AMPA-Type Glutamate Receptor Conductance Changes and Plasticity: Still a Lot of Noise

Abstract

Twenty years ago, we reported from the Collingridge Lab that a single-channel conductance increase through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type ionotropic glutamate receptors (AMPARs) could mediate one form of plasticity associated with long-term potentiation (LTP) in the hippocampus (Benke et al., Nature 395:793-797, 1998). Revealed through peak-scaled non-stationary fluctuation analysis (PS-NSFA, also known as noise analysis), this component of LTP could be exclusively mediated by direct increases in channel conductance or by increases in the number of high conductance synaptic AMPARs. Re-evaluation of our original data in the light of the molecular details regarding AMPARs, conductance changes and plasticity suggests that insertion of high-conductance GluA1 homomers can account for our initial findings. Any potential cost associated with manufacture or trafficking of new receptors could be mitigated if pre-existing synaptic AMPARs also undergo a modest conductance change. The literature suggests that the presence of high conductance AMPARs and/or GluA1 homomers confers an unstable synaptic state, suggesting state transitions. An experimental paradigm is proposed to differentiate these possibilities. Validation of this state diagram could provide insight into development, disease pathogenesis and treatment.

Mechanisms and Role of Dendritic Membrane Trafficking for Long-Term Potentiation

“…Support for increased number of synaptic AMPA receptors during LTP primarily comes from biochemical measurements demonstrating the level of surface receptors increases following LTP and from microscopy experiments directly visualizing tagged AMPA receptors as they cluster at postsynaptic sites following LTP induction (Shi et al, 1999 ; Heynen et al, 2000 ; Broutman and Baudry, 2001 ; Lu et al, 2001 ). Functional studies using peak-scaled non-stationary fluctuation analysis to estimate changes in receptor number and conductance following LTP are also consistent with insertion of AMPA receptors into the postsynaptic density (PSD) during LTP (Benke and Traynelis, 2018 ). While there is general agreement that AMPA receptors are recruited to the postsynaptic plasma membrane (PM) following LTP, the source of these receptors remains controversial.…”

PKA drives an increase in AMPA receptor unitary conductance during LTP in the hippocampus

“…The unitary conductance (γ) of AMPA receptors was estimated using NSFA according to 6 (see also [19][20][21] ). Whole-cell responses were carefully selected for analysis using WinWCP (University of Strathclyde, Glasgow) and Mini Analysis software on the basis of the following criteria: first, precise alignment of traces on the rise phase; second, no contamination by spontaneous or polysynaptic currents; third, complete decay from the peak EPSCs.…”

“…In the present study, we have tested the hypothesis that LTPγ is due to the insertion of CP-AMPARs in young adult rodents using two theta burst stimulation (TBS) induction protocols that differed only in the timing between episodes, and applied peak-scaled non-stationary fluctuation analysis (NSFA) [19][20][21] to estimate γ before and after the induction of LTP 6,15,[22][23][24][25] . We found that the compressed TBS protocol (cTBS -inter-episode interval of 10 s) resulted exclusively in LTPN, for which CaMKII was both necessary and sufficient.…”

PKA drives an increase in AMPA receptor unitary conductance during LTP in the hippocampus

“…In the present study, we have tested the hypothesis that LTP γ is due to the insertion of CP-AMPARs in young adult rodents using two theta burst stimulation (TBS) induction protocols that differed only in the timing between episodes, and applied peak-scaled non-stationary fluctuation analysis (NSFA) 19 – 21 to estimate γ before and after the induction of LTP 6 , 15 , 22 – 25 . We found that the compressed TBS protocol (cTBS – inter-episode interval of 10 s) resulted exclusively in LTP N , for which CaMKII was both necessary and sufficient.…”