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35 Purinergic Signaling intheCerebellum
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227
of P2 receptor activation on excitatory and inhibitory cells
make it difcult to predict their overall effect on cerebellar
circuit output.
35.5 Extracellular Metabolism ofATP
Once released into the extracellular space, ATP is rapidly
metabolized to adenosine by enzymes called ectonucleotidases (reviewed in Zimmermann etal. 2012). These enzymes
include ecto-ATPase (CD39) which converts ATP directly to
AMP without liberating ADP. This enzyme is expressed in
the soma and dendrites of Purkinje cells and weakly
expressed in the granule cell layer. Ecto-5′-nucleotidase
(CD73) converts AMP to adenosine and is localized in glial
cells and parallel and climbing ber synapses. Genetic
knockout of CD73 results in ~90% inhibition of AMP metabolism to adenosine in the cerebellum (Klyuch et al. 2012)
with the remainder probably broken down by alkaline phosphatase (ALP). ALP has the physiological role of dephosphorylating compounds and thus can convert ATP to ADP,
AMP and to adenosine.
35.6 Adenosine Release fromNeurons
andGlia intheBrain
Extracellular adenosine can not only arise from ATP metabolism (as outlined above) but can also arise by the direct
release of adenosine into the extracellular space via specic
nucleoside transporters (equilibrative nucleoside transporters (ENTs) and concentrative nucleoside transporters CNTs).
ENTs can only move adenosine down its concentration gradient (from high to low concentration), whereas CNTs can
move adenosine against the concentration gradient (thus
require ATP). Little is known about CNTs, as there are not
any potent and selective inhibitors available. Both ENTs
(Anderson et al. 1999a, b) and CNTs are expressed in the
cerebellum. Inhibition of ENTs in the cerebellum can
increase the extracellular concentration of adenosine, showing their active role in adenosine removal.
The extracellular concentration of adenosine in the brain
can be increased by a number of stimuli including hypoxia,
ischemia, epileptic seizures, and prolonged wakefulness.
Studies have also shown that adenosine can also be released
by brief trains of action potentials and thus is potentially
important in controlling physiological network activity. The
source of this adenosine appears to vary with brain region,
but it can arise from both neuronal and glial release. In many
of these examples, adenosine can be considered a “retaliatory” metabolite as a mismatch between activity and metabolism leads to an increase in extracellular adenosine which
then feeds back to inhibit activity.
35.7 Adenosine (P1) Receptors
intheCerebellum
Once released into the extracellular space, adenosine activates G protein-coupled receptors (P1) that are divided into
four subtypes: A1, A2A, A2B, and A3 (Fredholm etal. 2001).
Most of these receptors can be expressed by neurons but can
also be expressed by glial cells and in some cases blood vessels. The A1 receptor is the most widely expressed adenosine
receptor in the brain and is inhibitory: it opens K+ channels
and closes voltage-gated Ca2+ channels, leading to hyperpolarization of the membrane potential and inhibition of transmitter release. Activation of A2A and A2B receptors facilitates
transmitter release and modulate synaptic plasticity. The
effects of A3 receptors are unclear but they may play a role in
pain pathways.
In the cerebellum, there is high expression of the A1 adenosine receptor, possibly the A3 receptor, but not A2A or A2B
receptors. Activation of A1 receptors reduces glutamate
release at parallel ber–Purkinje cell synapses with a similar
but smaller effect at climbing ber synapses (Takahashi etal.
1995). Adenosine also inhibits GABA release at Golgi cell-
granule cell synapses via A1 receptor activation (Courjaret
etal. 2009).
35.8 Adenosine Release inCerebellum
Adenosine can be released in the molecular layer of the cerebellum by focal electrical stimulation and can be directly
measured using adenosine microelectrode biosensors (Wall
and Dale 2007). These biosensors contain a 3-enzyme cascade that produce hydrogen peroxide in the presence of adenosine. This hydrogen peroxide is then oxidized (by the
polarized electrode) to release electrons which are detected
as a current. The amplitude of this current is proportional to
the amount of adenosine present (Llaudet etal. 2003). The
adenosine release detected in the molecular layer by electrical stimulation is both action potential and Ca2+-dependent
(Wall and Dale 2007). Pharmacological evidence supports
the direct release of adenosine from parallel bers by exocytosis (Klyuch etal. 2012). Enough adenosine is released by
stimulation to activate A1 receptors and to inhibit transmitter
release at the parallel ber synapse (Wall and Dale 2007).
This activity-dependent adenosine release represents a
potentially important feedback mechanism for controlling
neural activity in the cerebellum. Adenosine can also be
released in the cerebellum by high K+ solutions (depolarizing neurons and glia), by addition of glutamate to cerebellar
slices and by hypoxia. As in other brain regions, hypoxia
releases adenosine into the extracellular space and it acts via
A1 receptors to inhibit synaptic transmission (at parallel
bers to Purkinje cell).
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M. J. Wall
35.9 Breakdown andUptake ofAdenosine
The extracellular concentration of adenosine is controlled by
several mechanisms including equilibrative (ENTs) and concentrative transporters (CNTs) which transport adenosine
into neurons and glia (Fig. 35.2). Adenosine can then be
metabolized to inosine (by adenosine deaminase, ADA) or
phosphorylated to AMP (by adenosine kinase, ADK), maintaining low concentrations of intracellular adenosine. In
adult brain, ADK is exclusively expressed in glial cells with
ADA present in glia and neurons and to a smaller extent in
the extracellular space. Both ADA (Geiger and Nagy 1986)
and ADK (Gebril et al. 2021) have been reported to be
expressed in the cerebellum. In common with many brain
regions, ADK activity is the major determinant of the basal
extracellular concentration of adenosine in the cerebellum,
with adenosine deaminase playing only a minor role (Wall
etal. 2007).
Fig. 35.2 Control of extracellular purine concentration. ATP can be
released from both neurons and glia by exocytosis. It can also be
released from glial hemi-channels. The released ATP is broken down in
the extracellular space to form adenosine. Adenosine is removed from
the extracellular space by nucleoside transporters and can then be con-
verted to AMP by adenosine kinase (ADK) in glia or metabolized to
inosine by adenosine deaminase (ADA) in neurons and glia. Under
basal conditions, ADK dominates adenosine clearance, leading to
replenishment of intracellular ATP, with little adenosine converted to
inosine
35 Purinergic Signaling intheCerebellum
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35.10 The Role ofPurinergic Signaling
intheCerebellum andinMotor
Control
The role that purinergic signaling (ATP and adenosine)
plays in cerebellar function remains unclear. Experiments in
which Bergmann glia (which utilize ATP signaling to produce Ca2+ waves) were transgenically removed, showed
defects in synaptic plasticity (long term depression) and
eyeblink conditioning, although motor coordination was
unaffected (Shibuki etal. 1996). It is tempting to suggest
that glial ATP signaling is important for cerebellar function,
but it could be that other roles of glia (such as glutamate
uptake) underlie the observed decits. A recent study also
showed a motor phenotype when Ca2+ signaling in astrocytes was attenuated (Yu etal. 2021) which, again could in
part be the result of a loss of glial purinergic signaling.
There are several P2Y receptor knockout mice but they
show no obvious cerebellar phenotype. Also knockout of the
adenosine A1 receptor had little effect on coordination and
locomotion (Johansson etal. 2001). Caffeine (the A1/A2a
receptor antagonist) has no effect on eyeblink conditioning
(Rasmussen etal. 2018), a cerebellar learning task. There is,
however, evidence that cerebellar adenosine signaling is
involved in the ataxia produced by alcohol and cannabinoid
intoxication and is impaired in some neurodegenerative diseases (Dar and Mustafa 2002). There is also evidence that
inhibiting purine receptors can prevent some of the cerebellar decits observed in a mouse model of autism (Naviaux
etal. 2013).
35.11 Conclusions andFuture Work
A great deal of work has dened the distribution of purine
receptors and their effects on cellular function within the cerebellum, but many questions still remain unanswered. What
effect does purine signaling have on cerebellar neural network activity, cerebellar output and motor control? Mixed
excitatory effects (P2X, P2Y) and inhibitory effects (A1 and
P2Y) on both excitatory (glutamatergic) and inhibitory
(GABAergic) neurons and on glial cells makes this difcult
to predict. What are the sources of extracellular ATP and
adenosine and what form of cerebellar activity results in
their release? ATP is released from Bergmann glia and astrocytes and also may be released from molecular layer interneurons. Adenosine appears to be released from parallel
bers, although there are probably other sources. Currently
neither ATP nor adenosine release or their actions on receptors has been directly linked to a change in motor behavior.
Acknowledgements The gures were produced by Dr. Emily Hill.
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ox
Neuropeptides intheCerebellum
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GeorgiaA.Bishop andJamesS.King
36
Abstract
The existence of neuropeptides in the central nervous system has been known for over 50years with the initial
studies being conducted in the early 1970s. At present, a
total of 33 neuropeptides have been identied in the cerebellum based on the use of different experimental techniques including immunocytochemistry, in situ
hybridization, and gene studies. Indirect evidence for the
presence of some neuropeptides has been based on studies that identify the presence of their G-protein coupled
receptors. Although 33 cerebellar peptides have been
identied, relatively little is conclusively known about the
modulatory role of the vast majority of these peptides on
cerebellar circuits. Further, the function of peptides produced by cerebellar neurons such as Purkinje cells, Golgi
cells, or Lugaro cells is poorly if at all dened. Questions
need to be addressed as to the role(s) of neuropeptides in
modulating the output of the cerebellum, as carried by the
axons of cerebellar nuclear neurons. Future research
should focus on determining the mechanism of action of
these peptides in modulating neuronal activity including
dening transduction pathways activated following the
binding of the peptide to its receptor. To truly understand
the cerebellar function, it is essential to address the effect
of the numerous peptides present within cerebellar circuits and the role they play in modulating neuronal activity in the cerebellum.
G. A. Bishop (*) · J. S. King
Department of Neuroscience, The Ohio State University,
Columbus, OH, USA
e-mail: bishop.9@osu.edu
Keywords
Neuropeptides · Neuromodulators · G-Protein coupled
receptors · Endopeptidase · Exopeptidase · Climbing
bers · Mossy bers · Purkinje cells · Cerebellar nuclear
neurons · Corticotropin-releasing factor · Developmental
peptides · Orexin · Dynorphin · Calcitonin gene-related
peptide · Spinocerebellar ataxia type 23
36.1 Introduction
The existence of neuropeptides in the central nervous system
has been known for over 50years with the initial studies
being conducted in the early 1970s (see Hokfelt for review
(Hokfelt 1991). Over the last 50years, the number of identied neuropeptides in the central nervous system has
increased from the initial 15–20 described in the 1970s to
nearly 100 today (Ito 2009). Neuropeptides are distinct from
cholinergic as well as amino acid and monoaminergic neurotransmitters as described in basic Neuropharmacology
textbooks. Nestler and Hyman (2009) provide an excellent
overview of neuropeptide synthesis, transport, release, and
removal. To summarize their description, neuropeptides are
polypeptides that exclusively bind to metabotropic G-protein
coupled receptors rather than direct channel ionotropic
receptors. Actions mediated by G-protein coupled receptors
require activation of second messengers which utilize complex intracellular transduction pathways to alter the response
properties of neurons. Thus, because of the steps involved in
engaging these signal transduction pathways, there is usually
a delay in detecting the onset of the effect of the neuropeptide on its target neuron. Also, the modulatory effect of the
peptide is prolonged, compared to that of an amino acid such
as glutamate or GABA. When present, the neuropeptides
have the potential to alter the responsiveness of neurons to
subsequent synaptic inputs. They may become more responsive, if the peptides action is to depolarize the neuron or less
responsive if the effect results in hyperpolarization.
© 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_36
231
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G. A. Bishop and J. S. King
The synthesis of neuropeptides, as for all transmitters,
requires transcription of DNA into mRNA and further translation of mRNA into protein (Nestler and Hyman 2009). A
unique feature of neuropeptide synthesis is the fact that a
single gene may produce several different related neuropeptides in different brain regions. Further, synthesis of peptides
occurs only within the cell body of neurons; unlike synthesis
of acetylcholine or amino acids which occurs within a nerve
terminal. The initial step involves the synthesis of a large
pre-propeptide that is further processed into one or more
active neuropeptides that are stored in large dense core vesicles in the Golgi apparatus and then actively transported to
the axon terminal. These peptide-containing vesicles are
present in terminals that also contain amino acid and/or
monoaminergic transmitters. Further, more than one peptide
may be present within a single terminal.
Within the terminal, large dense core vesicles that contain
neuropeptides tend to be located away from the active zone
of the terminal, the area immediately adjacent to the postsynaptic target. The mechanism of release is the same as for
small vesicles containing amino acids and involves inux of
calcium. However, for peptides to be released, more calcium
inux is required and it must occur over a longer period so it
has time to diffuse to the area of the terminal containing the
peptide-lled vesicles. One way to accomplish this enhanced
calcium inux would be to have a longer train of action
potentials coming down the axon. While a single action
potential may result in release of amino acids, a prolonged
train may be required to sufciently depolarize the terminal
to allow greater inux of calcium and subsequent release of
peptides into the synaptic cleft. Thus peptide release is activity dependent.
Finally, the method for terminating peptide activity is
unique from that for amino acids. Their activity is terminated
by endopeptidases and exopeptidases located on extracellular membranes of neurons. The concentration of these peptidases is relatively low so neuropeptides may diffuse great
distances from the site of their release to remote receptors
thus giving them the opportunity to effect larger populations
of neurons. These neuropeptides are not transported back
into the terminal. All neuropeptides within a terminal must
be synthesized within the neuronal cell body and transported
to the terminal thus there is the potential for temporary
decreases in the availability of peptides for release from axon
terminals.
36.2 Neuropeptides intheCerebellum
Ito (2009) wrote a review that focused on 22 neuropeptides
that have been identied in the cerebellum. In his review, Ito
(2009) described several different experimental techniques
that have been used to identify peptides in the cerebellum
including immunocytochemistry to detect the peptide itself
and to identify the neuronal element (e.g., axon, soma, axon
terminal, glia) in which it is located. A more recent study
using a semi-quantitative peptidomic approach (Corbiere
etal. 2018) increased the number of peptides in the cerebellum to 33. This study demonstrated that of these 33 peptides,
8 had a clear differential expression pattern during development. Four of these peptides (cerebellin 2, nociception,
somatostatin, and VGF [353–372]) exhibited high levels of
expression during the rst two postnatal weeks followed by
a signicant decrease in the adult cerebellum. Other studies
have used in situ hybridization to detect whether cerebellar
neurons express the mRNAs for different peptides. This
technique detects peptides produced by cerebellar neurons.
Another technique has been to identify genes for specic
neuropeptides or their precursors. Again this approach would
be limited as nding the gene for a precursor does not establish that the peptide itself is present. Finally, the presence of
some neuropeptides is indirectly implied by techniques that
identify the presence of their G-protein coupled receptors.
Table 36.1 summarizes the distribution of several peptides
that have been identied in the cerebellum and their localization in diverse components of cerebellar circuitry including
Table 36.1 Summary of neuropeptide distribution in different neuronal components in the cerebellum determined by immunohistochemistry. Several neurons within the cerebellar cortex express
different neuropeptides. Neuropeptides also have been found in
Purkinje cell
Lugaro cell
Golgi cell Climbing ber Mossy ber Beaded ber Receptors on granule cells
Atrial natriuretic
peptide
Cerebellin Insulin-like growth factor 1 Cholecystokinin Dynorphin Melanin-concentrating hormone
Motilin Calcitonin gene-related
Galanin Atrial natriuretic peptide Met-enkephalin Met-
afferent systems to the cerebellum including climbing bers, mossy
bers, and a beaded plexus of axons. Granule cells express receptors
for peptides; the origin is yet to be conclusively determined (Adapted
from Ito 2009)
Corticotropin-releasing factor Corticotropin-releasing
factor
Leu-enkephalin Leu-
peptide
Substance P Orexin Neuropeptide Y
Angiotensin II
enkephalin
enkephalin
Α-melanocyte-stimulating
hormone
Neuronal neurotensin
Somatostatin
36 Neuropeptides intheCerebellum
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various cerebellar neurons, the two major afferent systems,
climbing bers and mossy bers, as well as a beaded plexus
of axons. In addition, some granule cells express receptors
for specic peptides, although the presence of the neuropeptide itself has not been veried by immunocytochemical
techniques. It was suggested that they may be released by
mossy ber terminals although data do not yet support the
presence of these peptides in this primary afferent system.
36.3 Role ofPeptides intheCerebellum
It is not possible to discuss the role of all of these peptides in
this chapter. It should be noted that the function of most of
these peptides in regulating cerebellar circuits remains
unclear. One of the major issues with understanding a role
for peptides in the cerebellum is due to the fact that their
distribution is not uniform within the cerebellum of a particular species and at all ages. Further, it varies between species. However, the action of several peptides has been
delineated in some detail. This brief summary will provide
an idea of potential roles for some of these peptides in regulating the development and effect on adult cerebellar
circuitry.
36.4 Development oftheCerebellum
Cerebellar development is under the control of many different factors. Corbiere etal. (2018) carried out an age-specic
analysis to identify peptides at different stages of cerebellar
development. They found that four peptides including
Cerebellin 2, Nociceptin, Somatostatin, and VGF [353–372]
showed high expression at postnatal day (P)8 and were
essentially undetectable by P90. In contrast, Cerebellin 1,
Octadecaneuropeptide, Secretogranin 1, and WE-14 were
upregulated over the same time period. They, and others
(Nielsen et al. 1998), further determined that pituitary
adenylate cyclase-activated polypeptide (PACAP) was only
expressed by Purkinje cells during development. They concluded that peptides expressed only during cerebellar development modulated the survival, migration, and/or
differentiation of cerebellar granule cells.
36.5 Adult Cerebellum
The focus will be on four neuropeptides as exemplars for the
complex role played by these neuromodulators in the adult
cerebellum.
Corticotropin-Releasing Factor: Corticotropinreleasing factor (CRF) is present in climbing ber and mossy
ber afferent systems in all mammalian species studied to
date (Fig. 36.1a and b). CRF in climbing bers originates
from neurons in the inferior olive, whereas CRF in mossy
bers originates from several different brainstem areas
including the vestibular complex and the reticular formation
(Errico and Barmack 1993; Bishop 1998; Cummings 1989).
Neurophysiological studies have shown that CRF is essential
in the generation of long-term depression, a mechanism
associated with cerebellar learning (Miyata and Ito 1999).
Further, CRF has been shown to increase the ring rate of
Purkinje cells (Fig.36.1c and d) by decreasing the amplitude
and duration of the after hyperpolarizing potential (Fox and
Gruol 1993) and blocking GABA-induced inhibition (Bishop
1990, 1992) (Fig. 36.1e). Clinically, a recent study (Wang
etal. 2017) dened a role for CRF released from climbing
bers in the control of gait, posture, and motor coordination
which could lead to new strategies for the treatment of cerebellar ataxia. In this study, it was determined that a deciency
of CRF in the olivocerebellar system induces ataxia-like
motor abnormalities. Unlike other studies, they determined
that this effect was mediated by altering the activity of glutamatergic projection neurons in the cerebellar nuclei leading
to decits in motor coordination.
Orexin: Orexin is present in a beaded plexus of axons
that originate from neurons located in the perifornical area
and the lateral hypothalamic area of the hypothalamus
(Sakurai etal. 1998). These orexinergic axons terminate primarily, if not exclusively within the occulus of the cerebellum (Nisimaru 2013). Initially, it was hypothesized (Kayaba
etal. 2003) that the role of this peptide was to induce a temporary increase in mean arterial blood pressure. More
recently, Zhang etal. (2013) suggested that the hypothalamic
orexinergic system participates in motor control and integration of somatic (motor) and non-somatic (visceral, emotional, and cognitive) systems. They postulated that a
somatic-nonsomatic integration was critical for generation
of a coordinated behavioral response to changes in the internal and external environment. The primary effect of orexin
was on neurons located in the vestibular nuclei and the cerebellar interpositus nucleus (Yu etal. 2010) which represent
a peptidergic effect on the output neurons of the cerebellum
and closely related vestibular system. Chen et al. (2013)
demonstrated that orexin excited Purkinje cells in the cerebellar cortex as wells as neurons in the cerebellar nuclei.
They used eyeblink conditioning to analyze the effects of
orexin on this cerebellum-dependent motor learning paradigm. This response has been a standard model system of
cerebellar-mediated motor learning. They determined that if
they blocked the orexin 1 receptor the timing, rather than the
acquisition, of the conditioned eyeblink response was disrupted. This suggested that orexins may modulate motor
learning mediated by the cerebellum.
Calcitonin Gene-Related Peptide: Calcitonin GeneRelated Peptide (CGRP) is transiently expressed in climbing
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G. A. Bishop and J. S. King
a
c
b
d
e
Fig. 36.1 (a) CRF-immunolabeled climbing ber in the opossum cer-
ebellum. (b) CRF-immunolabeled mossy ber in the opossum cerebellum. (c) Extracellular recording from a Purkinje cell in the rat’s
cerebellum. Baseline ring rate was 94 spikes/sec. Four seconds after
application of CRF at a pressure of 40psi for 500ms, the ring rate
increased to 132 spikes/sec. The unit recovered to baseline 11s after
application of CRF. (d) Histogram derived from data shown in C.
X-axis is time. Y-axis is spikes/sec. The dashed lines indicate application of CRF at the designated pressure and time. Following application
of CRF the ring rate of the Purkinje cell increases and remains elevated for a prolonged period of time. The effect is dose-dependent. (e)
Histogram documenting interactions between CRF and GABA. This is
from a recording in the rat’s cerebellum. Application of aspartate causes
the neuron to re at approximately 60 spikes/sec. Application of GABA
blocks the aspartate induced excitation, even at low currents.
Co-application of CRF during the GABA-induced inhibition blocks the
suppressive effect of GABA, even if the inhibitory transmitter is applied
at higher doses
36 Neuropeptides intheCerebellum
https://t.me/medicina_free
235
bers during development (Morara etal. 1992). The receptor
for CGRP is present on glial cells during early stages of
development and on Purkinje cells at later stages (Morara
etal. 2008). A calcium imaging study carried out in newborn
mice (Morara et al. 2008) concluded that CGRP, released
from climbing bers, modulates calcium in astrocytes during
development. During later stages of development, CGRP
was shown to stimulate Purkinje cell dendrite growth in culture (D’Antoni etal. 2010) that was dependent on activation
of CGRP receptors on astrocytes. A different pattern was
observed in the cat’s cerebellum, compared to the rat’s which
demonstrates how peptides have unique distributions and
functions in different species. In the cat (Bishop 1992),
CGRP was found in mossy bers in the adult animal.
Physiological studies demonstrated that CGRP suppressed
spontaneous and excitatory amino acid-induced activity
(Bishop 1995). Further, this study demonstrated a synergistic
suppressive effect when serotonin and CGRP were administered at the same time. Another point made in this and a previous study (Bishop 1992) was that there was a heterogeneous
distribution of CGRP-immunoreactive mossy bers in the
cat’s cerebellum suggesting that the effect of this peptide is
restricted to specic populations of cerebellar neurons.
Dynorphin: Dynorphin is another peptide localized to a
beaded plexus of axons in the cerebellar cortex. Mutations in
the prodynorphin gene, the precursor of α-neoendorphin and
dynorphins A (Dyn A) and B.Dyn A has been shown to have
both opioid and non-opioid activities. Mutations in Dyn A
have been associated with the neurodegenerative disorder
spinocerebellar ataxia type 23 (SCA23) (Bakalkin et al.
2010; Watanabe etal. 2012; Smeets etal. 2015). SCA23 is
characterized by a progressive impairment of motor coordination and the development of classic cerebellar ataxia. This
neurodegenerative disorder has been correlated with Purkinje
cell death (Verbeek etal. 2004) and loss of climbing ber
innervation (Smeets etal. 2015); these effects are dependent
on the presence of NMDA receptors (Tan-No etal. 2001) and
appear to involve glutamate neurotoxicity (Bakalkin et al.
2010; Smeets et al. 2015). This, in turn results in loss of
Purkinje cells and ataxia seen clinically in a small percentage
of SCA23 cases.
36.6 Neuropeptide Receptors
All neuropeptides to date have been shown to bind to
G-Protein-Coupled Receptors (GPCRs). Many peptide
receptors have been shown to bind more than one peptide of
the same family (Nestler and Hyman 2009). For example, the
type I CRF receptor preferentially binds CRF but it also has
a high afnity for urocortin, a CRF analog. In contrast, the
type II CRF receptor binds CRF; however, it has a higher
afnity for urocortin. As reviewed in Nestler and Hyman
(2009), peptide receptors have a more extensive distribution
in the neuropil including extrasynaptic locations (e.g., axons,
dendrites outside the area of the synapse). As for the neuropeptides themselves, research on the role of different families of neuropeptide receptors is essential for understanding
the role of these ligands in regulating cerebellar activity.
36.7 Conclusion andFuture Directions
As is evident from this brief review, there are numerous neuropeptides within the cerebellum. A question might be, why
is there a stress hormone (i.e., CRF), or a hypothalamic hormone with a role in sleep (i.e., orexin) or an opioid peptide
(i.e., dynorphin) in the cerebellum? That is not the question
that should be asked. It is becoming evident that peptides are
widely distributed in the central nervous system and that they
have unique modulatory functions on different types of neurons. In the cerebellum, some of these peptides, in particular
those associated with the climbing ber and mossy ber system of afferents (e.g., CRF, orexin and CGRP), have been
studied and their physiological effect on Purkinje cells has
been reported. These peptides appear to be involved in modulating the excitability of Purkinje cells. In addition, CRF
has been shown to be essential for generation of long-term
depression in the cerebellar cortex and orexin is postulated to
play a role in motor learning as well as integrating inputs
from the somatic and autonomic nervous systems in the cerebellum. The opioid dynorphin has primarily been studied in
relationship to its role in modulating pain. However, in the
cerebellum, mutations in dynorphin have been linked to
Spinocerebellar ataxia type 23. This is a unique role for an
opioid peptide. The question should not be why are they in
the cerebellum, but what is their role in cerebellar control of
movement. Functionally, it is important to determine the
mechanism by which these peptides modulate neuronal
activity. For example, identication of specic second messenger and associated signal transduction pathways is essential. Continued studies on the differential roles for peptides
during different stages of development and in the adult also
need to be carried out. Further, the role of peptides found
within cerebellar neurons such as Purkinje cells, Golgi cells
or Lugaro cells is poorly if at all dened. Questions remain
as to the effect of these neuropeptides on their postsynaptic
targets in the cerebellar cortex and cerebellar nuclei. Another
area that requires elucidation is the role of neuropeptides in
the cerebellar nuclei. This would include peptides released
from the collaterals of climbing and mossy bers that may
release peptides into the nuclei, as well as analysis of peptidergic Purkinje cell axons that terminate in the nuclei. In
conclusion, to truly understand cerebellar function, it is
essential to incorporate the functional role of the numerous
peptides present within cerebellar circuits.
236
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G. A. Bishop and J. S. King
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