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31 Norepinephrine intheCerebellum
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205
cerebellar circuits would uctuate and inuence both motor
control and cognitive operations. Many previous studies
have shown that activation of LC and/or elevation of NE in
sensory networks facilitates sensory-guided behaviors
according to an inverted-U dose–response function (Berridge
and Waterhouse 2003; Waterhouse and Navarra 2019).
Extrapolating from these results, we can predict that increasing NE neurotransmission within the cerebellum would
improve balance, postural control, and motor coordination;
as well as performance in cognitive tasks. Accordingly, under
conditions of elevated LC output such as might occur during
ght or ight responses, we might expect faster and more
accurate motor responses to threatening stimuli.
In addition to cerebellar reexes, general motor coordination, and cognitive function, motor learning is also heavily
inuenced by NE in the cerebellum. It has been shown that
rats trained to walk across a series of regularly spaced horizontal pegs are able to perform the same task without impairment following 6-OHDA infusion into the cerebellum to
destroy NE bers. The same held true when the pegs were
irregularly spaced before and after 6-OHDA infusion.
However, when rats were trained initially to walk across the
regularly spaced pegs, then received a NE-specic lesion,
and later tested on the irregularly spaced pegs, their performance was signicantly lower when compared to those performing the same sequence of tasks without the NE-specic
lesion (Watson and McElligott 1983, 1984). This suggests
that the ability of the rats to learn a novel motor task is largely
dependent on projections from the LC-NE system to the
cerebellum.
31.5 Clinical Considerations
Aging and Neuroanatomical Changes in the Cerebellum As described earlier, the β-adrenergic receptor system
is an important mechanism through which NE modulates
cerebellar function (Yeh and Woodward 1983). Several
studies have demonstrated an age-related decrease in the
ability of the β receptor to modulate Purkinje cell ring rates
(Bickford-Wimer etal. 1991; Partt and Bickford-Wimer
1990; Bickford et al. 1986). Other studies show that the
spine density of the Purkinje cells decreases with age (Pentney 1986), an effect which may impact their sensitivity to
afferent drive. Similarly, there are also fewer Purkinje cell
synapses with parallel bers, and a decrease in the conduction velocity of parallel bers in the aged cerebellum (Rogers etal. 1981). The concentration of NE in the cerebellum
is reduced with advancing age, an effect that diminishes the
signal processing capabilities of cerebellar neurons, and
reduces the transmission of information through the cerebellar network, thereby producing motor decits (McElligott etal. 1986).
Learning Decits are Associated with Age-Related
Changes in the Cerebellum There is evidence that the
modulatory actions of NE in the cerebellum are involved in
the learning and acquisition of new motor skills, and that the
positive inuence of NE over these behaviors diminishes
with advancing age (Cartford etal. 2004). Using the same
peg walking task described previously (Watson and
McElligott 1983, 1984), the performance of aged rats was
compared to that of normal adult and 6-OHDA lesioned
adult animals. While aged rats were able to improve their
performance to the same degree as the adult rats, the aged
rats take a signicantly longer time to do so (Bickford etal.
1992). In addition, depletion of cerebellar NE by 6-OHDA in
adult rats produced decits in motor learning similar to those
seen in untreated aged rats (Watson and McElligott 1984;
Bickford etal. 1992), suggesting a possible functional loss of
cerebellar NE with age (Bickford etal. 1992). In this same
motor learning task, aged rats did not respond to the
β-adrenergic receptor agonist isoproterenol, which enhances
the rate of learning in the younger animals (Bickford 1993).
This suggests that the impaired acquisition of the novel
learning task is related to the decline of the β receptor function with advancing age.
Clinical Interventions may Ameliorate Age-Related
Decline in Cerebellar Function Studies demonstrate that
oxidative stress is a major component of age-related cell
death, which may play a role in several common aging
pathologies (Ames etal. 1993). One study investigated the
possible relationship between oxidative stress and decline in
cerebellar noradrenergic function by exposing young rats to
conditions of hyperoxia. Once these animals reached adulthood, their β-adrenergic receptor function was assessed by
measuring the electrophysiological response of Purkinje
neurons to isoproterenol (a β-adrenergic receptor agonist)
administration. Neurons in both the aged rats and the young
rats exposed to hyperoxia show signicantly decreased augmentation of GABA signaling in response to isoproterenol
when compared to adult controls. Signicantly, this decit in
β receptor function was reversible with the supplementation
of antioxidant-rich foods (Bickford etal. 1999). Furthermore,
several studies demonstrated that foods with high oxygen
radical absorbance capacity (ORAC) reversed age-related
decreases in β receptor function in the cerebellum (Bickford
etal. 2000; Gemma et al. 2002; Shukitt-Hale et al. 2008).
Additional evidence suggests that foods rich in antioxidants
can downregulate the production of pro-inammatory cytokines tumor necrosis factor (TNF)α and TNFβ, which are
increased in the cerebellum of aged animals (Gemma etal.
2002).
Other studies suggest that a reduced calorie diet may slow
the onset of age-related decline in cerebellar function. In one
report, rats fed a 40% reduced calorie diet showed signi-
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H. K. Predale et al.
cantly less impairment at 22 months of age in a standard
motor learning task when compared to controls fed an unrestricted diet (Bickford etal. 1999). The calorie-restricted rats
also demonstrated improved β receptor function, as determined by the percentage of neurons that responded normally
to isoproterenol (Bickford etal. 1999). Similar results were
found using a calorie-restricted aged mouse model to assess
performance in learning and memory tasks (Kim and Choi
2000).
Cerebellum and Developmental Disorders Although well
known for its role in disorders of balance and movement, the
cerebellum is also linked to cognitive and emotional decits
associated with neurodevelopmental disorders, e.g., attention decit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD).
ADHD: Prefrontal and parietal association cortices
involved in cognition and attention project to the cerebellum
via the pontine nuclei. In turn, the cerebellum projects back
to these association areas via dentate nucleus projections to
the thalamus (Arnsten 2006). This connection to circuits that
modulate attention and cognition indicates that the cerebellum may be involved in the clinical symptoms of attentiondecit hyperactivity disorder (ADHD), a developmental
disorder characterized by general inattentiveness, impulsivity, and hyperactive behavior. Imaging studies have also
found that the size of the cerebellum is reduced in children
and adolescents diagnosed with ADHD (Seidman et al.
2005). Current pharmacotherapy for ADHD targets the cen-
tral catecholaminergic systems with selective NE and dopamine reuptake inhibitors such as methylphenidate and
atomoxetine (Arnsten 2006). These drugs increase the levels
of NE signicantly in several brain regions, including the
cerebellum. Some investigators postulate that this increase in
cerebellar NE is a signicant contributor to the attenuation of
symptoms in ADHD (Swanson etal. 2006). Because of its
functional connections to cortical areas involved in attention
and its responsiveness to ADHD medications, the cerebellum may play a role in the pathology of ADHD.However,
further study is needed in this area before cerebellar-targeted
treatment options can be considered.
ASD: The basis for the cerebellum’s role in ASD is its
broad connections to non-motor regions of the brain that
sub-serve executive functions and provide emotional context
for social interactions (Strick et al. 2009; Schmahmann
2019). Recent reviews (Becker and Stoodley 2013; Wang
etal. 2014; Stoodley 2016; Bruchhage etal. 2018) point to
periods of pre- and postnatal development where stress or
other environmental pressures delay or disrupt the formation
of connections between the cerebellum and cognitive/emotive circuitries of the brain, thereby depriving these regions
of information critical for driving optimal executive function
and for generating appropriate emotional responses. Studies
using fMRI in autistic males at rest have found that there is
reduced connectivity between the LC-NE system and cerebellum (Huang et al. 2021). LC-NE system decits have
been linked to attentional abnormalities that appear early in
ASD and impact the development of socio-communicative
functions (Keehn etal. 2021). Furthermore, a recent study by
Yin etal. in mice found that delayed motor learning, a symptom of ASD associated with the cerebellum, can be rescued
through activation of the LC-NE system (Yin etal. 2021).
Taken together, it may be that reduced LC-NE connectivity
in the cerebellum affects the ability of NE to modulate cerebellar outputs, resulting in the some of the symptoms associated with ASD.However, at present, the role of the cerebellar
noradrenergic system in ASD remains speculative as does
the use of catecholamine drugs in treatment options.
31.6 Summary
The cerebellum is prominently innervated by NE bers arising from the brainstem nucleus LC. The responses of
Purkinje neurons in the cerebellar cortex to amino acid transmitters and afferent synaptic inputs are subject to modulation
by release of NE from these bers. Thus, the factors that
inuence output from the LC also impact the network properties of the cerebellum, e.g., changes in arousal, exposure to
stressors. The net outcome of LC-NE regulation of cerebellar
circuit operations may be that voluntary and reex motor
activities, cognitive operations, and emotive responses are
optimized with respect to ongoing goal-directed behaviors
and unexpected environmental challenges. Still, there are
many unanswered questions regarding the details and net
impact of LC-NE regulation of cerebellar function. Key
issues for future investigation are as follows: (1) determine
the organization of LC-NE inputs to motor and non-motor
sub-regions of the cerebellum, (2) determine if there is a
functionally organized distribution of LC axon collaterals to
sub-regions of the cerebellum and other brain regions
engaged in motor control or cognitive/emotive operations
such that NE release and action can be selectively directed to
like-modality circuits, and (3) demonstrate that LC output to
cerebellum can inuence performance of motor tasks that
require balance, coordination, and ne motor control.
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Serotonin intheCerebellum
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JohannesA.van Hooft andMarliesOostland
32
Abstract
Serotonin (5-hydroxytryptamine, 5-HT) is widely present
in the brain, including in the cerebellar cortex and cere-
bellar nuclei, which are richly innervated by serotonergic
bers. A variety of serotonin receptors mediate the com-
plex effects of serotonergic modulation of the cerebellum.
These serotonin receptors all have their own specialized
role but share some similar effects. It is through the tem-
porally and spatially restricted expression of these differ-
ent serotonin receptors in the cerebellum that such a
widely expressed neurotransmitter as serotonin can exert
very specic functions. These functions include regula-
tion of neuronal activity, synaptic transmission, and cere-
bellar development, as well as aging. Disruptions to the
serotonergic system in the cerebellum can lead to move-
ment- and cognition-related disorders.
Keywords
Cerebellum · Serotonin · Development · Aging
Neuromodulation · Lugaro cells · Cerebellar cortex
Cerebellar nuclei · Movement · Cognition
J. A. van Hooft
Kaya Pilcomaya 5, Kralendijk,
Bonaire, Dutch Caribbean, Netherlands
M. Oostland (*)
Wolfson Institute for Biomedical Research, University College
London, London, UK
Swammerdam Institute for Life Sciences, University of
Amsterdam, Amsterdam, The Netherlands
e-mail: marlies.oostland@uva.nl
32.1 Serotonergic Innervation
intheCerebellum
Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter playing a variety of roles in regulating physiology, including cognition, learning, and memory (Berger et al. 2009).
Malfunctioning of the serotonergic system is involved in
neurodevelopmental disorders such as autism and schizophrenia (Lin et al. 2014; Dayer 2014). The cerebellum is
richly innervated by serotonin: serotonergic bers are the
third main afferent bers into the cerebellum, after the mossy
bers and the climbing bers (Kerr and Bishop 1991).
Serotonergic bers that innervate the cerebellum originate
mainly in the medullary- and pontine reticular formation
(Chan-Palay 1975; Takeuchi et al. 1982; Bishop and Ho
1985), although some serotonergic inputs originate from the
raphe nuclei and the gigantocellular reticular formation adjacent to the raphe nuclei, and the cerebellar nuclei (Kerr and
Bishop 1991). These serotonergic bers form a dense network in the granular layer and are found around the somata
of Purkinje cells, and in the overlying molecular layer.
Serotonin axon terminals innervate not only Purkinje cell
dendrites (Sotelo and Beaudet 1979; Crivellato etal. 1992),
but also granule cell dendrites (Chan-Palay 1975; Sotelo and
Beaudet 1979; Chan-Palay etal. 1977; Beaudet and Sotelo
1981), parallel bers (Sotelo and Beaudet 1979), and basket,
stellate, and Golgi cells (Chan-Palay 1975; Chan-Palay etal.
1977). In adult rats, the density of serotonergic bers is
higher in vermal lobules VII–X, paramedian lobule, and crus
II (Bishop and Ho 1985). Serotonergic bers in the molecular layer usually ascend toward the pia and bifurcate into tangential bers parallel to the parallel bers (Chan-Palay 1975;
Takeuchi etal. 1982; Bishop and Ho 1985). However, in the
occulus, paraocculus, and some regions of the hemispheres, serotonergic bers are more tangential and oblique
(Takeuchi etal. 1982; Bishop and Ho 1985).
There is a great diversity in serotonin receptors (Nichols
and Nichols 2008), of which serotonin 1–2 and 4–7 receptors
© 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_32
209
210
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J. A. van Hooft and M. Oostland
Fig. 32.1 Localization of serotonin receptors in the cerebellar cortex. Reproduced with permission from (Oostland and van Hooft 2013), based
on (Geurts etal. 2002)
are all G protein-coupled receptors. The serotonin 3 (5-HT3)
receptor is the only ligand-gated ion channel for serotonin.
Different serotonin receptors have distinct functions and can
mediate both excitatory and inhibitory neurotransmission.
The expression of the different serotonin receptors is summarized in Fig.32.1. Each serotonin receptor has a unique
temporal expression pattern: some are only present during
development, while others start to be expressed when the
cerebellum reaches a more mature stage (see also Sect. 32.4).
parallel ber – Purkinje cell synapse can be mediated via
5-HT2 receptors expressed presynaptically by granule cells
(Oostland etal. 2014) as well as via postsynaptic expression
of 5-HT7 receptors by Purkinje cells (Lippiello etal. 2016).
Serotonin also inhibits hyperpolarization-activated cyclic
nucleotide-gated (HCN) channels in Purkinje cells, thereby
reducing their spontaneous ring rate (Li et al. 1993).
Serotonergic activation of 5-HT2A receptors on Golgi cells
increases Golgi cell ring, resulting in increased tonic inhibition onto granule cells as well as other Golgi cells (Fleming
and Hull 2019). In this way, serotonin can alter granule cell
32.2 Serotonergic Modulation
oftheCerebellar Cortex
excitability without altering spike timing (Fleming and Hull
2019).
One other cell type involved in the serotonergic control of
In the cerebellar cortex, serotonin can shape the ring patterns of several cell types by modulating their activity.
Serotonin reduces inputs to the Purkinje cells from the parallel bers, reduces Purkinje cell output, reduces granule cell
and Golgi cell ring, and increases Lugaro cell ring. The
reduction in Purkinje cell output due to serotonin occurs by
both decreasing excitatory inputs and increasing inhibitory
inputs to Purkinje cells. Serotonin can tonically inhibit
endogenous glutamate release from parallel bers to Purkinje
cells, via 5-HT1 and 5-HT2 receptors (Maura et al. 1988).
Application of serotonin results in long-lasting enhancement
of GABA-mediated inhibitory postsynaptic currents
observed in Purkinje cells (Mitoma etal. 1994). Serotonergic
inuence on short- and long-term synaptic plasticity at the
the neuronal activity in the cerebellar cortex is the Lugaro
cell. Lugaro cells are dually glycinergic/GABAergic interneurons located directly beneath the Purkinje cell layer,
which innervate stellate cells, basket cells, and Golgi cells
(Lainé and Axelrad 1998; Dieudonné and Dumoulin 2000;
Dean etal. 2003; Miyazaki etal. 2021). Lugaro cells are specically innervated by serotonin and viewed as the primary
target of serotonergic input into the cerebellar cortex. Lugaro
cells in the rat cerebellum are electrically silent and become
intensively active following the application of serotonin
(Dieudonné and Dumoulin 2000; Hirono et al. 2012). By
making long-distance connections with the other cerebellar
inhibitory interneurons, Lugaro cells can disinhibit the cerebellar cortex and can control the pattern of activity in granule
32 Serotonin intheCerebellum
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211
and Purkinje cells, allowing for a serotonin-operated intracortical switch (Miyazaki etal. 2021). Serotonin bidirectionally modulates GABAergic transmission from Purkinje cells
to globular cells, a subgroup of Lugaro cells (Hirono etal.
2012). GABA release between Purkinje cell axon collaterals
and globular cells is depressed by serotonin via presynaptic
5-HT1B receptors (Hirono etal. 2017).
Taken together, this indicates strong serotonergic control
of the cerebellar output via presynaptic inhibitory (from
Lugaro cells) and excitatory (from granule cells) inputs to
and postsynaptic modulations in Purkinje cells.
32.3 Serotonergic Modulation
ofCerebellar Nuclei
Serotonergic innervation to the cerebellar nuclei is independent from the serotonergic innervation to the cerebellar cortex (Kitzman and Bishop 1994). Thus, serotonin can
modulate the cerebellar cortex and the cerebellar nuclei independently. Serotonin increases the ring rate of cerebellar
nuclei neurons (Saitow et al. 2009; Gardette et al. 1987).
This is because serotonin induces a slow depolarization
resulting in an inward current in cerebellar nuclei neurons by
the activation of 5-HT5 receptors, thereby increasing spike
frequency (Saitow etal. 2009). In 2-week-old rats, serotonin
decreases the amplitude of stimulation-evoked excitatory
and inhibitory postsynaptic currents in cerebellar nuclei neurons via 5-HT1B receptors (Saitow etal. 2009; Murano etal.
2011). In adult rats, 5-HT2A but not 5-HT2B or 5-HT2C recep-
tors are expressed in the fastigial nucleus (Zhang etal. 2014).
Similar to results in the cerebellar cortex, serotonin regulates
long-term synaptic plasticity in the cerebellar nuclei, at
mossy ber–cerebellar nuclei synapses (Murano etal. 2011).
Bilateral serotonin injections into the fastigial nucleus
improves motor performance in adult rats via postsynaptic
5-HT2A receptors (Zhang etal. 2014). Activation of serotonergic bers from the dorsal raphe nucleus projecting directly
onto the fastigial nucleus induces stress-induced dystonia
mediated via 5-HT2A receptors in mice (Kim etal. 2021).
during which the cerebellum shows the greatest development
and maturation.
Serotonin controls cerebellar development in three
phases: (1) stimulation of dendritic growth and formation of
synapses, (2) hard-wiring of neuronal connections with limits to dendritic growth but ensuring synaptic plasticity, and
(3) stabilization of synapses. During the rst postnatal week,
activation of 5-HT1 receptors expressed by both granule cells
and Purkinje cells stimulates dendritic growth and synapse
formation (Oostland etal. 2014). Later, activation of 5-HT3
receptors expressed by granule cells limits the dendritic
growth of Purkinje cells via mediating the secretion of reelin,
inuences physiological maturation of Purkinje cells, modulates synaptic plasticity at parallel ber–Purkinje cell synapses, and thereby affects competition with the climbing
bers on Purkinje cell dendrites resulting in proper climbing
ber elimination (Oostland etal. 2011; Oostland etal. 2013).
Last, activation of 5-HT2 receptors expressed by granule
cells and Purkinje cells both during late postnatal development and in the mature cerebellum promotes the stability of
synaptic activity (Oostland etal. 2014). For a full review on
the role of serotonin during cerebellar development, see
Oostland & van Hooft (Oostland and van Hooft 2013).
Similar to changes in serotonin throughout early development, serotonin differentially affects cerebellar functioning
during aging. Serotonin levels in the cerebellum have been
reported to decrease with age in mice (Kabuto etal. 1995)
and rats (Arivazhagan and Panneerselvam 2002). In both
aging mice and aging humans, there is a decrease in 5-HT1A
and 5-HT2A receptor-positive cells in the molecular and granular cell layers in the cerebellar cortex (Yew etal. 2009).
Conversely, other studies found increased serotonin levels in
the cerebellum of aging mice (DeKorver etal. 2017), and a
slight increase in serotonin levels in the cerebellum of aging
rats between 18 and 29months, although no signicant overall change in serotonin levels with aging could be detected
(Ponzio etal. 1982).
32.5 Altered Serotonergic Modulation
oftheCerebellum inHuman Patients
32.4 The Role ofSerotonin
intheDeveloping andAging
Cerebellum
Malfunctioning of the serotonergic system is involved in
neurodevelopmental disorders, indicating a specic role for
serotonin in early development (Lin etal. 2014; Dayer 2014).
There is a developmentally critical window during which
altered serotonin levels permanently inuence neuronal circuitry (Daubert and Condron 2010). In rodents, this developmentally critical window is in the early postnatal period,
Although it is difcult to study the behavioral effects of
serotonin in isolation, it is clear that serotonergic modulation of the cerebellum can affect behaviors related to both
movement and cognition (Kawashima 2018; Mittal et al.
2021), and disruptions to the serotonergic system in the cer-
ebellum can lead to movement- and cognition-related disorders (Lin etal. 2014; Dayer 2014). Patients with cerebellar
ataxia have decreased serotonin levels (Trouillas 1993), and
treatment with a 5-HT1 receptor agonist improves symptoms of mild ataxia (Lou etal. 1995; Takei etal. 2005). In
patients with multiple sclerosis, functional connectivity
212
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J. A. van Hooft and M. Oostland
between the raphe nuclei and the cerebellum was reduced,
suggesting an involvement of the serotonergic system in the
cerebellum (Carandini et al. 2021). In patients with
Alzheimer’s disease, dementia severity correlated signicantly with serotonin levels in the cerebellar cortex
(Vermeiren etal. 2014). Patients with schizophrenia have
altered serotonin receptor expression in the cerebellum.
There is an increase in 5-HT1A receptor density (Slater etal.
1998), and 5-HT2A receptors expressed by Purkinje cells
were redistributed from the soma to the dendrites in patients
with schizophrenia (Eastwood et al. 2001). Concordantly,
atypical antipsychotics have the opposite effect in the cerebellum (Willins etal. 1999).
32.6 Concluding Remarks
In this chapter, we describe a powerful role for serotonin in
the modulation of the physiology in the cerebellar cortex and
in the cerebellar nuclei, from early development to late age,
through distinct temporal expression of its receptors. New
research in this direction can help us to understand better
how serotonin affects the function of the cerebellum and may
provide insight into pathophysiological conditions in which
the serotonergic system is compromised.
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Nitric Oxide
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ShoKakizawa
33
Abstract
Nitric oxide (NO) is a gaseous molecule with the chemical
formula NO.In biological systems, NO is produced from
L-arginine by three distinct NO synthases (NOSs), two of
which, neuronal (nNOS) and endothelial (eNOS), are calcium-dependent, whereas inducible NOS (iNOS) is calcium-independent. In the cerebellum, expressions of all
types of NOS are observed in physiological and/or pathological conditions. NO has two downstream- signaling pathways, activation of soluble guanylyl cyclase (sGC)—cyclic
guanosine monophosphate (cGMP)—protein kinase G
(PKG) cascade and chemical modication (S-nitrosylation)
of target proteins. In the cerebellum, both pathways are indicated to be involved in various biological events. Although
identied originally as the endothelium-derived relaxing
factor (EDRF), it is now well recognized that NO is involved
in a wide range of neurobiological functions such as neurogenesis, synaptic plasticity, cerebellar-dependent learning,
neuroprotection, and neuronal-cell death.
Keywords
Nitric oxide · cGMP · Soluble guanylyl cyclase
S-nitrosylation · Nitric oxide synthase · Granule cell
Synaptic plasticity · Parallel ber · Purkinje cell · Motor
learning
33.1 Chemical Properties andGeneral
Functions
Nitric oxide (nitrogen oxide or nitrogen monoxide; NO) is a
colorless gas with the formula NO.It is one of the principal
oxides of nitrogen and a free radical. NO has an unpaired
S. Kakizawa (*)
Department of Biological Chemistry, Graduate School of
Pharmaceutical Science, Kyoto University, Sakyo-ku, Kyoto, Japan
e-mail: kakizawa.sho.4u@kyoto-u.ac.jp
electron, which is sometimes expressed by a dot in its chemical formula (·NO or ·N=O). It is a biological product in
almost all types of organisms, including bacteria, fungi,
plants, and animal cells (Roszer 2012). On the other hand,
various kinds of NO donors have been developed (Ignarro
et al. 2002; Wang et al. 2002). In mammals including
humans, NO is a signaling molecule involved in a wide range
of physiological and pathological processes. It is a powerful
vasodilator with a half-life of a few seconds in the blood and
was originally identied and reported as an endotheliumderived relaxing factor (EDRF). Because NO is highly reactive, yet diffuses freely across membranes, the endothelium
(inner lining) of blood vessels uses NO to signal the surrounding smooth muscle to relax, resulting in vasodilation
and increasing blood ow (Ignarro 2000). Standard pharmaceuticals such as nitroglycerine and amyl nitrite are precursors to nitric oxide.
33.2 Nitric Oxide Synthase
Nitric oxide synthase (NOS) catalyzes the conversion of
L-arginine to NO and L-citrulline, in the presence of nicotinamide adenine dinucleotide phosphate (NADPH), O2, and
various cofactors (Abbott and Nahm 2004). NOS exists in
three major isoforms. These are named type I/neuronal NOS
(NOS1/nNOS), type II/inducible NOS (NOS2/iNOS), and
type III/endothelial NOS (NOS3/eNOS) (Alderton et al.
2001; Stuehr etal. 2004). Two of them, nNOS and eNOS, are
constitutively expressed mainly in the nervous system and the
vascular endothelium, respectively, and synthesize NO in a
calcium-dependent manner under basal conditions and upon
stimulation. By contrast, iNOS is induced when stimulated by
microbial endotoxins or certain proinammatory cytokines
and produces NO in a calcium-independent manner.
Among the three enzymatic isoforms of NOSs, nNOS and
eNOS are expressed in the cerebellum in physiological conditions, while iNOS starts to appear in pathologic states.
High levels of nNOS are detected in cerebellar granule, bas-
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