Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_24_библиотеки_им_акад_М_И_Перельмана
.pdf
216
https://t.me/medicina_free
ket, and stellate cells (Knowles and Moncada 1994; Rodrigo
etal. 1994). eNOS is also expressed in the granule cells at a
lesser level than nNOS (Dinerman etal. 1994). Glial cells,
such as Bergmann glia, also express NOS (Tiburcio-Félix
etal. 2019). Specically, iNOS has been detected in microglia and astrocytes upon stimulation by cytokines and other
compounds (Schilling et al. 1994; Stojkovic et al. 1998).
Mutant mice lacking each NOS isoform as well as doubleand triple-knockout mice have been developed (Huang etal.
1993, 1995; Wei etal. 1995; Morishita etal. 2005). Because
long-term depression (LTD) at parallel ber to Purkinje cell
synapse is almost completely abolished in the cerebellar
slice from nNOS
−/−
mutant mice, nNOS is indicated to be the
major source of NO involved in the LTD induction (LevRam etal. 1997a).
Some chemical and physical stimuli inuence the expression of nNOS. Acute ethanol induces a dose-dependent
increase in ethanol blood levels associated with the impairment of motor coordination performance and decreased
expression of nNOS in rat cerebellum (Logsdon etal. 2020).
In rat cerebellum, mRNA and protein levels as well as activities of nNOS and eNOS are increased 48hours after physical
training (Chalimoniuk et al. 2015). It is also reported that
nNOS is signicantly decreased in the cerebellum of aged
rats, coincident with lowered performance in learning and
memory in aged rats (Yu etal. 2000).
A number of cerebellar mutant mice are reported to
exhibit alterations in NOS expression (Abbott and Nahm
2004). Several mutant mice carry mutation affecting calcium
ion (Ca2+) homeostasis, which is important in light of the fact
that nNOS expression is regulated by Ca2+.
33.3 Signal Transduction
The effects of NO on cellular functions are mediated by two
pathways (Fig.33.1). One of the main enzymatic targets of
NO is guanylyl cyclase. In the presence of iron, the binding
of NO to the haem region of the enzyme leads to activation,
and results in the production of cyclic guanosine monophosphate (cGMP) (Ignarro 2000). Another pathway for NO signal transduction is mediated by reversible post-translational
modication of proteins, S-nitrosylation of thiol groups in
cysteine (a term “S-nitrosation” is also used for this modication, Iyer et al. 2014). Although another type of posttranslational modication of proteins, tyrosine nitration, is
well known, this is an irreversible modication and is not a
direct reaction of NO, but a reaction of peroxynitrite (ONOO
−
) produced from NO and superoxide (O
2007; Ischiropoulos 2009).
The activation of sGC by NO results in surge of cellular
cGMP, which is the main cellular transducer of NO signals
whose concentration and kinetics are affected by phosphodi-
−
) (Pacher et al.
2
S. Kakizawa
Fig. 33.1 Two pathways for NO signaling. NO signal is mediated by
activation of soluble guanylyl cyclase (sGC) and resulting increase in
cyclic GMP (cGMP) level (upper), or by S-nitrosylation (also called
S-nitrosation) of thiol groups in cysteine residue (lower). PKG protein
kinase G
esterases (PDEs), a catalytic enzyme for cGMP (Francis
etal. 2010). In addition to regulating various channel proteins by direct binding (Kaupp and Seifert 2002), cGMP activates protein kinases G (PKGs), regulating functions of a
wide range of other proteins through phosphorylation
(Fig. 33.1, upper) (Friebe and Koesling 2003; Garthwaite
2010).
S-nitrosylation is a covalent addition of an NO group to a
cysteine thiol/sulfhydryl (-SH), which results in the formation of an S-nitrosothiol derivative (-SNO). S-nitrosylation is
now well established as a major source of NO bioactivity,
and proteins shown to be modied in situ by S-nitrosylation
participate in a wide range of biological processes (Fig.33.1,
lower) (Foster etal. 2009; Shahani and Sawa 2011).
NO is also involved in signal transduction via
8- nitroguanosine 3′,5′-cyclic monophosphate (8-nitrocGMP) formation (Fujii and Akaike 2013; Sawa etal. 2013).
8-nitro-cGMP is a nitrated form of cGMP and produced
from GTP in the presence of NO and reactive oxygen species
(ROS). In addition to PKG activation in the same manner
with cGMP, 8-nitro-cGMP also induce post-translational
modication of proteins, S-guanylation. Although accumulating evidence suggests the occurrence of S-guanylation on
proteins that critically involved in the regulation of cellular
responses to oxidative, metabolic or environmental stress,
functional roles of 8-nitro-cGMP in the cerebellum are yet to
be examined.
33.4 Physiological andPathophysiological
Functions
33.4.1 Granule Cell Neurogenesis
In mammals, NO has been shown to downregulate adult neurogenesis, occurring in granule cells in hippocampal dentate
gyrus, for example.
In the cerebellum, negative regulation of cerebellar gran-
ule cells precursor proliferation by NO is indicated from several lines of studies invitro. During a restricted time window
of the rst three postnatal days, pharmacological blockade of
nitric oxide production in rat pups resulted in increased cerebellar proliferation rate, indicating that proliferation of cer-
33 Nitric Oxide
https://t.me/medicina_free
217
ebellar precursor cells is negatively regulated by nitric oxide
in newborn rat (Ciani etal. 2006). In neonatal rat cerebellar
slices, NOS inhibition maintains an age-dependent higher
proliferation rate among neuronal precursors localized in
external granular layer. In primary cultures of dissociated
cerebellar granule cells, NOS inhibition increases precursor
proliferation (Contestabile 2012).
33.4.2 Synaptic Plasticity intheCerebellar
Cortex
Purkinje cell (PC), a principal neuron in the cerebellar cortex, receives two types of excitatory inputs: climbing bers
(CF), originate from inferior olive, and parallel bers (PF),
axons of granule cells. Both CF-PC synapse and PF-PC synapse show bidirectional plasticity, long-term depression
(LTD), and long-term potentiation (LTP)) (Bosman et al.
2008; Jörntell and Hansel 2006). However, neither LTD nor
LTP at CF-PC synapse show NO dependency, consistent
with the negative staining of these architectures with nNOS
antibody. On the other hand, many studies indicate that both
LTD and LTP at PF-PC synapse (PF-LTD and PF-LTP,
respectively), are dependent on NO signals. In cerebellar
slices, photorelease of caged NO in PC with either depolarization or uncaged Ca2+ induce PF-LTD (Lev-Ram et al.
1997b), whereas application of NO donor is sufcient to
elicit PF-LTP (Kakegawa and Yuzaki 2005).
A currently accepted model for contribution of NO signal
on the LTD induction is that NO produced by PF activity diffuses into PC where it stimulates sGC and activates PKG,
which phosphorylate G-substrate, a PKG substrate
specically localized in PCs (Endo et al. 1999).
Phosphorylation of G-substrate inhibits protein phosphatase
2A (PP2A) and enhances the phosphorylation levels of
α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid
(AMPA)-type glutamate receptors 2/3 (GluA2/3), which is
increased by PKC- mediated signaling pathway. Increase in
phosphorylation level of AMPA receptors results in their declustering and endocytotic recycling, thus lowering the excitatory response to glutamate (Ito etal. 2014).
In addition to PF-LTD, involvements of NO signals in
PF-LTP are indicated. However, in contrast to PF-LTD,
PF-LTP is not inhibited by a selective inhibitor of sGC activation by NO (ODQ, 1H-[1,2,4]oxadiazolo[4,3-a]
quinoxalin- 1-one) that abolishes PF-LTD (Lev-Ram et al.
2002). Instead, the action of NO is mediated by S-
nitrosylation of N-ethyl maleimide sensitive factor (NSF)
and type 1 ryanodine receptor (RyR1), a Ca2+ release channel
expressed in the membrane of sarco/endoplasmic reticulum,
an organelle in which intracellular Ca2+ stored. S-nitrosylation
of NSF results in the insertion of AMPA receptor to plasma
membrane and increases the response to glutamate
(Kakegawa and Yuzaki 2005). S-nitrosylation of RyR1 elicits
NO-induced Ca2+ release (NICR), a novel type of intracellular Ca2+ release, from the intracellular store of PCs, which is
essential for the induction of PF-LTP (Kakizawa et al.
2012a). NO-induced S-nitrosylation of proteins as well as
PF-LTP are impaired by aging and pretreatment of cerebellar
slices with ROS (Kakizawa etal. 2012b). These results indicate possible involvement of ROS-dependent inhibition of
protein S-nitrosylation in age-dependent decline in neuronal
functions.
Activity-dependent production of NO is demonstrated in
both PF-LTD and PF-LTP. Using an electrochemical microprobe, release of endogenous NO is observed at the induction of PF-LTD (Shibuki and Okada 1991). An imaging
study using GFP-based uorescent probe for NO revealed
that burst stimulations of PF, which induce LTP at the synapse, induce NO production (Namiki etal. 2005).
33.4.3 Involvement inCerebellar-Dependent
Learning
PF-LTD is implicated in specic forms of motor learning
such as adaptation of vestibule-ocular reex (VOR). Because
NO signaling is indicated to be necessary for the LTD, it is
reasonable to speculate that NO signals are involved in the
cerebellar-dependent motor learning such as VOR (Yuzaki
2013; Ito etal. 2014).
Actually, several types of studies indicate possible
involvement of NO signals in the motor learning. NOS inhibitors or NO scavengers, which block PF-LTD, impair some
forms of motor learning, such as adaptation of the horizontal
VOR, smooth pursuit eye movement, coordinated locomotion, and eyeblink conditioning. Moreover, adaptation of
optokinetic response eye movements is impaired in nNOSknockout mice (Katoh etal. 2000). Vestibulo-ocular reex
(VOR), as well as PF-LTD, is also impaired in mice lacking
cGMP-dependent protein kinase (PKG) type I (Feil et al.
2003).
33.4.4 Neurotoxic andNeuroprotective Roles
ofNO intheCerebellum
Numerous studies indicate that NO is neuroprotective, facilitating normal neuronal function, or neurotoxic, contributing
to neuronal damage or death (Abbott and Nahm 2004;
Mohanakumar etal. 2002).
NO reacts with superoxide to form peroxynitrite (ONOO −),
a strong oxidizing agent inducing various neurotoxic effects
through tyrosine nitration (Cobb and Cole 2015).
218
https://t.me/medicina_free
S. Kakizawa
NO is also indicated to function as an antioxidant by scavenging oxygen-free radicals (Contestabile 2012). For example, NO is demonstrated to protect against CNS lesions
induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP), an inhibitor of complex 1in mitochondria inducing
overproduction of ROS.
References
Abbott LC, Nahm SS (2004) Neuronal nitric oxide synthase expression
in cerebellar mutant mice. Cerebellum 3:141–151
Alderton WK, Cooper CE, Knowles RG (2001) Nitric oxide synthases:
structure, function and inhibition. Biochem J 357:593–615
Bosman LWJ, Takechi H, Hartmann J, Eilers J, Konnerth A (2008)
Homosynaptic long-term synaptic potentiation of the "winner"
climbing ber synapse in developing Purkinje cells. J Neurosci
28:798–807
Chalimoniuk M, Chrapusta SJ, Lukačova N, Langfort J (2015)
Endurance training upregulates the nitric oxide/soluble guany-
lyl cyclase/cyclic guanosine 3′,5′-monophosphate pathway in
the striatum, midbrain and cerebellum of male rats. Brain Res
1618:29–40
Ciani E, Calvanese V, Crochemore C, Bartesaghi R, Contestabile A
(2006) Proliferation of cerebellar precursor cells is negatively regu-
lated by nitric oxide in newborn rat. J Cell Sci 119:3161–3170
Cobb CA, Cole MP (2015) Oxidative and nitrative stress in neurode-
generation. Neurobiol Dis 84:4–21
Contestabile A (2012) Role of nitric oxide in cerebellar development
and function: focus on granule neurons. Cerebellum 11:50–61
Dinerman JL, Dawson TM, Schell MJ, Snowman A, Snyder SH (1994)
Endothelial nitric oxide synthase localized to hippocampal pyrami-
dal cells: implications for synaptic plasticity. Proc Natl Acad Sci U
S A 91:4214–4218
Endo S, Suzuki M, Sumi M, Nairn AC, Morita R, Yamakawa K,
Greengard P, Ito M (1999) Molecular identication of human
G-substrate, a possible downstream component of the cGMP-
dependent protein kinase cascade in cerebellar Purkinje cells. Proc
Natl Acad Sci U S A 96:2467–2472
Feil R, Hartmann J, Luo C, Wolfsgruber W, Schilling K, Feil S, Barski JJ,
Meyer M, Konnerth A, De Zeeuw CI, Hofmann F (2003) Impairment
of LTD and cerebellar learning by Purkinje cell- specic ablation of
cGMP-dependent protein kinase I.J Cell Biol 163:295–302
Foster MW, Hess DT, Stamler JS (2009) Protein S-nitrosylation in health
and disease: a current perspective. Trends Mol Med 15:391–404
Francis SH, Busch JL, Corbin JD, Sibley D (2010) cGMP-dependent
protein kinases and cGMP phosphodiesterases in nitric oxide and
cGMP action. Pharmacol Rev 62:525–563
Friebe A, Koesling D (2003) Regulation of nitric oxide-sensitive guany-
lyl cyclase. Circ Res 93:96–105
Fujii S, Akaike T (2013) Redox signaling by 8-nitro-cyclic guanosine
monophosphate: nitric oxide- and reactive oxygen species-derived
electrophilic messenger. Antioxid Redox Signal 19:1236–1246
Garthwaite J (2010) New insight into the functioning of nitric oxide-
receptive guanylyl cyclase: physiological and pharmacological
implications. Mol Cell Biochem 334:221–232
Huang PL, Dawson TM, Bredt DS, Snyder SH, Fishman MC (1993)
Targeted disruption of the neuronal nitric oxide synthase gene. Cell
75:1273–1286
Huang PL, Huang Z, Mashimo H, Bloch KD, Moskowitz MA, Bevan
JA, Fishman MC (1995) Hypertension in mice lacking the gene for
endothelial nitric oxide synthase. Nature 377:239–242
Ignarro LJ (ed) (2000) Nitric oxide:biology and pathobiology.
Academic Press, San Diego, CA
Ignarro LJ, Napoli C, Loscalzo J (2002) Nitric oxide donors and car-
diovascular agents modulating the bioactivity of nitric oxide- an
overview. Circ Res 90:21–28
Ischiropoulos H (2009) Protein tyrosine nitration – an update. Arch
Biochem Biophys 484:117–121
Ito M, Yamaguchi K, Nagao S etal (2014) Long-term depression as a
model of cerebellar plasticity. Prog Brain Res 210:1–30
Iyer AK, Rojanasakul Y, Azad N (2014) Nitrosothiol signaling and pro-
tein nitrosation in cell death. Nitric Oxide 42C:9–18
Jörntell H, Hansel C (2006) Synaptic memories upside down: bidirec-
tional plasticity at cerebellar parallel ber-Purkinje cell synapses.
Neuron 52:227–238
Kakegawa W, Yuzaki M (2005) A mechanism underlying AMPA recep-
tor trafcking during cerebellar long-term potentiation. Proc Natl
Acad Sci U S A 102:17846–17851
Kakizawa S, Yamazawa T, Chen Y etal (2012a) Nitric oxide-induced
calcium release via ryanodine receptors regulates neuronal function.
EMBO J 31:417–428
Kakizawa S, Masahiko Shibazaki M, Nozomu Mori N (2012b) Protein
oxidation inhibits NO-mediated signaling pathway for synaptic
plasticity. Neurobiol Aging 33:535–545
Katoh A, Kitazawa H, Itohara S, Nagao S (2000) Inhibition of nitric
oxide synthesis and gene knockout of neuronal nitric oxide synthase
impaired adaptation of mouse optokinetic response eye movements.
Learn Mem 7:220–226
Kaupp UB, Seifert R (2002) Cyclic nucleotide-gated ion channels.
Physiol Rev 82:769–824
Knowles RG, Moncada S (1994) Nitric oxide synthases in mammals.
Biochem J 298:249–258
Lev-Ram V, Nebyelul Z, Ellisman MH, Huang PL, Tsien RY (1997a)
Absence of cerebellar long-term depression in mice lacking neuronal nitric oxide synthase. Learn Mem 4:169–177
Lev-Ram V, Jiang T, Wood J, Lawrence DS, Tsien RY (1997b)
Synergies and coincidence requirements between NO, cGMP, and
Ca2+ in the induction of cerebellar long-term depression. Neuron
18:1025–1038
Lev-Ram V, Wong ST, Storm DR etal (2002) A new form of cerebellar
long-term potentiation is postsynaptic and depends on nitric oxide
but not cAMP.Proc Natl Acad Sci U S A 99:8389–8393
Logsdon AF, Schindler AG, Meabon JS, Yagi M, Herbert MJ, Banks
WA, Raskind MA, Marshall DA, Keene CD, Perl DP, Peskind ER,
Cook DG (2020) Nitric oxide synthase mediates cerebellar dysfunction in mice exposed to repetitive blast-induced mild traumatic brain
injury. Sci Rep 10:9420
Mohanakumar KP, Thomas B, Sharma SM, Muralikrishnan D,
Chowdhury R, Chiueh CC (2002) Nitric oxide: an antioxidant and
neuroprotector. Ann N Y Acad Sci 962:389–401
Morishita T, Tsutsui M, Shimokawa H, Sabanai K, Tasaki H, Suda O,
Nakata S, Tanimoto A, Wang KY, Ueta Y, Sasaguri Y, Nakashima Y,
Yanagihara N (2005) Nephrogenic diabetes insipidus in mice lacking all nitric oxide synthase isoforms. Proc Natl Acad Sci U S A
102:10616–10621
Namiki S, Kakizawa S, Hirose K, Iino M (2005) NO signalling decodes
frequency of neuronal activity and generates synapse-specic plasticity in mouse cerebellum. J Physiol 566:849–863
Pacher P, Beckman JS, Liaudet L (2007) Nitric oxide and peroxynitrite
in health and disease. Physiol Rev 87:315–424
Rodrigo J, Springall DR, Uttenthal O, Bentura ML, Abadia-Molina
F, Riveros-Moreno V, Martinez-Murillo R, Polak JM, Moncada S
(1994) Localization of nitric oxide synthase in the adult rat brain.
Phil Trans R Soc Lond B 345:175–221
Roszer T (2012) The biology of subcellular nitric oxide. Springer,
NewYork
33 Nitric Oxide
https://t.me/medicina_free
219
Sawa T, Ihara H, Ida T, Fujii S, Nishida M, Kaike T (2013) Formation,
signaling functions, and metabolisms of nitrated cyclic nucleotide.
Nitric Oxide 34:10–18
Schilling K, Schmidt HH, Baader SL (1994) Nitric oxide synthase
expression reveals compartments of cerebellar granule cells and
suggests a role for mossy bers in their development. Neurosci
59:893–903
Shahani N, Sawa A (2011) Nitric oxide signaling and nitrosative
stress in neurons: role for S-nitrosylation. Antioxid Redox Signal
14:1493–1504
Shibuki K, Okada D (1991) Endogenous nitric oxide release required
for long-term synaptic depression in the cerebellum. Nature
349:326–328
Stojkovic T, Colin C, Le Saux F etal (1998) Specic pattern of nitric
oxide synthase expression in glial cells after hippocampal injury.
Glia 22:329–337
Stuehr DJ, Santolini J, Wang ZQ et al (2004) Update on mecha-
nism and catalytic regulation in the NO synthases. J Biol Chem
279:36167–36170
Tiburcio-Félix R, Cisneros B, Hernández-Kelly LCR, Hernández-
Contreras MA, Luna-Herrera J, Rea-Hernández I, Jiménez-Aguilar
R, Olivares-Bañuelos TN, Ortega A (2019) Neuronal nitric oxide
synthase in cultured cerebellar bergmann glia: glutamate-dependent
regulation. ACS Chem Neurosci 10:2668–2675
Wang PG, Xian M, Tang XP, Wu XJ, Wen Z, Cai TW, Janczuk AJ
(2002) Nitric oxide donors: chemical activities and biological applications. Chem Rev 102:1091–1134
Wei XQ, Charles IG, Smith A, Ure J, Feng GJ, Huang FP, Xu D, Muller
W, Moncada S, Liew FY (1995) Altered immune responses in mice
lacking inducible nitric oxide synthase. Nature 375:408–411
Yu WJ, Juang SW, Liu TP, Cheng JT (2000) Decrease of neuronal
nitric oxide synthase in the cerebellum of aged rats. Neurosci Lett
291:37–40
Yuzaki M (2013) Cerebellar LTD vs. motor learning-lessons learned
from studying GluD2. Neural Netw 47:36–41
Cannabinoids
https://t.me/medicina_free
GaryJ.Stephens
34
Abstract
The endocannabinoid system (eCBS) consists principally
of (i) endogenous transmitters, including the lipid media-
tor 2-arachidonoyl glycerol (2-AG) and also arachidonoyl
ethanolamide (anandamide), (ii) the metabolic enzymes
that control endocannabinoid (eCB) production and deg-
radation, and (iii) the cannabinoid CB1 and CB2 receptors
(CB1Rs and CB2Rs) upon which eCBs exert their action.
Acting in concert, these elements of the eCBS coordinate
the endocannabinergic tone in the cerebellum and
throughout the CNS.This tone mediates short- and long-
term plasticities to control cerebellar functions, including
ne motor control and associative learning paradigms.
Decits in eCBS cerebellar circuitry are associated not
only with disease phenotypes, most notably spinocerebel-
lar ataxias (SCAs), but also with increasing evidence for
roles in other psychopathologies and cognitive disorders.
The eCBS is also the target of exogenous cannabis, prin-
cipally due to the actions of Δ9-tetrahydrocannabidol (Δ9-
THC). Δ9-THC mediates the “high” associated with illicit
cannabis use, but some advocate that Δ9-THC also has
medicinal benets. Less controversial is the recent use of
cannabidiol (CBD) as the main cannabis constituent with
reported medicinal benets; here, CBD in isolation from
the plant is the preferred option. A previous review
focused on CB1R signaling in the cerebellum and its asso-
ciation with cerebellar dysfunction. This updated review
will consolidate the description of the eCBS bringing new
ndings into light and will explore potential new thera-
peutic targets and consider associated strategies that tar-
get the eCBS.
G. J. Stephens (*)
School of Pharmacy, University of Reading, Reading, UK
e-mail: g.j.stephens@reading.ac.uk
Keywords
Endocannabinoid system · Cannabinoid CB1 receptors
Cannabinoid CB2 receptors · 2-arachidonoyl glycerol
Diacylglycerol lipase · Monoacylglycerol lipase
Δ9-tetrahydrocannabidol · Cannabidiol
34.1 Introduction toCannabinergic
Cerebellar Circuitry
It is well known that eCBs, principally 2-AG (Szabo etal.
2006), are released “on-demand” from Purkinje cells (PCs),
the neuronal element which represents the sole controlling
output of the cerebellar cortex. 2-AG is released predominantly from PC dendrites to act retrogradely on CB1Rs
expressed on presynaptic axons, including excitatory parallel
bers (PF), climbing bers, and inhibitory basket cell interneurons (INs), and stellate cells (Kawamura et al. 2006;
Rodríguez-Cueto etal. 2014a; Stephens 2016a; Fig. 34.1).
CB1Rs are the most prominently expressed G proteincoupled receptors in the cerebellum, and indeed in the CNS
(Herkenham etal. 1991). These features combine to afford
the cannabinergic circuitry a unique and privileged role in
controlling cerebellar function. CB1Rs are known to play a
major role in long-term plasticity at PF-PC synapses (Carey
etal. 2011), proposed to be critical for cerebellar learning
(Ito 1972). The role of presynaptic CB1R signaling in shortterm plasticity in the cerebellum is well studied using protocols such as depolarization-induced suppression of inhibition
(DSI) or depolarization-induced suppression of excitation
(DSE) (Kreitzer and Regehr 2001). It has been shown that
presynaptic CB1R expression can be regulated by physiological synaptic activity patterns and that such activity is linked
to the regulation of eCB levels by degradative enzymes
(Yang etal. 2019); this plasticity is proposed to be important
for associative learning paradigms. Genetic deletion of CB1R
causes impairment of ne motor control, rather than gross
changes in motor function, and also impairs cerebellar devel-
© 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_34
221
222
https://t.me/medicina_free
astrocyte
MGL
cannabidiol:
CB
R negative allosteric antagonist;
1
CB
R antagonist
2
MGL
-
-
G. J. Stephens
parallel fibre
CB1R
interneuron
-
GABA
CB
R
2
GABAAR
CB2R antagonist
Fig. 34.1 Cerebellar endocannabinoid system and potential pharmacological targets. In Purkinje cell postsynaptic dendritic spines, 2-AG is
synthesized by DAGLα from DAG. 2-AG is released retrogradely to act
on presynaptic CB1Rs at excitatory PF and inhibitory IN terminals to
suppress release of glutamate (Glu) or GABA, respectively. Astrocytes
opment (Kishimoto and Kano 2006; Martinez etal. 2020).
Endogenous or exogenous activation of CB1Rs, the latter for
example by Δ9-THC in cannabis, developmentally regulates
synaptic strength and network activity (Barnes etal. 2020).
In particular, CB1R expression has been reported to undergo
a development switch, with pronounced but transient expression at presumptive mossy ber afferent terminals in the cerebellum of newborn rodents, prior to the establishment of the
well-described dominant CB1R expression on excitatory or
inhibitory afferents to PCs in the adult cerebellum (Barnes
et al. 2020). Glial cell elements, including astrocytes and
microglial, are also reported to express CB1R within the cerebellar cortex (Rodríguez-Cueto etal. 2014a). Such studies
point to the critical importance not only of cannabinergic
pathways in the cerebellum but also to the potential of illicit
cannabis use to disrupt cerebellar circuitry and cause decits
in function. At a functional level, we have shown that du2J
“ducky” ataxic mice have decits in CB1R-mediated signaling that could contribute to disease phenotype (Wang etal.
CB1R
FAAH
FAAH inhibitor
CB1R
Glu
CB1R antagonist/
inverse agonists
dendritic
spine
DAG
2-AG
2-AG
and microglial also express CB1Rs. PCs also express CB2Rs, predominantly in soma. 2-AG is degraded by MGL, produced in presynaptic PF
terminals, and also in astrocytes. FAAH is expressed in PC soma. Red
boxes indicate potential pharmacological intervention strategies
2013). Disruptions in eCBS signaling have been implicated
in cerebellar disease states including SCA2 and SCA3
(Kasumu and Bezprozvanny 2012; Rodríguez-Cueto etal.
2016). In a similar manner, a signicant reduction in CB1R
protein expression within the cerebellum has also been
reported in a mouse model of Dravet syndrome (DS) carrying a knock-in missense mutation in the Scn1a gene (which
is defective in DS) (Satta etal. 2021); these decits are correlated with altered, potentially cerebellar-related, behaviors.
At a human level, the partial CB1R agonist Δ9-THC is well
known to mediate the “high” associated with illegal cannabis
use. While there are some proponents that advocate the benets of medicinal cannabis use, it is much less clear if Δ9THC is the cannabis component that mediates any proposed
benet(s). The general medical consensus is, rather, that Δ9THC is deleterious for CNS and cerebellar function. For
example, neuroimaging studies examining effects of exogenous cannabis reported reductions in cerebellar volume,
activity patterns, and decits in cerebellar-dependent work-
DAGLα
DAGLα inhibitor
Purkinje cell
34 Cannabinoids
https://t.me/medicina_free
223
ing memory and learning (Blithikioti etal. 2019); moreover,
these decits were correlated positively with heavy cannabis
use in adolescents.
CB2Rs may also contribute to eCBS effects in the cerebellum. In general, the roles of CB2Rs in other CNS regions
have come under recent research focus. Within the cerebellum, studies have reported some contradictory ndings
regarding CB2R expression; however, functional electrophysiological data support the role of CB2R in cerebellar circuitry. Thus, Sadanandan et al. (2020) reported a variable
expression of CB2R in PC soma from juvenile mice and,
moreover, that exogenous CB2R agonists can reduce evoked
inhibitory (but not excitatory) transmission at PCs. Of further interest was that CB2R-mediated responses were postsynaptic in origin and that DSI was entirely dependent on
CB1Rs, and not CB2Rs. Hence, it appears that CB2R signaling differs from that of CB1R, in that it is not mediated by
retrograde signaling by PC-derived eCBs. The authors suggest that CB2R signaling may be more relevant under conditions of sustained eCB release or, potentially, when activated
by exogenous agents such as Δ9-THC (Sadanandan et al.
2020). Some further support for a potential pathophysiologi-
cal role of CB2Rs in the cerebellum is the report of elevated
CB2R expression postmortem in patients with SCAs
(Rodríguez-Cueto et al. 2014a); of further interest, this
increase in CB2R expression was reported to be co-incident
with that of CB1R, suggesting a potential symbiotic change
in eCBS signaling during cerebellar disease.
34.2 Metabolic Control oftheeCBS
eCBS function is intimately controlled by a series of metabolic enzymes. 2-AG is synthesized from diacylglycerol
(DAG) by the lipase DAGLα in PC postsynaptic dendritic
spines and is degraded by serine hydrolases, predominantly
monoacylglycerol lipase (MGL), produced in presynaptic
terminals and also in astrocytes (Yoshida and Fukaya 2006;
Tanimura et al. 2012; Viader et al. 2015; Stephens 2016a;
Fig.34.1). Work using conditional MGL knockout mice has
demonstrated that neuronal and astrocytic cells act cooperatively to regulate eCB-mediated retrograde synaptic
depression in the cerebellum (Viader etal. 2015). Moreover,
Chen etal. (2016) have shown that neurons and astrocytes
combine effectively to regulate spatial 2-AG levels, limiting
distribution and, hence, synapse-specic signaling within the
cerebellum. While 2-AG is recognized as the most prominent eCB in the cerebellum, there is evidence that the enzyme
fatty acid amide hydrolase (FAAH), which acts to degrade
the eCB anandamide, is expressed throughout the cerebellum, in particular in PCs, cerebellar nuclei and the molecular
layer (Suárez etal. 2008). Thus, there is potential to target a
series of enzymes, including DAGLα, MGL, and FAAH to
modulate eCB tone (see Fig.34.1). In this regard, levels of
degrative MGL and FAAH have both been reported to be
increased in postmortem cerebellar tissue in patients with
SCAs (Rodríguez-Cueto etal. 2014b).
34.3 Therapeutic Targeting oftheeCBS
intheCerebellum
The cerebellum frequently overcomes its “little brain” status
and is now recognized for its importance in cognitive and
emotional learning and neurodevelopment. By extension,
decits in cerebellar circuitry can lead to a range of psychopathologies and cognitive disorders, including SCAs, autism,
schizophrenia, and attention decit and hyperactivity disorders (Stephens 2016a; Stoodley 2016; Hariri 2019).
Knowledge of the different elements within the eCBS may
be exploited to develop therapeutic agents. General pharmacological strategies are also summarized in Fig.34.1. These
strategies include the use of CB1R antagonist/inverse agonists such as prototypic rimonabant; such agents most likely
work by reducing constitutive endocannabinergic tone via an
inverse agonism action. However, rimonabant, introduced as
an anti-obesity agent, was subsequently withdrawn amid
post-marketing identication of potential adverse psychiatric
effects. The therapeutic targeting of different eCB enzymes
has also been explored. For example, the DAGLα inhibitor,
orlistat, is an anti-obesity agent that targets the gastrointestinal tract. However, the FAAH inhibitor, BIA 10–247, under
investigations for various central indications including anxiety and Parkinson’s disease as well as for anti-obesity potential, was another high-prole case where serious adverse
events, including the death of one volunteer, resulted in termination of human trials. Overall, reports of adverse central
effects have somewhat curtailed drug discovery in this area,
although peripherally acting drugs are still under investigation and such avenues may lead to improved safety proles
and re-ignite this area.
A compound of on-going therapeutic interest is
CBD.CBD is licensed to treat severe childhood epilepsies
(Williams and Stephens 2020) and has potential to treat cerebellar diseases including SCAs (Stephens 2016b). Although
an exact mechanism of action is still under debate, CBD has
potential to modulate the eCBS via different proposed mechanisms, including a negative allosteric antagonism of CB1Rs
and antagonism of CB2Rs. In general, there is now good evidence that CBD, rather than Δ9-THC, mediates many of the
proposed benecial effects of medicinal cannabis. Indeed,
CBD is reported to ameliorate the effects of the CB1R partial
agonist Δ9-THC, including in cerebellar tissue (Whalley
etal. 2019), and may act to limit effects of endogenous can-
224
https://t.me/medicina_free
G. J. Stephens
nabinoid agonists in a similar manner (e.g., Hohmann etal.
2019). Functional magnetic resonance imaging studies have
shown that CBD decreases blood oxygen level-dependent
signaling in the mammalian cerebellum (Sadaka etal. 2021),
consistent with a general inhibition of activity; such a mechanism may support CBD positive therapeutic effects on disease states linked to over activity of the cerebellar circuitry.
Overall, diseases of the cerebellum continue to be ripe for
therapeutic invention involving the eCBS and there are clear
opportunities to exploit the critical contribution of the eCBS
to cerebellar circuitry, in particular output of PCs, using different pharmacological strategies. However, lessons will
need to be learned from the identication of different adverse
effects associated with some high-prole therapeutic failures
in order to progress this area over the next few years.
References
Barnes JL, Mohr C, Ritchey CR etal (2020) Developmentally transient
CB1Rs on cerebellar afferents suppress afferent input, downstream
synaptic excitation, and signaling to migrating neurons. J Neurosci
40:6133–6145
Blithikioti C, Miquel L, Batalla A etal (2019) Cerebellar alterations
in cannabis users: a systematic review. Addict Biol 24:1121–1137
Carey MR, Myoga MH, McDaniels KR etal (2011) Presynaptic CB1
receptors regulate synaptic plasticity at cerebellar parallel ber syn-
apses. J Neurophysiol 105:958–963
Chen Y, Liu X, Vickstrom CR et al (2016) Neuronal and astrocytic
monoacylglycerol lipase limit the spread of endocannabinoid sig-
naling in the cerebellum. eNeuro 3:ENEURO.0048-16.2016
Hariri AR (2019) The emerging importance of the cerebellum in broad
risk for psychopathology. Neuron 102:17–20
Herkenham M, Lynn AB, Johnson MR etal (1991) Characterization
and localization of cannabinoid receptors in rat brain: a quantitative
invitro autoradiographic study. J Neurosci 11:563–583
Hohmann U, Pelzer M, Kleine J et al (2019) Opposite effects of
neuroprotective cannabinoids, palmitoylethanolamide, and
2- arachidonoylglycerol on function and morphology of microglia.
Front Neurosci 13:1180
Ito M (1972) Neural design of the cerebellar motor control system.
Brain Res 40:80–84
Kasumu A, Bezprozvanny I (2012) Deranged calcium signaling in
Purkinje cells and pathogenesis in spinocerebellar ataxia 2 (SCA2)
and other ataxias. Cerebellum 11:630–639
Kawamura Y, Fukaya M, Maejima T etal (2006) CB1 is the major can-
nabinoid receptor at excitatory presynaptic site in the hippocampus
and cerebellum. J Neurosci 26:2991–3001
Kishimoto Y, Kano M (2006) Endogenous cannabinoid signaling
through the CB1 receptor is essential for cerebellum-dependent dis-
crete motor learning. J Neurosci 26:8829–8837
Kreitzer AC, Regehr WG (2001) Cerebellar depolarization-induced
suppression of inhibition is mediated by endogenous cannabinoids.
J Neurosci 21:RC174
Martinez LR, Black KC, Webb BT etal (2020) Components of endo-
cannabinoid signaling system are expressed in the perinatal mouse
cerebellum and required for its normal development. eNeuro
7:ENEURO.0471-19.2020
Rodríguez-Cueto C, Benito C, Fernández-Ruiz J etal (2014a) Changes
in CB1 and CB2 receptors in the post-mortem cerebellum of humans
affected by spinocerebellar ataxias. Br J Pharmacol 171:1472–1489
Rodríguez-Cueto C, Benito C, Romero J etal (2014b) Endocannabinoid-
hydrolysing enzymes in the post-mortem cerebellum of humans
affected by hereditary autosomal dominant ataxias. Pathobiology
81:149–159
Rodríguez-Cueto C, Hernández-Gálvez M, Hillard CJ et al (2016)
Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3. J Neurosci 339:191–209
Sadaka AH, Ozuna AG, Ortiz RJ etal (2021) Cannabidiol has a unique
effect on global brain activity: a pharmacological, functional MRI
study in awake mice. J Transl Med 19:220
Sadanandan SM, Kreko-Pierce T, Khatri SN etal (2020) Cannabinoid
type 2 receptors inhibit GABAA receptor-mediated currents in cerebellar Purkinje cells of juvenile mice. PLoS One 15:e0233020
Satta V, Alonso C, Diez P etal (2021) Neuropathological characteriza-
tion of a Dravet syndrome knock-in mouse model useful for investigating cannabinoid treatments. Front Mol Neurosci 13:602801
Stephens GJ (2016a) Cerebellar circuits: biochemistry, neurotrans-
mitters and neuromodulators: cannabinoids as modulators in the
cerebellum. In: Gruol DL, Koibuchi N, Manto M, Molinari M,
Schmahmann JD, Shen Y (eds) Essentials of cerebellum and cerebellar disorders: a primer for graduate students. Springer, Dordrecht,
pp255–259
Stephens GJ (2016b) Does modulation of the endocannabinoid sys-
tem have potential therapeutic utility in cerebellar ataxia? J Physiol
594:4631–4641
Stoodley CJ (2016) The cerebellum and neurodevelopmental disorders.
Cerebellum 15:34–37
Suárez J, Bermúdez-Silva FJ, Mackie K et al (2008)
Immunohistochemical description of the endogenous cannabinoid
system in the rat cerebellum and functionally related nuclei. J Comp
Neurol 509:400–421
Szabo B, Urbanski MJ, Bisogno T etal (2006) Depolarization-induced
retrograde synaptic inhibition in the mouse cerebellar cortex is
mediated by 2-arachidonoylglycerol. J Physiol 577:263–280
Tanimura A, Uchigashima M, Yamazaki M et al (2012) Synapse
type- independent degradation of the endocannabinoid
2- arachidonoylglycerol after retrograde synaptic suppression. Proc
Natl Acad Sci U S A 109:12195–12200
Viader A, Blankman JL, Zhong P et al (2015) Metabolic interplay
between astrocytes and neurons regulates endocannabinoid action.
Cell Rep 12:798–808
Wang X, Whalley BJ, Stephens GJ (2013) The du2J mouse model of
ataxia and absence epilepsy has decient cannabinoid CB1 receptormediated signalling. J Physiol 591:3919–3933
Whalley BJ, Lin H, Bell L etal (2019) Species-specic susceptibility
to cannabis-induced convulsions. Br J Pharmacol 176:1506–1523
Williams CM, Stephens GJ (2020) Development of cannabidiol
as a treatment for severe childhood epilepsies. Br J Pharmacol
177:5509–5517
Yang Y, Kreko-Pierce T, Howell R etal (2019) Long-term depression of
presynaptic cannabinoid receptor function at parallel bre synapses.
J Physiol 597:3167–3181
Yoshida T, Fukaya M, Uchigashima M et al (2006) Localization of
diacylglycerol lipase-alpha around postsynaptic spine suggests
close proximity between production site of an endocannabinoid,
2- arachidonoyl-glycerol, and presynaptic cannabinoid CB1 receptor. J Neurosci 26:4740–4751
Purinergic Signaling intheCerebellum
https://t.me/medicina_free
MarkJ.Wall
35
Abstract
Purinergic signaling is a complex and evolutionarily con-
served mechanism of extracellular communication
involved in many physiological and pathological func-
tions. The complexity arises from many different purine
receptor subtypes and multiple endogenous purine recep-
tor ligands (including ATP, ADP, UTP, and adenosine)
which can either be directly released from neurons or glia
or can arise from extracellular metabolism. Although
much work has dened the distribution of purine recep-
tors in the cerebellum and the cellular effects of purine
receptor activation, relatively little is known about how
and when purines are released, the role of purinergic sig-
naling in controlling cerebellar circuit output, and the
importance of purines in cerebellar motor control.
Keywords
ATP · Adenosine · P2X receptors · P2Y receptors
A1 receptors
35.1 Introduction
35.2 Mechanisms ofATP Release
fromNeurons andGlia
All cells contain ATP (at 1–10 mM, as energy currency), and
hence all cells are potential sources of ATP for extracellular signaling. But how does the ATP move from the intracellular compartment into the extracellular space? ATP can be co- released
from neurons by exocytosis from synaptic vesicles, together
with classical neurotransmitters such as glutamate and GABA.
ATP is packaged into synaptic vesicles by a transporter protein
called the vesicular nucleotide transporter (VNUT). In the cerebellum, VNUT is expressed by granule cells (MenéndezMéndez etal. 2017) and thus parallel bers may be a source of
ATP. ATP can also be released by exocytosis from glial cells
(termed a gliotransmitter). Another mechanism of ATP release
is via specic ion channels, which have a sufciently large pore
size, that once open allow the movement of ATP down its concentration gradient into the extracellular space. These channels
include hemi-channels (pannexins and connexions) and a subset
of ATP receptors (P2X7) which appear to be involved in pathology. These receptors are expressed by a large variety of cell
types including neurons, glia and in particular microglia, underlying their role in inammation.
Purines are important extracellular signaling molecules that
mediate diverse physiological and pathological effects via
cell-surface receptors, (for review see Burnstock 2007).
There are several potential endogenous purine receptor
ligands, but this review will concentrate on the two major
ligands: ATP and adenosine.
M. J. Wall (*)
School of Life Sciences, University of Warwick, Gibbet Hill, UK
e-mail: Mark.wall@warwick.ac.uk
© 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_35
35.3 ATP (P2) Receptors
Following its release into the extracellular space, ATP activates two types of cell surface receptor, termed P2X and
P2Y.Both of these receptors are expressed by neurons and
glia throughout the brain (Fig. 35.1). P2X receptors are
ligand-gated ion channels. At least seven P2X receptor subunits have been cloned (P2X
either homomeric or heteromeric receptors with distinct
properties and pharmacology. P2X receptors are permeable
to monovalent cations such as Na+ and K+ and to divalent
cations such as Ca2+. As mentioned above, P2X7 receptors
have a large enough pore to allow the movement of ATP. For
) and can combine to produce
1–7
225
226
https://t.me/medicina_free
M. J. Wall
Fig. 35.1 Actions of ATP and adenosine. ATP activates both ionotropic (P2X) and metabotropic receptors (P2Y) and is then metabolized to
adenosine which activates P1 receptors (metabotropic). Adenosine does not just arise from the metabolism of ATP but can also be directly released
a full review of the molecular physiology of P2X receptors,
see (Burnstock and Kennedy 2011). Many P2X receptor subtypes have been localized within synapses, where their activation produces depolarization. However, when compared to
GABA and glutamate, the responses produced are very small
and this has led to the hypothesis that they have a modulatory
action.
P2Y receptors are G protein-coupled receptors (belonging to the class A family) with seven transmembrane
domains. As many as 12 P2Y receptor subtypes have been
described and act to modulate synaptic transmission and
plasticity, regulate ion channels, and release Ca2+ from intracellular stores. For a comprehensive review of P2Y receptors, see (von Kugelgen 2006).
accompanying functional data. Recently, there has been
some nice data published on P2X2 expression in the cerebellum. Kim etal. (2020) used a mouse reporter strain for
P2X2 receptors and found P2X2 receptor expression on
mossy ber axons within the white matter layer and in
mossy ber terminals within the molecular layer. In addition, a minor subset of Purkinje cells were found to express
P2X2 receptors.
Several studies have shown that activation of P2 receptors
can increase the intracellular Ca2+ concentration in Purkinje
cells, granule cells, and glial cells. P2 receptor activation can
also initiate Ca2+ waves that spread between coupled glial
cells. The rise in intracellular Ca2+ concentration probably
stems from P2Y receptor activation (Ca2+ coming from intracellular stores), although whole-cell and single-channel P2X
receptor currents have also been recorded in Purkinje cells,
35.4 ATP (P2) Receptors intheCerebellum
granule cells, and astrocytes.
Activation of presynaptic P2 receptors (probably both
There is evidence to support the expression of many of the
possible P2 receptor subtypes in the cerebellum, although
the strength of this evidence is variable. In many cases, the
receptor subtype has been identied with either immunohistochemistry or in-situ hybridization, with little or no
P2X and P2Y) on basket cells, parallel bers, and Lugaro
cells modulates excitatory and inhibitory synaptic transmission to Purkinje cells (reviewed in Deitmer etal. 2006). P2Y
receptors expressed by Purkinje cells enhance GABAA
receptor sensitivity (Saitow etal. 2005). These mixed effects
Соседние файлы в папке Библиотека им академика М.И. Перельмана