J Physiol 599.2 (2021) pp 471–483 471
SYMPOS IUM REV IEW
Modulation of information processing by AMPA receptor
auxiliary subunits
Eric Jacobi1,2 and Jakob von Engelhardt1,2
1Institute of Pathophysiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
2Focus Program Translational Neurosciences (FTN), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
Edited by: Ian Forsythe & Jean-Claude Béı̈que
Abstract AMPA-type glutamate receptors (AMPARs) are key molecules of neuronal
communication in our brain. The discovery of AMPAR auxiliary subunits, such as proteins
of the TARP, CKAMP and CNIH families, fundamentally changed our understanding of how
AMPAR function is regulated. Auxiliary subunits control almost all aspects of AMPAR function
in the brain. They influence AMPAR assembly, composition, structure, trafficking, subcellular
localization andgating.This influencehas important implications for synapse function. In thepre-
sent review, we first discuss how auxiliary subunits affect the strength of synapses by modulating
number and localization of AMPARs in synapses as well as their glutamate affinity, conductance
and peak open probability. Next we explain how the presence of auxiliary subunits alters temporal
precision and integrative properties of synapses by influencing gating kinetics of the receptors.
Auxiliary subunits of the TARP and CKAMP family modulate synaptic short-term plasticity by
Eric Jacobi holds a PhD from the University of Heidelberg and a Diploma in Human and Molecular
Biology from Saarland University. Currently, he is a postdoctoral researcher and lecturer at the Institute
for Pathophysiology of the University Medical Centre of the Johannes Gutenberg University Mainz. His
research focus lays on the synaptic communication of neurons with a special emphasis on glutamatergic
synapses. Jakob von Engelhardt received his MD at the Philipps-University Marburg. After his
residency in neurology at the Department of Neurology of the University Hospital Heidelberg he did
his postdoctoral work in the Department of Clinical Neurobiology in Heidelberg. In 2012, he became a
group leader at the DZNE in Bonn and the DKFZ in Heidelberg. Since 2017 he has been Director of the
Institute of Pathophysiology at the Johannes Gutenberg University Mainz. His main research interest is
the regulation of excitatory synapse function and role of glutamate receptors in the CNS.
©C 2020 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society DOI: 10.1113/JP276698
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution
and reproduction in any medium, provided the original work is properly cited.
The Journal of Physiology
472 E. Jacobi and J. von Engelhardt J Physiol 599.2
increasing anchoring of AMPARs in synapses and by altering their desensitization kinetics. We
then describe how auxiliary subunits of the TARP, CKAMP and CNIH families are involved
in Hebbian and homeostatic plasticity, which can be explained by their influence on surface
trafficking and synaptic targeting. In conclusion, the series of studies covered in this review show
that auxiliary subunits play a pivotal role in controlling information processing in the brain by
modulating synaptic computation.
(Received 20 March 2020; accepted after revision 25 June 2020; first published online 6 July 2020)
Corresponding author J. von Engelhardt: Institute of Pathophysiology, University Medical Centre of the Johannes
Gutenberg University Mainz, Mainz, Germany. Email: engelhardt@uni-mainz.de
Abstract figure legendAMPAreceptor auxiliary subunits: AMPAreceptors interactwithmanydifferent types of proteins.
Up to now more than 30 distinct interaction partners have been identified (Schwenk et al. 2009, 2012; Engelhardt et al.
2010; Shanks et al. 2012). However, only a small subset of these interacting proteins belongs to the class of auxiliary
subunits. In contrast to other interacting partners such as FRRS1L and ABHD6 that interact with AMPARs exclusively
intracellularly (Schwenk et al. 2019), auxiliary subunits interact with AMPA receptors on the cell surface, where they
modulate their gating and localization (Jacobi & Engelhardt, 2018). The four different protein families that comprise
the class of auxiliary subunits are TARPs, CNIHs, CKAMPs and GSG1L. Over the past 20 years, substantial progress
has been made in the understanding of how auxiliary subunits interact with AMPA receptors and what the functional
consequences of this interaction are. Very recently, for example, the atomic structure of AMPA receptors in complex with
TARP γ-8 or CNIH-2 has been resolved (Herguedas et al. 2019; Nakagawa, 2019; reviewed in Kamalova & Nakagawa,
2020). Table 1 provides an overview of the main effects of the different AMPA receptor auxiliary subunits.
Introduction that AMPA receptor function depends to a large extent
on the interaction with auxiliary subunits. They influence
Synaptic transmission via chemical synapses is the main AMPA receptor trafficking to the cell surface, subcellular
route of neuronal communication and forms the back- localization and gating of the receptors (see Table 1).
bone of information processing in the central nervous Currently, the group of auxiliary subunits of AMPA
system. Plastic changes in strength and mode of single receptors includes the families of TARPs (transmembrane
synapses alter the way information is integrated and AMPA receptor regulatory proteins), CNIHs (cornichon
computed in our brain. Fast excitatory synaptic trans- homolog proteins), CKAMPs (cysteine-knot AMPA
mission in the central nervous system is mostly mediated receptor modulating proteins; aka Shisas) and GSG1L
by AMPA-type glutamate receptors (AMPA receptors). (germ cell-specific gene 1 like protein) (Figure 1,
Their central position in excitatory synapses makes these Table 1). Auxiliary subunits differ in their influence
receptors key targets for the regulation of excitatory on AMPA receptor function and, additionally, display
synaptic communication. Consequently, alteration in distinct regional and developmental expression profiles.
neuronal communication is often mediated by a change Interestingly, the expression of some auxiliary subunits
in number and function of AMPA receptors. is activity dependent. This indicates an important role
Structurally, AMPA receptors are heterotetramers that of auxiliary subunits in homeostatic synaptic scaling and
assemble from different combinations of the four AMPA neuronal adaptation processes. Several recent reviews
receptor subunits GluA1–GluA4 (AMPA-type glutamate discuss in detail the influence of auxiliary subunits
receptor subunit 1–4) (Traynelis et al. 2010). The on AMPA receptor trafficking, assembly, receptor
combination of the subunits in the final receptor composition, and structure (Eibl & Plested, 2017;
determines its basic electrophysiological parameters. Greger et al. 2017; Jacobi & Engelhardt, 2017, 2018;
Moreover, AMPA receptors are embedded into networks Bissen et al. 2019; Chen & Gouaux, 2019; Kamalova
of interacting proteins several of which strongly impact & Nakagawa, 2021). This review will specifically focus
AMPA receptor function (Schwenk et al. 2009 (CNIHs), on how AMPA receptor auxiliary subunits influence
2012 (CNIHs, TARPs, GSG1L); Engelhardt et al. 2010 function and localization of synaptic AMPA receptors
(CKAMP44); Shanks et al. 2012 (GSG1L); Greger et al. and the consequences of this influence on computation
2017 (TARPs)).The importanceof these auxiliary subunits of synapses.
becomes evident if one looks at the broad variety of AMPA
receptor-mediated currents in various neuron types in
the brain. These currents only partially resemble the ones
from heterologous expressed receptors. This discrepancy Synaptic strength
can be explained by the interaction of auxiliary subunits The strength of a synapse depends on the number of
with AMPA receptors in the brain. In fact, we know today synaptic AMPA receptors (Fig. 2). Throughout the brain,
©C 2020 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society
J Physiol 599.2 Modulation of information processing by AMPA receptor auxiliary subunits 473
Table 1. Modulation of AMPA receptors by the different auxiliary subunits
TARPs CKAMPs CNIHs
γ-2 γ-3 γ-4 γ-5 γ-7 γ-8 39 44 52 59 CNIH-2 CNIH-3 GSG1L
Trafficking ↑ ↑ ↑ 0 ↑ ↑ N/A ↑ N/A N/A ↑ ↑ N/A
Synaptic localization ↑ ↑ ↑ 0 ↑ ↑ N/A ↑ N/A N/A ↑ N/A ↑
Deactivation rate ↓ ↓ ↓ ↑ ↓ ↓ 0/↓ ↓ 0/↓ 0 ↓ ↓ ↓
Desensitization rate ↓ ↓ ↓ ↑ ↓ ↓ 0/↑ ↑ ↓/0/↑ 0/↑ ↓ ↓ ↓
Recovery from desensitization ↑ N/A N/A N/A N/A ↑ ↓ ↓ ↓/0/↑ 0/↓ 0 0 ↓
Conductance ↑ ↑ ↑ ↑ ↑ ↑ N/A ↑ N/A N/A ↑ ↑ ↓
Glutamate affinity ↑ ↑ ↑ ↓ 0 ↑ ↑ ↑ ↑ N/A 0 ↓ N/A
Long-term plasticity ↑ N/A N/A N/A N/A ↑ N/A 0 N/A ↑ ↑ ↑ ↓
Short-term plasticity 0 0 N/A N/A N/A ↑ N/A ↓ ↑ 0 N/A N/A N/A
Opposing effects are probably due to different AMPA receptor subunits or expression systems (e.g. oocytes, HEK293 cells, cultured
neurons or acute brain slices). N/A, not available. References: TARPs: Tomita et al. 2003; Yamazaki et al. 2004; Priel et al. 2005; Rouach
et al. 2005; Cho et al. 2007; Milstein et al. 2007; Kott et al. 2009; Shi et al. 2010; Kato et al. 2008, 2010; Khodosevich et al. 2014;
CKAMPs: von Engelhardt et al. 2010; Khodosevich et al. 2014; Farrow et al. 2015; Klaassen et al. 2016; Schmitz et al. 2017; CNIHs:
Schwenk et al. 2009; Coombs et al. 2012; Kato et al. 2010; Herring et al. 2013; Boudkkazi et al. 2014; GSG1L: Shanks et al. 2012; McGee
et al. 2015; Gu et al. 2016; Mao et al. 2017.
synaptic AMPA receptor density varies from synapse to mechanism. Some auxiliary subunits affect the trafficking
synapse and is subject to constant changes. The control of AMPA receptors to the cell surface, others (and
of synaptic AMPA receptor number is perhaps one of sometimes the same ones) control the anchoring of
the most obvious effects of auxiliary subunits. However, AMPA receptors at the postsynaptic density. Yet others
the strength of a synapse depends not only on the are thought to affect removal of AMPA receptors from the
number of synaptic receptors, but also on their gating synapse. To date, the mechanisms of how AMPA receptor
properties. Thus, strength of synaptic communication is auxiliary subunits control receptor trafficking to the cell
additionally influenced by glutamate affinity, conductance surface are not fully understood (reviewed in Jacobi &
and peak open probability of AMPA receptors (Fig. 2; Engelhardt, 2018).Genetic deletionofmany auxiliary sub-
Clements, 1996; Kullmann et al. 1999; Bredt & Nicoll, units leads to a significant reduction in surface AMPA
2003;MacGillavry et al. 2013). Finally, anchoringofAMPA receptor levels. This reduction of AMPA receptor number
receptors in subsynaptic nanodomains has been shown to is especially dramatic in TARP γ-2-deficient stargazer
influence synaptic strength (Nair et al. 2013). All these mice, where the deletion of TARP γ-2 leads to a total
receptor properties are differentially influenced and/or loss of surface AMPA receptors on cerebellar granule cells
controlled by auxiliary subunits, making these proteins in postnatal day 14 mice (Chen et al. 2000). Deletion
key regulators of synaptic strength (Table 1). of other auxiliary subunits shows a less severe impact
The regulation of AMPA receptor density by auxiliary on AMPA receptor surface levels, presumably due to
subunits does not depend on a single, uniform the high functional and spatial redundancy of large
Figure 1. Schematic illustration of the
membrane topology of the different
families of AMPA receptor auxiliary
subunits
Additionally, highlighted are locations of
specific domains of the different protein
families: the PDZ binding motifs for TARPs
and CKAMPs, the C-terminal
phosphorylation site of TARPs (that
interacts with the cell membrane and
influences synaptic anchoring) and the
characteristic region of CKAMPs
(cysteine-rich region) and CNIH-2/3
(adapted from Monyer & von Engelhardt,
2015 and Kamalova & Nakagawa, 2021).
©C 2020 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society
474 E. Jacobi and J. von Engelhardt J Physiol 599.2
groupsof auxiliary subunits.Hence, deletionofCKAMP44 peak glutamate concentration rapidly decreases with
or TARP γ-8 reduces somatic AMPA receptor currents increasing distance from the presynaptic release site.
by approximately 50% in dentate gyrus granule cells. Simulations and experimental data show that synaptic
However, the deletion of both auxiliary subunits reduces glutamate concentration is non-saturating, i.e. results
somatic AMPA receptor currents to approximately 8% in the opening of only a fraction of the postsynaptic
(Khodosevich et al. 2014). Based on the numbers, the AMPA receptors (Liu et al. 1999; Rusakov et al. 1999;
deletion of both subunits seems to be additive. In contrast, Jonas, 2000; McAllister & Stevens, 2000; Wu et al.
in cerebellar Golgi cells synaptic AMPA receptor number 2007). Consequently, synaptic strength should depend
is not affected by deletion of TARP γ-2 or TARP γ-3 alone, on glutamate affinity of AMPA receptors. As a corollary,
but is virtually absent in TARP γ-2/γ-3 double knockout one would assume that auxiliary subunits may influence
mice (estimated from synaptic current amplitudes). This synaptic strength not only by controlling the number
suggests that the two auxiliary subunits are functionally of synaptic AMPA receptors, but also by modulating
redundant and can compensate for the loss of the other their glutamate affinity. Several auxiliary subunits of the
auxiliary subunit (Menuz et al. 2008). On the other hand, CKAMP-, CNIH- and TARP-families increase glutamate
TARP γ-3 is not expressed in cerebellar granule cells affinity (Yamazaki et al. 2004; Tomita et al. 2005a; Coombs
(Tomita et al. 2003; Fukaya et al. 2005),which explainswhy et al. 2012; Khodosevich et al. 2014; Farrow et al. 2015). An
it cannot compensate for the loss of TARP γ-2 in this cell exception is TARP γ-5, which decreases glutamate affinity
type. Interestingly, cerebellar granule cells express TARP of GluA2-containing AMPA receptors (Kato et al. 2008).
γ-7. Knockdown of TARP γ-7 in stargazer mice rescues Although there is no direct experimental evidence, it is
synaptic currents, suggesting that TARP γ-7 prevents therefore likely that the change in synaptic strength in
synaptic localization of AMPA receptors in the absence mice with genetic deletion of auxiliary subunits results
of TARP γ-2 (Bats et al. 2012). Hence, the effect of the not only from an alteration in AMPA receptor number
genetic deletion of an AMPA receptor auxiliary subunit but also from a change in glutamate affinity (Rouach et al.
depends on the presence of other functionally redundant 2005; Tomita et al. 2005a; Menuz et al. 2008; Coombs et al.
subunits. 2012; Herring et al. 2013; Khodosevich et al. 2014; Chen
The amplitude of AMPA receptor-mediated currents et al. 2018).
dependsnot only on thenumber of postsynaptic receptors, The strong decline of the glutamate concentration with
but also on their affinity to glutamate. AMPA receptors growing distance from the vesicle release site explains
show a relatively low glutamate affinity compared the relevance of the precise subsynaptic position of
to other glutamate receptors, especially the NMDA AMPA receptors for synaptic strength. In fact, AMPA
receptor-type (Liu et al. 1999). Peak synaptic glutamate receptors do not distribute uniformly in the synapse,
concentration has been estimated to be in the milli- but cluster in nanodomains (Masugi-Tokita et al. 2007;
molar range (Rusakov et al. 1999; Jonas, 2000). However, MacGillavry et al. 2013). Interaction of AMPA receptors
Figure 2. Schematic overview of the
influence of AMPA receptor density,
gating and postsynaptic organization
on synaptic strength
Top, synaptic strength correlates with the
number of synaptic AMPA receptors.
Middle, synaptic strength depends on
peak-open probability, glutamate affinity
and conductance of synaptic AMPA
receptors. Bottom, postsynaptic AMPA
receptor organization is relevant for
synaptic strength. Precise localization of
AMPA receptors opposite to presynaptic
release sites (in so-called nanocolumns)
increases synaptic strength, while a more
random postsynaptic distribution of AMPA
receptors decreases synaptic strength.
©C 2020 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society
J Physiol 599.2 Modulation of information processing by AMPA receptor auxiliary subunits 475
with membrane-associated guanylate kinases (MAGUKs) by CKAMPs and GSG1L (Menuz et al. 2008; Schwenk
such as PSD95 explains low diffusion rates and hence et al. 2009, 2012; Shanks et al. 2012; Straub & Tomita,
long dwell times of AMPA receptors in nanodomains 2012; Boudkkazi et al. 2014; Khodosevich et al. 2014). The
(Nair et al. 2013). In addition, the N-terminal domain deactivation time constants of heterologously expressed
is important for synaptic localization of AMPA receptors AMPA receptors without auxiliary subunits are in the
(Dı́az-Alonso et al. 2017;Watson et al. 2017). Importantly, range of 0.7 ms (homomeric GluA2o) and 1.3 ms
the nanodomains are in close proximity with presynaptic (homomeric GluA1o), i.e. a difference of 600 μs. In
vesicle release sites (Tang et al. 2016), a structural contrast, incorporation of TARP γ-8 or CNIH-2 into
organization that ismost likelymediated by trans-synaptic AMPA receptors increases the deactivation time constant
protein-protein interaction, e.g. between Neuroligin and of homomeric GluA1 receptors to ca 5 ms and 9 ms,
Neurexin. This alignment of a postsynaptic nanodomain respectively (Kato et al. 2010). Similarly, desensitization
with a presynaptic release site in, so called, nanocolumns time constants are several-fold larger in TARP γ-8
ensures high glutamate concentration at the postsynaptic or CNIH-2-containing GluA1 receptors compared to
site of AMPA receptor anchoring. Consistently, disruption pure homomeric GluA1 receptors (Kato et al. 2010).
of nanocolumns by expression of a truncated form Deactivation and desensitization time constants of AMPA
of NLG1 reduces synaptic strength (Haas et al. 2018). receptors are, in most neurons, considerably slower
Auxiliary subunits of the CKAMP and TARP families than those of heterologously expressed receptors. For
interact with MAGUKs, and in particular with PSD95 example, principal cells of the hippocampus display
(Dakoji et al. 2003; Khodosevich et al. 2014; Klaassen et al. deactivation time constants in the range of 2.3 ms
2016; Schmitz et al. 2017). CKAMPs and TARPs therefore (dentate gyrus) and 3 ms (CA1, Colquhoun et al. 1992).
increase synaptic strength not only by augmenting The most likely explanation for these slow kinetics is
synaptic number of AMPA receptors but most likely also the presence of AMPA receptor complexes that contain
by anchoring AMPA receptors in nanodomains in close auxiliary subunits. Indeed, genetic deletion of TARP
vicinity of presynaptic vesicle release sites. γ-8, CKAMP44, CKAMP52, GSG1L and CNIH-2 and 3
Finally, the strength of a synapse depends also on decreases deactivation time constants of AMPA receptors
the conductance and peak open probability of its in CA1 neurons and dentate gyrus granule cells (Rouach
receptors.Most auxiliary subunits increaseAMPAreceptor et al. 2005; Herring et al. 2013; Boudkkazi et al. 2014;
conductance and/or peak open probability (Tomita et al. Khodosevich et al. 2014; Gu et al. 2016; Klaassen et al.
2005a; Cho et al. 2007; Schwenk et al. 2009; Pierce & 2016). Importantly, the magnitude of the influence of
Niu, 2019). One exception is GSG1L, which decreases auxiliary subunits on gating kinetics strongly depends
synaptic strength in cerebellar and hippocampal neurons, on the AMPA receptor composition and presence of
presumably by decreasing the synaptic AMPA receptor the flip/flop cassette (Turetsky et al. 2005; Tomita et al.
density and channel conductance of calcium permeable 2005a, 2007; Kato et al. 2007, 2010; Kott et al. 2007;
receptors (McGee et al. 2015; Gu et al. 2016; Mao et al. Morimoto-Tomita et al. 2009; Dawe et al. 2019)
2017). Experiments with fast application of glutamate onto
patches of neurons therefore indeed showed that auxiliary
subunits influence gating properties of AMPA receptors in
AMPA receptor kinetics thebrain, such asdeactivation anddesensitization. Inmost
neurons, decays of synaptic currents are mainly dictated
The computation of excitatory synapses depends not only by deactivation kinetics of AMPA receptors. This suggests
on the peak size of the depolarizing current but also on its that auxiliary subunits shape decays of synaptic currents.
shape. Hence, rise time, deactivation and desensitization There are a few neuron types that express AMPA receptors
kinetics of synaptic AMPA receptors determine the charge with gating kinetics similar to those of homomeric AMPA
transfer and timing of synaptic currents and therefore receptors. Particularly fast deactivation (0.5 ms) has been
directly affect synaptic communication. Core subunit observed for neurons of the auditory system (Raman
composition of AMPA receptors (i.e. GluA1-4, flip/flop) et al. 1994; Raman & Trussell, 1995). It is likely that
determines gating kinetics (Mosbacher et al. 1994; AMPA receptors with such fast kinetics contain few
Traynelis et al. 2010). However, especially deactivation auxiliary subunits that slow deactivation such as TARPs
and desensitization rates of AMPA receptors are more or CNIHs. Importantly, decay time constants of synaptic
strongly affected by the presence of auxiliary subunits. currents are also extremely fast in auditory neurons
Most known auxiliary subunits decrease the deactivation (<1 ms). Axosomatic synapses and short membrane time
rate of AMPA receptors, with the exception of TARP γ-5, constants ensure little filtering of synaptic currents and
which increases the deactivation rate. The desensitization explain negligible temporal summation of auditory inputs
rate and/or the steady-state desensitization of AMPA (Rothman et al. 1993; Raman et al. 1994). Several auditory
receptors is decreased by TARPs and CNIHs but increased neurons form giant synapses with a high number of
©C 2020 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society
476 E. Jacobi and J. von Engelhardt J Physiol 599.2
AMPA receptors. The fast kinetics and large amplitude receptors in these cell types (Menuz et al. 2008; Bats
of AMPA receptor-mediated currents in auditory neurons et al. 2012). However, since TARPs themselves attenuate
are crucial for conveying temporal information with high the polyamine block (Soto et al. 2014; Brown et al.
fidelity (Rothman et al. 1993). Very fast EPSC decays were 2017), it is also reasonable that the change in polyamine
observed additionally in amacrine, basket and stellate cells block in TARP γ-2/γ-3 knockout mice is not only due
(Geiger et al. 1997; Crowley et al. 2007; Osswald et al. to a decrease in GluA2-containing AMPA receptors, but
2007), suggesting that in these neurons AMPA receptor also due to the loss of the direct influence of TARPs
auxiliary subunits are also not strongly expressed or exert on polyamine block. TARP γ-8 controls, together with
only a small influence on EPSC decays. the auxiliary subunits CNIH-2 and CNIH-3, the surface
However, compared to the extremely fast kinetics levels of GluA1-containing receptors in CA1 pyramidal
in the aforementioned cells, AMPA receptor decay neurons. The presence of TARP γ-8may prevent the inter-
kinetics are considerably slower in most synapses. For action of CNIH-2/-3 with subunits other than GluA1
example, AMPA receptor decay rates are around 2–7 ms and, thus, selectively promotes the trafficking of these
in hippocampal synapses (Geiger et al. 1995; McGee et al. receptors to the cell surface (Herring et al. 2013; but see
2015; Klaassen et al. 2016; Schmitz et al. 2017). Consistent also Boudkkazi et al. 2014). Yet another mechanism of
with the hypothesis that slow decay kinetics depend the regulation of subunit composition by auxiliary sub-
on the influence of auxiliary subunits, the deletion of units has been described byMcGee and colleagues (McGee
GSG1L, CKAMP52 or CKAMP59 decreases decay rates et al. 2015). The auxiliary subunit GSG1L specifically
in these synapses (McGee et al. 2015; Klaassen et al. 2016; supresses currents of calcium permeable AMPA receptors
Schmitz et al. 2017). Auxiliary subunits therefore alter by decreasing their Ca2+-permeability and conductance.
computational properties of synapses by influencing decay Thus, in contrast to the other auxiliary subunits, GSG1L
kinetics. Synapses of hilar mossy cells display comparably directly supresses the function of certain receptors, rather
slowdecay kinetics (ca 12ms), which is explained by a high than promoting it.
expression of CNIH-2 in this cell type (Boudkkazi et al.
2014). The slow kinetics make these synapses less suitable Short-term plasticity
for transmission of information with high temporal
precision, but ideal for the integration of information. The main determinant for synaptic short-term plasticity
in many synapses is the release probability of presynaptic
AMPA receptor Ca2+ permeability vesicles. However, in synapses that frequently have two
consecutive vesicle releases in a short period of time,
Ca2+ permeability and conductance of AMPA AMPA receptor desensitization is relevant for short-term
receptors depends on their subunit composition. plasticity in addition to the presynaptic factors. High
Thus, GluA2-containing AMPA receptors are Ca2+ release probability, but also spill-over of glutamate from
impermeable, and GluA2-lacking AMPA receptors are one release site to a neighbouring release site and slow
Ca2+ permeable. Moreover, the presence of the subunit diffusionof glutamateoutof a synapse favour the influence
GluA2 decreases the conductance (Verdoorn et al. 1991; of AMPA receptor desensitization on short-term plasticity
Burnashev et al. 1992). Consequently, the composition (Blitz et al. 2004).Hence, the specific geometryof a synapse
of AMPA receptors directly affects the computation of and the proximity of neighbouring release sites affects
synapses. short-term plasticity via the desensitization of AMPA
The regulation of AMPA receptor composition by receptors. For example, AMPA receptor desensitization
auxiliary subunits is mainly based on the specific inter- alters short-term plasticity in retinogeniculate synapses of
action with certain receptor subunits and takes place relay neurons in the lateral geniculate nucleus (Chen et al.
on different functional levels. These different levels of 2002; Hauser et al. 2014). Retinogeniculate synapses are
regulationononehand, and the presence ofmore thanone very large synapses that contain many release sites (Rafols
auxiliary subunit per cell on the other, leads to a complex &Valverde, 1973). This allows spill-over of glutamate from
and sometimes not uniform effect of auxiliary subunits active to non-active release sites. In addition, the geometry
on receptor composition throughout the brain. TARP of retinogeniculate synapses precludes fast diffusion of
γ-2, for example, specifically protects GluA1-containing glutamate out of the synaptic cleft (Rafols & Valverde,
receptors from lysosomal degradation and thereby alters 1973; Budisantoso et al. 2012). Hence, presynaptic release
receptor composition inCA1neurons (Kessels&Malinow, of glutamate effectively desensitizes AMPA receptors in
2009). On the other hand, enhancement of cytoplasmic active and non-active neighbouring release sites of the
polyamine block of AMPA receptors in stellate cells of same synapse (Budisantoso et al. 2012).
TARP γ-2 knockout mice or in Golgi cells of TARP Examining the effect of receptor desensitization on
γ-2/γ-3 knockout mice suggests that TARP γ-2 and/or short-termplasticitymore closely shows that it is especially
γ-3 increase the number of GluA2-containing AMPA the time course of the recovery from desensitization of
©C 2020 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society
J Physiol 599.2 Modulation of information processing by AMPA receptor auxiliary subunits 477
AMPA receptors that affects synaptic short-termplasticity. domain (Dı́az-Alonso et al. 2017; Watson et al. 2017)
AMPA receptor desensitization and the recovery from via which AMPA receptors may interact with extracellular
desensitization are differentially modulated by different or presynaptic proteins. It remains to be shown whether
auxiliary subunits (Boudkkazi et al. 2014; Khodosevich the N-terminal domain influences short-term plasticity
et al. 2014; Farrow et al. 2015; McGee et al. 2015). For by affecting diffusion of AMPA receptors. In addition, the
example, while heterologously expressed AMPA receptors N-terminal domain is highly mobile (Dawe et al. 2019)
that contain no auxiliary subunits recover very quickly and it is possible that the agonist induced compression
fromdesensitization (timeconstantsbetween16and44ms of the N-terminal domain alters synaptic anchoring and
for GluA2–4; GluA1i = 151 ms, GluA1o = 105 ms; diffusion of AMPA receptors.
Kessler et al. 2008), the presence of the two auxiliary sub- Klaassen and colleagues showed that auxiliary subunits
units CKAMP39 and CKAMP44 strongly slows recovery can also influence short-term plasticity by affecting the
from desensitization. Thus, CKAMP39 and CKAMP44 decay kinetics of synaptic AMPA receptors (Klaassen et al.
increase the time constant of recovery fromdesensitization 2016). Short-term plasticity may be influenced by decay
of AMPA receptors ca 10-fold. The time constants kinetics if firing frequency of presynaptic cells is high,
from heterologously expressed CKAMP44-containing i.e. when the activation of AMPA receptors occurs during
AMPA receptors is consistent with the comparably slow the decay phase of a previous activation. CKAMP52 (aka
recovery from desensitization of AMPA receptors found shisa6) reduces the rate of AMPA receptor deactivation.
in neurons with highCKAMP44 expression (Khodosevich Consistently, genetic deletion renders the decay of synaptic
et al. 2014; Chen et al. 2018). TARPs on the other currents in CA1 neurons faster. This explains the decrease
hand, decrease the time constant of recovery from in short-term facilitation in CKAMP52 knockout mice
desensitization (Priel et al. 2005; Khodosevich et al. 2014). when CA1 neurons are stimulated with high frequency of
Importantly, the genetic deletion of CKAMP44 or TARP 50 Hz (Klaassen et al. 2016).
γ-8 affects short-term plasticity in the hippocampus. Short-term plasticity is usually tested in acute brain
Thus, short-term depression is stronger in TARP γ-8 slices with artificial stimulation protocols. Neuronal
knockout mice and less pronounced in CKAMP44 firing patterns, but also release probability, glutamate
knockout mice (Khodosevich et al. 2014). Short-term diffusion and reuptake may be different in vivo. To
plasticity experiments in the presence of cyclothiazide, a understand whether AMPA receptor auxiliary sub-
potent blocker of AMPA receptor desensitization, proved units influence synaptic computation also in vivo,
that the influence of the two proteins on short-term we recorded firing rates of lateral geniculate nucleus
plasticity indeed results from their effect on the rate relay neurons in head-fixed non-anaesthetized mice in
of recovery from desensitization of AMPA receptors response to visual stimuli. The magnitude of On- and
(Khodosevich et al. 2014). Off-responses was increased in CKAMP44 knockout mice
AMPA receptor diffusion mitigates the effect compared to wild-type mice. These findings confirmed
of desensitization on short-term plasticity. Thus, the data from acute brain slice experiments showing
desensitized AMPA receptors diffuse out of the synapse that CKAMP44 influences computation of synapses by
and are replaced by non-desensitized AMPA receptors affecting short-term depression (Fig. 3). Interestingly,
(Heine et al. 2008; Constals et al. 2015). Auxiliary CKAMP44 reduces relay neuron responses by this
subunits such as TARPs and CKAMPs reduce AMPA mechanism despite the fact that it increases the number of
receptor diffusion by anchoring receptors to scaffolding synaptic AMPA receptors (Chen et al. 2018). The data also
proteins at the postsynaptic density (PSD) (Bats et al. imply that the influence of CKAMP44 on relay neuron
2007; Opazo et al. 2010; Sumioka et al. 2010; Klaassen firing is relevant in particular when presynaptic retinal
et al. 2016). Auxiliary subunits should therefore in ganglion cells fire at high frequency (Chen et al. 2018).
principle prolong the time that a desensitized AMPA
receptor dwells in the synapse. However, synaptic Long-term plasticity (LTP/LTD)
anchoring by auxiliary subunits seems to depend on the
conformation of the receptors and is weakened upon Long lasting alterations of the strength of synapses
AMPA receptor desensitization (Constals et al. 2015). are believed to be the foundation of learning and
Thus, desensitizedAMPAreceptors showahighermobility memory. Since the first description of LTP by Bliss
than non-desensitized AMPA receptors. Consequently, and Lomo in 1973, it has become clear that long
desensitized receptors diffuse out of the synapse and lasting synaptic plasticity is not uniform, but exists
can be replaced by non-desensitized receptors. This can in many different variations (reviewed in Huganir &
be explained by an unbinding of desensitized AMPA Nicoll, 2013). A fundamental mechanism underlying
receptors from TARPs (Constals et al. 2015). The dwell LTP and LTD in many synapses is a change in the
time of AMPA receptors in synapses depends not only number of synaptic AMPA receptors. Several AMPA
intracellular anchoring but also on their N-terminal receptor auxiliary subunits including TARP γ-2 and γ-8,
©C 2020 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society
478 E. Jacobi and J. von Engelhardt J Physiol 599.2
CKAMP59, CNIH-2/-3 and GSG1L influence synaptic Homeostatic plasticity
long-term plasticity (Rouach et al. 2005; Tomita et al.
2005b; Herring et al. 2013; Khodosevich et al. 2014; In order to integrate a broad spectrum of synaptic input
Gu et al. 2016; Schmitz et al. 2017). This effect of and, at the same time, maintain a relatively stable output,
auxiliary subunits on long-term plasticity is perhaps not neurons adjust the strength of their synapses by altering
too surprising, considering their role in the control of synaptic AMPA receptor density (O’Brien et al. 1998;
trafficking and subcellular localizationofAMPAreceptors. Turrigiano et al. 1998). This form of long-term plasticity
The mechanisms of how auxiliary subunits influence LTP is termed homeostatic scaling and has to be separated
have been extensively investigated forTARPs. For example, from the Hebbian forms of synaptic plasticity that have
hippocampal LTP depends on phosphorylation of TARP been described above. However, similarly to Hebbian
-2 (Tomita et al. 2005b). Hippocampal and cerebellar plasticity, changes inAMPAreceptordensity are theunder-γ
LTD on the other hand require dephosphorylation of lying mechanisms of up- and down-scaling of synapses.
TARP γ-2 (Tomita et al. 2005b; Nomura et al. 2012). Additionally, other processes, such as alterations in the
Similarly, phosphorylation of TARP -8 by CaMKII is subunit composition of synaptic AMPA receptors andγ
needed for expression of LTP in hippocampal neurons their phosphorylation pattern play a role during homeo-
(Park et al. 2016). Phosphorylation of TARPs initiates static scaling (Siddoway et al. 2013; Soares et al. 2013;
diffusion and synaptic trapping of AMPA receptor Diering et al. 2014; Kim & Ziff, 2014). The influence
complexes via interaction with PDZ-domain containing of auxiliary subunits on AMPA receptor trafficking
proteins such as PSD95 (Hafner et al. 2015). Besides TARP suggests that they may play a role in homeostatic scaling.
-2 and -8, the auxiliary subunitsCNIH-2/-3 andGSG1L Indeed, visual deprivation or TTX treatment increasesγ γ
also affect LTP.However,whileCNIH-2/-3, like theTARPs, the expression and phosphorylation of TARP γ-2 in
is needed for normal LTP expression, GSG1L seems to the lateral geniculate nucleus or in cortical cultures,
suppress LTP (Herring et al. 2013; Gu et al. 2016). respectively (Louros et al. 2014). Importantly, synaptic
up-scaling in response to visual deprivation depends on
Electrical Stimulation Electrical Stimulation increased
Electrical Stimulation
A B C
wildtype
pA mV mV
CKAMP44-/-
synaptic synaptic action
currents potentials potentials
Figure 3. Effect of AMPA receptor auxiliary subunits on neuronal computation by the example of
CKAMP44
A, short-term depression of synaptic currents is less strong in retinogeniculate synapses of lateral geniculate relay
neurons of CKAMP44−/− mice than in wild-type mice. B, the weaker short-term depression in CKAMP44−/− mice
explains the augmented postsynaptic depolarization in response to train stimulation of retinogeniculate synapses.
C, relay neurons fire action potentials when the same stimulus train as in B is delivered with stronger stimulation
strength. Relay neurons show increased firing probability in response to this stimulus train than relay neurons
of wild-type mice. This difference is also explained by the difference in short-term plasticity (adapted from Chen
et al. 2018).
©C 2020 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society
J Physiol 599.2 Modulation of information processing by AMPA receptor auxiliary subunits 479
the phosphorylation of TARP γ-2 (Louros et al. 2014). Bats C, Soto D, Studniarczyk D, Farrant M & Cull-Candy SG
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downscaling of cortical synapses (Louros et al. 2018). TARPed and TARPless AMPARs in stargazer neurons. Nat
It is not known whether synaptic properties, and in Neurosci 15, 853–861.
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©C 2020 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society