Postsynaptic GluA1 enables acute retrograde enhancement of presynaptic function to coordinate adaptation to synaptic inactivity

Abstract

Prolonged blockade of AMPA-type glutamate receptors in hippocampal neuron cultures leads to homeostatic enhancements of preand postsynaptic function that appear correlated at individual synapses, suggesting some form of transsynaptic coordination. The respective modifications are important for overall synaptic strength but their interrelationship, dynamics, and molecular underpinnings are unclear. Here we demonstrate that adaptation begins postsynaptically but is ultimately communicated to presynaptic terminals and expressed as an accelerated turnover of synaptic vesicles. Critical postsynaptic modifications occur over hours, but enable retrograde communication within minutes once AMPA receptor (AMPAR) blockade is removed, causing elevation of both spontaneous and evoked vesicle fusion. The retrograde signaling does not require spiking activity and can be interrupted by NBQX, philanthotoxin, postsynaptic BAPTA, or external sequestration of BDNF, consistent with the acute release of retrograde messenger, triggered by postsynaptic Ca 2+ elevation via Ca 2+ -permeable AMPARs.homeostasis | synaptic scaling | calcium signaling | miniature excitatory postsynaptic currents P rolonged perturbations in the level of activity of neuronal circuits initiate major changes in excitatory transmission. Such retuning is generally homeostatic and is proposed to counterbalance other forms of plasticity and to help keep neuronal firing rate within an optimal range for efficient transfer of information (1-3). There is growing agreement about the functional significance of adaptation to inactivity (2, 4), but much uncertainty remains about where and how such adaptation is expressed.The increase in postsynaptic function in response to prolonged inactivity, evident as an increase in the amplitude of unitary synaptic events (miniature excitatory postsynaptic currents, mEPSCs, or minis), is by now well-established (2, 4). The enlargement of mEPSCs is mediated by an accumulation of AMPA receptors (AMPARs) at postsynaptic sites (5-8). Sometimes the increase is attributed to an increase in Ca 2+ -permeable AMPARs that lack GluA2 subunits (7, 9, 10), but in other cases comparable elevations in both GluA1 and GluA2 have been seen (6,8,11,12). Furthermore, adaptation to inactivity induced by postsynaptic blockade may also involve presynaptic changes, reflected by an elevated frequency of mEPSCs and increased vesicular turnover (7,(13)(14)(15)(16).Although evidence is mounting for both pre-and postsynaptic modifications, the fundamental nature of such alterations remains incompletely understood. On one hand, neuronal inactivity causing cellwide changes in transmitter release and receptivity (2) would fit with descriptions of synaptic homeostasis as a global phenomena. This idea is supported by evidence showing that glial cells can serve as general activity sensors and modulate all synapses in an area (17). On the other hand, findings of tight coordination between closely neighboring synapses (18) and of differential regulation of different types...

β Ca 2+ /CaM-dependent kinase type II triggers upregulation of GluA1 to coordinate adaptation to synaptic inactivity in hippocampal neurons

“…We recently found that these slow, adaptive changes enable retrograde communication within minutes once AMPAR blockade is removed. Indeed, relief of inactivity allows Ca 2+ permeation through GluA1 homomers, triggering rapid BDNF signaling back to the presynaptic terminal to elevate release probability that can be interrupted by chelation of postsynaptic Ca 2+ (6). Consistent with this scheme (Fig.…”

“…By the same token, generation of GluA1 homomers would favor Ca 2+ entry when AMPAR blockade is removed, possibly aiding in the rebound of neuronal activity levels. Both changes can be viewed as adaptive to a state of reduced neurotransmission; together, the changes help explain how retrograde transmission can be set in motion by spontaneous minis alone (6).…”

“…Here we show that, in response to synaptic inactivity, increased βCaMKII activity is necessary to bring about increases in postsynaptic strength. In turn, alteration of the composition of postsynaptic AMPARs enables retrograde signaling from the postsynaptic cell to its immediately presynaptic terminals once transmission block is removed (6).…”

Homeostatic plasticity in Drosophila central neurons, and implications in human diseases

“…These results are similar to mammalian studies. 24,27,28 These results suggest the existence of presynaptic changes following inactivity that lead to a higher vesicle release probability. Thus, it is possible that decreased Ca 2+ influx during synaptic blockade, or perhaps increased Ca 2+ influx immediately following synaptic blockade may contribute to retrograde signaling to pre-synaptic terminals.…”

“…It is interesting that GluA2 lacking AMPA receptors, which are Ca 2+ permeable (Cp-AMPARs), have also been shown to play an important role in glutamatergic homeostatic plasticity. [24][25][26] Studies have shown that blocking AMPARs induces increased surface expression of both Ca 2+ -impermeable (Ci) and Cp-AMPARs. Ca 2+ permeable receptors, such as α7 nAChRs or Cp-AMPARs, likely mediate Ca 2+ -dependent pathways involved in homeostasis, regulation of homeostasis, and/or additional forms of plasticity.…”