoked [(3)H]D-ASP release from synaptosomes enriched with peptides that impede the interaction of GluA2 subunits with cytosolic proteins involved in receptor movements [namely Glutamate Receptor-Interacting Protein (GRIP), Protein Interacting with C kinase 1 (PICK1), N-ethyl-maleimide-Sensitive Fusion protein NSF proteins] was monitored. (S)AMPA alone had no effect on the spontaneous release of [(3)H]D-ASP from control synaptosomes, but became efficacious in the presence of cyclothiazide or when preventing GluA2/GRIP/PICK1, but not GluA2/NSF, interaction. Hippocampal glutamatergic terminals also possess NMDA autoreceptors. 10 μM NMDA/1 μM glycine-induced [(3)H]D-ASP release was concentration-dependently increased by (S)AMPA. Cyclothiazide potentiated the 10 μM NMDA/1 μM glycine/50 μM (S)AMPA-induced [(3)H]D-ASP overflow, while NBQX halved and MK-801 abolished it, suggesting NMDA-AMPA autoreceptor cross-talk. Western Blot analysis of sub-synaptic fractions confirmed presynaptic GluN2B-GluA2/3 co-localization. Impeding GluA2/GRIP/PICK1 interaction facilitated the NMDA/glycine/(S)AMPA-induced release of [(3)H]D-ASP, while competing for GluA2/NSF interaction reduced it, indicating that NMDA receptor favours AMPA receptor insertion in synaptosomal plasmamembranes. Finally, rearing mice in enriched environment unveiled the (S)AMPA-induced release of [(3)H]D-ASP, but leaved unmodified that caused by NMDA/glycine. The NBQX-sensitive, 50 μM (S)AMPA-evoked release of [(3)H]D-ASP was insensitive to cyclothiazide and to peptide interfering with GluA2/GRIP/PICK1 interaction but was addictive to that caused by NMDA/glycine. Presynaptic GluA2/3 immunoreactivity in EE hippocampal terminals was increased, while GluN2B was unchanged. We conclude that hippocampal AMPA autoreceptors positively coupled to NMDA autoreceptors traffic in a constitutive manner and undergo functional up-regulation in EE animals.
