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Plasticity oftheCerebellum
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Xin-TaiWang andYingShen
43
Abstract
Since 1990s, long-term depression of (LTD) at parallel
ber–Purkinje cell synapses has been regarded as a cellular phenomenon for motor learning. However, parallel
ber LTD by itself cannot account for motor learning.
Here, we review a rich variety of use-dependent plasticity
in the cerebellar cortex and nuclei, including long-term
potentiation (LTP) and LTD at excitatory and inhibitory
synapses, and persistent modulation of intrinsic excitability. Prevailing studies demonstrated that intrinsic and
extrinsic factors, including neuronal excitation, specic
molecular mechanisms, theta oscillation, and external
neuromodulators, are essential to different forms of plasticity in the cerebellum.
Keywords
Long-term depression · Long-term potentiation
Purkinje cell · Granule cell · Parallel ber · Climbing ber
43.1 Parallel Fiber LTD
A persistent attenuation of parallel ber–Purkinje cell synapse
is produced when parallel ber and climbing ber inputs to a
Purkinje cell are stimulated together at low frequency (Ito
et al. 1982). Parallel ber LTD is associative and saturable
upon repeated parallel ber stimulation. Strong parallel ber
stimulation or conjunctive climbing ber/parallel ber stimulation induces parallel ber LTD through the activation of
postsynaptic metabotropic glutamate receptors (mGluRs) and
α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid
receptors (AMPARs), and subsequent rise of internal Ca2+.
The activation of protein kinase Cα (PKCα) and α-Ca2+/
calmodulin-dependent protein kinase II (αCaMKII) is required
for its induction as well. Cytosolic phospholipase A2α
(cPLA2α)/cyclooxygenase-2 cascade plays important roles in
this plasticity by acting on PKCα. Serotonin type 7 receptor
(5-HT7R) also activates PKC and mitogen-activated protein
kinase (MAPK) pathway and thereby induces parallel ber
LTD (Lippiello etal. 2016). Cannabinoid receptor 1 (CB1R)
and nitric oxide/soluble guanylyl cyclase/cGMP-dependent
protein kinase/phosphatase pathways are also involved (Bear
and Linden 2000; Safo and Regehr 2005). Parallel ber LTD
is also subject to the modulation of secretary molecules, for
example, nitric oxide (NO), which is produced by N-methylD-aspartate receptors (NMDARs) activation at parallel berinterneurons synapses (Kono etal. 2019). Parallel ber LTD is
expressed postsynaptically, as a reduction in the number of
surface AMPARs produced by clathrin-dependent endocytosis
(Wang and Linden 2000). Clathrin complex-associated molecules, Numb and transferrin receptor 1 (TFR1), are able to
modulate the trafcking of mGluR1, and their deletion in
Purkinje cells inhibits parallel ber LTD (Zhou et al. 2015,
2017) (Fig.43.1).
X.-T. Wang · Y. Shen (*)
Department of Physiology, Zhejiang University School of
Medicine, Hangzhou, P.R. China
e-mail: yshen@zju.edu.cn
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_43
281
282
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Fig. 43.1 A diagram
showing signaling cascades
that are involved in parallel
ber LTD
X.-T. Wang and Y. Shen
43.2 Parallel Fiber LTP
Parallel ber–Purkinje cell synapses undergo two forms of
homosynaptic LTP, depending on stimulus frequency. Four
to eight Hertz parallel ber stimulation induces presynaptically expressed LTP, which is ascribed to increased transmitter release and associated with a decrease in paired-pulse
facilitation (Salin etal. 1996) and evoked glutamate transport currents in glial cells (Linden 1998). Furthermore,
4–8 Hz LTP is mediated by presynaptic adenylyl cyclase/
cyclic adenosine monophosphate (cAMP)/protein kinase A
(PKA) pathway (Hansel etal. 2001). Evidence from cerebellar cultures shows that 4-Hz LTP is mediated by PKAmediated phosphorylation of active zone protein RIM1α
(Lonart etal. 2003). Again, presynaptically expressed parallel ber LTP is also subject to NO modulation (Bouvier etal.
2016). It is also shown that β-adrenergic receptor (β1AR)/
EPAC signaling participates in this form of LTP upon 10-Hz
parallel ber stimulation (Martín etal. 2020).
In contrast, 1-Hz parallel ber stimulation induces a postsynaptically expressed LTP. This LTP requires a low level of
Ca2+ in Purkinje cells (Coesmans etal. 2004), which leads to
the activation of cPLA2α, the liberation of arachidonic acid,
and the production of 2-arachidonoylglycerol (2-AG) that
diffuses to presynaptic terminals. Activated CB1R on presynaptic terminals by 2-AG triggers the activation of nitric
oxide synthase and produces a low level release of nitric
oxide from parallel ber terminals (Wang et al. 2014).
Afterward, nitric oxide works postsynaptically with serine/
threonine phosphatases to promote the required trafcking
of AMPARs. In these processes, nitric oxide activates soluble guanylate cyclase, which induces the phosphorylation of
GluA1-S845 by cGMP-dependent protein kinase II (cGKII)
and upregulates synaptic expression of AMPARs (Serulle
et al. 2007). Further evidence shows that 5-HT7R participates in this form of plasticity via PKC-MAPK signaling
pathway (Lippiello etal. 2016). The regulation of P/Q-type
2+
channels (Cav2.1) by calcium sensor proteins is also
Ca
required for postsynaptically expressed LTP (Mark et al.
2015). Interestingly, this form of LTP requires the change of
open probability of GluA3-containing AMPARs, but not the
trafcking of GluA1-containing AMPARs (GutierrezCastellanos etal. 2017). Since 1-Hz LTP and parallel ber
LTD are both expressed postsynaptically, it is suggested that
1-Hz LTP is a resetting mechanism for motor learning and
causes the extinction of learned associations (Fig.43.2).
43 Plasticity oftheCerebellum
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Fig. 43.2 A diagram
showing signaling cascades
that are involved in
postsynaptically expressed
LTP
283
43.3 Climbing Fiber LTD
Five Hz tetanization of climbing bers evokes LTD at climbing ber–Purkinje cell synapse, which is homosynaptic and
saturable (Hansel and Linden 2000). Climbing ber LTD
requires intracellular Ca2+ and the activation of mGluR1 and
PKC and is expressed postsynaptically (Shen etal. 2002).
Climbing ber LTD is hypothesized to control the integrative
response of Purkinje cell because complex spikes are attenuated after 5Hz tetanization. Interestingly, 5Hz tetanization
at climbing bers also induces LTP of glutamate transporter
EAAT4, which is expressed on Purkinje neurons (Shen and
Linden 2005).
43.4 Interneuron-Purkinje Cell
SynapticLTP
The LTP of GABAA receptor-mediated inhibitory postsynaptic currents at interneurons–Purkinje cell GABAergic synapses is induced by repetitive climbing ber activation (Kano
etal. 1992). This inhibitory LTP requires a postsynaptic Ca2+
transient from internal Ca
CaMKII and PKA.An early study showed that simultaneous
activity of inhibitory synapses is needed for the induction of
2+
stores and the activation of
inhibitory LTP (Kano 1996), but another later study showed
that simultaneous inhibitory activity suppresses this LTP
(Kawaguchi and Hirano 2000). Interneuron-Purkinje cell
synaptic LTP has a major inuence on Purkinje cell throughput, as it modulates the spike ring pattern of Purkinje cells
(Häusser and Clark 1997).
43.5 Plasticity ofMossy Fiber-Granule Cell
Synapses
Mossy ber–granule cell synapses provide a large potential
substrate for information storage. The activation of mossy
bers combined with postsynaptic depolarization of granule
cells results in mossy ber LTP (D’Angelo et al. 1999),
which requires postsynaptic depolarization, Ca
activation of NMDAR, mGluR, and PKC. Besides, the
increase of glutamate released by granule cells can activate
mGluRs at parallel ber-Golgi cell synapses, enhancing
inward rectier currents, and hyperpolarizing Golgi cells.
The inhibitory input by Golgi cells also affects the expression of mossy ber LTP.In contrast, protracted low- frequency
stimulation causes mossy ber LTD (Gall etal. 2005). Mossy
ber LTP and LTD promote the population (summated) and
sparse (local) coding, respectively, in the granular layer.
2+
inux and
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X.-T. Wang and Y. Shen
43.6 Plasticity intheDeep Cerebellar
Nuclei (DCN)
Mossy ber-DCN plasticity depends on the excitation of
DCN cells (Pugh and Raman 2006), while Purkinje cellDCN plasticity depends on the excitation of both DCN cells
and Purkinje cells (Aizenman et al. 1998). DCN cells can
also generate a plasticity of intrinsic excitability (Aizenman
etal. 2003). Mossy ber-DCN plasticity and intrinsic excitability can work together to generate a coincidence detection
driven by intracellular calcium transients.
43.7 Plasticity ofIntrinsic Excitability
inPurkinje Cells
Purkinje cell excitability can be enhanced by somatic current
injections or parallel ber stimulation. Signal cascades for
LTP of intrinsic excitability include local Ca2+ in spines and
protein phosphatases. The interactions between these molecules and PKA and casein kinase 2 result in a downregulation of small conductance Ca2+-activated potassium (SK)
channels, thereby reducing an intrinsic inhibitory inuence.
SK channels contribute to intrinsic excitability and plasticity
by regulating ring frequency and Ca2+ transients in Purkinje
cells (Grasselli etal. 2020). In addition, mGluR1 and PKA
pathways are involved in the homeostatic intrinsic plasticity
of Purkinje cells (Shim etal. 2016). Stromal interaction molecule 1 (STIM1) participates somatic Ca2+ inux and regulates intrinsic ring of Purkinje cells (Ryu etal. 2017). More
evidence shows that the disease-linked molecules regulate
intrinsic excitability as well, for example, tuberous sclerosis
complex 1 (TSC1), corticotropin-releasing factor (CRF), and
tumor necrosis factor alpha (TNF-α) released from microglia. TSC1 dysfunction results in increased mTOR activity,
which is critical to cellular homeostasis (Tsai etal. 2012).
CRF increases the excitability of Purkinje neurons by modulating sodium, potassium, and hyperpolarization-activated
cation-selective current (Ih) currents (Libster et al. 2015).
TNF-α released from microglia via toll-like receptor 4
induces a potentiation of intrinsic excitability in Purkinje
cells (Yamamoto et al. 2019). LTP of intrinsic plasticity
occludes subsequent parallel ber LTP, but facilitates parallel ber LTD (Coesmans etal. 2004). LTP of intrinsic plasticity can not only be locally restricted to one synapse but
also affects a large number of synapses, depending on the
identity and location of intrinsic conductance altered. Both
intrinsic and synaptic plasticities are required for motor
memory consolidation (Jang etal. 2020).
43.8 Spike–Timing-Dependent Plasticity
(STDP) intheCerebellum
Ever since the rst report by Ekerot and Kano (1989), a
series of studies have determined that parallel LTD is induced
best when parallel ber stimulation precedes climbing berevoked complex spikes in Purkinje cells by 50–250ms, suggesting an anti-Hebbian STDP mechanism in the cerebellum.
Cerebellar STDP differs from that at hippocampal synapses,
in that it is independent of axonal spike output. Rather, external climbing ber stimulation and locally elicited Ca2+ spikes
play a key role (Piochon etal. 2013).
43.9 Conclusions
It is clear now that cerebellar learning is an integrated process involving numerous forms of synaptic plasticity in the
cerebellar cortex and nuclei, where various specic spatial
patterns are organized. Channeling begins from granular
layer and is concluded in the molecular layer, where
Purkinje cells integrate signals from different inputs.
Plasticity is also organized in specic temporal patterns in
the granular and molecular layer. In this view, the mechanisms for cerebellar learning should be viewed as the integration of various forms of plasticity in the cerebellar
cortex and nuclei (Fig.43.3).
43 Plasticity oftheCerebellum
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Fig. 43.3 A summary of
plasticity in the cerebellar
circuit (modied from Hansel
etal. 2001). The occurrence
of long-term plasticity is
coded with color: red
indicating potentiation and
blue indicating depression.
The intrinsic excitability is
labeled with action potentials
in somata, whereas
conventional synaptic LTP or
LTD is labeled with bars of
colors at synapses
285
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Long-Term Depression at Parallel
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Fiber–Purkinje Cell Synapses
MichisukeYuzaki
44
Abstract
Long-term depression (LTD) at parallel ber (PF)–
Purkinje cell (PC) synapses plays an important role in
cerebellar oculomotor control and classical conditioning.
Climbing ber inputs represent an error signal to generate
specic temporal and spatial Ca2+ dynamics at PC spines
leading to endocytosis of postsynaptic AMPA receptors at
PF synapses during LTD induction.
Keywords
Albus · Climbing ber · LTD · Long-term depression
Marr · Motor learning · Nitric oxide · Parallel ber
44.1 Introduction
According to the Marr–Albus–Ito theory, long-term depression (LTD) at parallel ber (PF)–Purkinje cell (PC) synapses
serves as supervised learning machinery underlying
cerebellum- dependent motor learning (Ito et al. 2014).
Climbing ber (CF) inputs to PCs represent error signals to
trigger endocytosis of postsynaptic AMPA receptors leading
to LTD at PF–PC synapses. Motor learning is impaired in animals treated with various pharmacological reagents or genetically engineered to modify signaling cascades involved in
LTD at PF-PC synapses (Yuzaki 2013). In recent years, however, many different types of synapses, including PF to molecular-layer interneuron (MLI) synapses, CF–PC synapses, and
mossy ber to granule cell synapses, have been shown to be
plastic and contribute to cerebellum-dependent learning (Gao
etal. 2012). Thus, many synaptic sites at which a variety of
plastic changes can modulate learning in a similar manner
M. Yuzaki (*)
Department of Physiology, Keio University School of Medicine,
Tokyo, Japan
e-mail: myuzaki@keio.jp
(Edelman and Gally 2001). However, PF–PC synapses outnumber other types of synapses at least by a factor of 50, indicating the larger capacity of learning (Kawato etal. 2021).
Indeed, the number of postsynaptic AMPA receptors at PF–PC
synapses is more variable than that at CF–PC and PF–MLI
synapses, indicating that plastic changes mainly occur at PF–
PC synapses invivo (Masugi-Tokita etal. 2007). It was controversial whether long-term potentiation (LTP)
(Gutierrez- Castellanos etal. 2017; Schonewille etal. 2010) or
LTD mediates cerebellum-dependent motor learning. Here,
we summarize recent ndings supporting a crucial role of
LTD in the oculomotor control and molecular mechanisms
underlying it.
44.2 LTD-Dependent Endocytosis ofAMPA
Receptors
Similar to LTD in many brain regions, LTD at PF–PC synapses is mediated by clathrin-dependent endocytosis of postsynaptic AMPA receptors. A key event triggering this is
phosphorylation of the GluA2 subunit of AMPA receptors at
serine 880 residue (GluA2-S880) by protein kinase Cα
(PKC; Fig. 44.1b) (Matsuda et al. 2000; Xia et al. 2000).
AMPA receptors are stabilized at synapses via their binding
with glutamate-interacting protein (GRIP). Phosphorylation
at S880 drastically reduces GluA2’s afnity for GRIP, but
not for protein interacting with C kinase 1 (PICK1), another
anchoring protein that promotes AMPA receptor endocytosis. Therefore, inhibiting GluA2 interactions with GRIP or
PICK1 impairs LTD induction (Matsuda et al. 2000;
Steinberg etal. 2006; Xia etal. 2000).
PF inputs activate postsynaptic metabotropic glutamate
receptor subtype 1 (mGluR1), leading to phospholipase C
activation and production of inositol 1, 4, 5-trisphosphate
(IP3) and diacylglycerol. IP3 then induces Ca2+ release
through IP3 receptors, while diacylglycerol stimulates PKCα
in coordination with Ca2+. On the other hand, CF inputs gen-
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_44
287
288
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M. Yuzaki
a
AMPA receptors freed from anchoring proteins diffuse
into the endocytic zone located at perisynaptic sites. There,
AMPA receptors rst associate with clathrin adaptor protein
complex-2 (AP-2). AP-2 binds to dephosphorylated forms of
transmembrane AMPA receptor regulatory proteins (TARPs)
(Matsuda et al. 2013; Nomura et al. 2012). Eventually,
TARPs change their binding partner to AP-3, which regulates the late endosomal and lysosomal trafcking of AMPA
receptors, a step necessary for the late phase of hippocampal
(Matsuda etal. 2013) as well as cerebellar (Kim etal. 2017)
LTD.Thus, LTD consists of two Ca2+-dependent steps: phosphorylation of GluA2 to dissociate from GRIP at postsynaptic sites, and dephosphorylation of TARPs to recruit AP-2 at
the endocytic zone.
b
Aside from activity-dependent changes, morphological
changes are also observed at PF–PC synapses after motor
learning in vivo (Aziz et al. 2014). In cultured PCs, LTD
reportedly transits into a late phase (> ~60 min), which
requires transcription of mRNAs, such as Arc (Smith-Hicks
etal. 2010). However, whether and how late-phase LTD is
induced invivo remains elusive.
44.3 Optogenetic Control ofCerebellarLTD
Fig. 44.1 LTD and its signaling cascades. (a) A typical diagram of
LTD in a whole-cell patch-clamp recording. Excitatory postsynaptic
currents (EPSCs; insets) of a Purkinje cell were elicited by stimulating
parallel bers (PFs) and their amplitudes are plotted against time.
Conjunctive stimulations (CJ-stim) of PFs and a climbing ber induced
enduring reduction of PF-EPSCs. (b) A positive-feedback model
together with NO and GluD2 pathways for LTD induction
erate large depolarizations triggering Ca2+ inux through
voltage-gated Ca2+ channels. Interestingly, combined PF and
CF activity is detected by the supralinear summation of signals coming from two Ca2+ sources: IP3-mediated Ca2+
release from intracellular stores and Ca2+ inux through Ca2+
channels. Temporal and spatial Ca2+ dynamics in dendritic
spines can explain several features of LTD, such as synapse
specicity and dependence on the timing of PF and CF activation (Finch etal. 2012). Moreover, concurrent activation of
PF and CF inputs induces a sustained (>20min) increases in
PKC activity by the positive-feedback cycle, consisting of
mitogen-activated protein kinase (MAPK), phospholipase
A2 (PLA2), and their related molecules (Fig.44.1b) (Tanaka
and Augustine 2008).
The controversy about the role of LTD in oculomotor learning is partly caused by various LTD induction protocols used
in invitro slice preparations (Suvrathan etal. 2016). In addition, compensatory mechanisms could modify synaptic plasticity in the remaining circuits and affect motor learning in
genetically engineered mice (Gao etal. 2012; Ito etal. 2014).
To circumvent these problems, an optogenetic tool, termed
PhotonSABER, has been developed to inhibit postsynaptic
AMPA receptor endocytosis, the nal common step of LTD,
by neutralizing the lumen of early endosomes with a photosensitive proton pump (Kakegawa etal. 2018) (Fig. 44.2a).
Light stimulation acutely and reversibly inhibited LTD in
acute slice preparations, in which PhotonSABER was specically expressed in PCs, without affecting basal synaptic
transmission or other forms of synaptic plasticity, such as
LTP. Furthermore, beroptic illumination to PCs expressing
PhotonSABER invivo inhibited adaptation of the horizontal
optokinetic response (Fig.44.2b) and vestibulo-ocular reex.
Importantly, analyses using quantitative and highly sensitive
SDS-digested freeze-fracture replica labeling (SDS-FRL)
revealed that the decrease in the number of postsynaptic
AMPA receptors in the occulus after the adaptation of the
optokinetic response (Wang et al. 2014b) was completely
inhibited by beroptic illumination to PCs expressing
PhotonSABER (Kakegawa etal. 2018) (Fig. 44.2c). These
ab
44 Long-Term Depression at Parallel Fiber–Purkinje Cell Synapses
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289
c
Fig. 44.2 PhotonSABER regulates AMPA receptor endocytosis and oculomotor learning. (a) Schematic drawing of PhotonSABER.PhotonSABER
regulates the endocytosis of AMPARs by de- acidifying the endosomal
lumen through light-stimulated H+ pump activities. LS, light stimulation.
(b) PhotonSABER inhibits the optokinetic response (OKR). Without light
stimulation (LS(−)), the eye movements increase after 60-min exposures
to sinusoidal oscillation (15°) of a checked-pattern screen (black traces,
pre-exposure; red traces, post-exposure) in front of mice. Fiberoptic illumination (LS(+)) to the bilateral occuli inhibits OKR adaptation. (c)
PhotonSABER inhibits decrease in AMPA receptors following OKR.The
number of AMPA receptors on freeze-fracture replicas from the occulus
decrease after OKR.The decrease is inhibited by beroptic illumination to
the occuli during OKR
results indicate a crucial role of LTD in the occulus in
mediating the oculomotor learning invivo.
44.4 Unique Features ofCerebellar LTD
There are several unique features of cerebellar LTD.First,
backpropagation of action potentials to dendrites, which
releases voltage-dependent block of NMDA receptors by
Mg2+, serves as a coincidence detector for LTP/LTD induction in most neuronal circuits in the cortex, striatum, and hippocampus. In contrast, action potentials do not backpropagate
to PC dendrites because of their long electrotonic distance
(Vetter et al. 2001) and the low density of Na
+
channels
(Stuart and Hausser 1994). In addition, functional NMDA
receptors are not highly expressed in Purkinje cells in adult
rodents (Perkel etal. 1990). Indeed, LTD is normally induced
in acute cerebellar slices prepared from PC-specic NMDA
receptor knockout mice (Kono etal. 2019). Instead of Ca2+
inux through NMDA receptors, the supralinear summation
of Ca2+ signals from PF-evoked Ca2+ release from IP3 receptors and CF-evoked Ca2+ inux through voltage-gated Ca2+
channels serves as a coincidence detector for LTP/LTD in
cerebellar PCs. Thus, compared to the detection of coincidence by NMDA receptors with a temporal window of
~10 ms (Markram et al. 1997) in hippocampalal neurons,
CF-evoked Ca2+ changes are very slow, reecting activation
of mGluR1, production of IP3 and Ca2+ release from IP3
receptors in PCs. Therefore, PCs are suited to detect coincidence of PF/CF activities in a wider time window. For example, the window is expected to be ~30ms for controlling
ocular-following responses in the paraocculus, and longer
than 100ms for regulating reaching tasks in the cerebellar
hemisphere (Suvrathan etal. 2016). It remains unclear how
such time windows matching the motor-sensory time delay
associated with different movements are achieved by PCs
located in different cerebellar regions.
Instead of NMDA receptors, cerebellar LTD requires the
δ2 glutamate receptor (GluD2). GluD2 is highly and predominantly expressed in PC dendrites. While GluD2’s channel activities are not required for LTD induction, its
intracellular C-terminal region is indispensable (Kakegawa
etal. 2008; Kohda etal. 2007) since it binds to PTPMEG, a
protein tyrosine phosphatase that dephosphorylates a tyrosine residue (Y876) of GluA2. Interestingly, prior phosphorylation of Y876 hindered subsequent phosphorylation at
S880 by PKC (Kohda etal. 2013). Thus, in GluD2-null or
PTPMEG-null PCs, GluA2-Y876 is highly phosphorylated
and LTD- inducing stimuli fail to phosphorylate S880
(Fig. 44.3). Therefore, GluD2 controls LTD induction by
regulating interactions between the two phosphorylation
sites of GluA2. Cbln1, a C1q family protein released from
PFs, binds to the extracellular N-terminal region of GluD2
(Matsuda etal. 2010). Although it remains unclear why LTD
is impaired in Cbln1-null mice (Hirai etal. 2005), PTPMEG
signaling at the C-terminus may be regulated by binding of
Cbln1 at the N-terminus of GluD2.
Nitric oxide (NO), which is produced by NO synthase
2+
(NOS) following Ca
inux through NMDA receptors,
serves as a retrograde messenger to induce long-term
potentiation (LTP) in hippocampal neurons (Padamsey
and Emptage 2014). LTD is impaired in mice genetically
lacking neuronal NOS (Lev-Ram etal. 1997). LTD and
oculomotor learning are impaired in MLI/PC-specic, but
not granule cell- or PC-specic NMDA receptor knockout
290
https://t.me/medicina_free
M. Yuzaki
a
b
Fig. 44.3 A proposed model of how GluD2 regulates cerebellar LTD.
(a) Basal state. GluD2 maintains low phosphorylation levels at Y876 of
the GluA2 subunit of AMPA receptors via PTPMEG, a protein tyrosine
phosphatase. (b) LTD induction. LTD-inducing stimuli further dephosphorylate this tyrosine residue. Y876 dephosphorylation allows S880
phosphorylation by protein kinase C, which leads to the replacement of
GRIP, a membrane anchoring protein, with PICK1 to allow AMPA
receptor endocytosis
mice, indicating an important role of NMDA receptors in
MLIs (Kono et al. 2019). Since application of an NO
donor restored LTD in MLI/PC-specic NMDA receptor
knockout cerebellar slices, NO is likely produced by activation of NMDA receptors in MLIs during LTD. NO
upregulates the MAPK pathway in the positive-feedback
loop of LTD induction (Fig.44.1b). NO is also necessary
for postsynaptic LTP induced by stimulation of PFs at
1Hz (Kakegawa and Yuzaki 2005; Lev-Ram etal. 2002).
However, this form of LTP is intact in NMDA receptor
knockout mice (Kono etal. 2019). Instead, 1Hz PF stimulation activates cannabinoid receptor 1 to produce NO in
PFs (Wang etal. 2014a). Thus, NO may not be directly
involved in LTD induction, but rather plays a role in other
aspects, such as the spread of plasticity across synapses.
Acknowledgements This work was supported by the JST CREST
(JPMJCR1854) and MEXT KAKENHI (20H05628).
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