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T. Hirano and S.-y. Kawaguchi

Purkinje cells during development and show motor discoordination (Jacobson 1991). Purkinje cell-specic vesicular GABA transporter knockout mice are defective in GABA release and show motor discoordination without apparent morphological abnormality (Kayakabe et al. 2014). A transgenic mouse line in which Golgi cells can be ablated at a desired timing was constructed (Watanabe etal. 1998). Golgi cell ablation in this mouse model induces severe motor discoordination followed by partial recovery, which is accompanied with suppressed NMDA receptor-mediated synaptic response in granule cells. This suppression of excitatory response in a granule cell seems to counteract the loss of GABAergic inhibition caused by Golgi cell ablation, potentially contributing to the partial recovery of motor coordination.

Transgenic mouse lines in which GABAergic synaptic transmission onto Purkinje cells are depressed have also been generated. In one type, GABAA receptor γ2 subunit was knocked out (Wulff et al. 2009a). The mice show drastic reduction in GABAergic synaptic response in a Purkinje cell and motor learning defects. However, the mice show apparently normal motor coordination. A previous study reported that acute suppression of GABAergic synaptic transmission by drug application causes severe motor discoordination (Wulff et al. 2009b). Therefore, a relatively mild effect of chronic suppression of GABAergic transmission might be ascribed to some compensatory mechanisms in the cerebellum.

29.5 GABA inCerebellar Ataxia

As mice models with defects in GABAergic neurons or synapses show motor discoordination and/or motor learning failures, some dysfunction in the cerebellar GABAergic systems might be a cause of cerebellar ataxia in human patients. Indeed, some patients have autoantibody against glutamate decarboxylase (GAD), an enzyme catalyzing production of GABA from glutamate (Vianello etal. 2003). The antibody suppresses GABA release from basket cells depressing inhibitory synaptic transmission to Purkinje cells. The autoantibodies against GAD65, one of the two types of GAD, collected from patients of cerebella ataxia were shown to be internalized into cytoplasm, and indeed pathogenic when applied to rodents (Mitoma etal. 2017). An agrypnia patient showing ataxia has autoantibody against GABAB receptor, which might affect GABA systems in the cerebellum (Frisullo etal. 2007).

In a mouse model of episodic ataxia type 1, mutation of a type of K+ channel increases the frequency and amplitude of spontaneous GABAergic postsynaptic currents in a Purkinje cell, which might be a cause of episodic ataxia (Herson etal.

2003). On the other hand, GABA-mimetic drug gabapentin

improves motor coordination in some spinocerebellar ataxia type six patients (Nakamura etal. 2009), suggesting that the drug treatment to modulate GABA system is therapeutically effective in some ataxic patients.

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Glutamatergic Pathways andReceptors

https://t.me/medicina_free

SusumuTomita

Abstract

Glutamate is a major excitatory neurotransmitter in the

vertebrate brain and is utilized at distinct synapses in the

cerebellum. Glutamate released from presynaptic termi-

nals binds to various types and classes of glutamate recep-

tors at pre- and post-synapses. Glutamate receptors are

classied as metabotropic (mGluR) or ionotropic (iGluR).

iGluRs function as glutamate-gated cation channels and

are classied pharmacologically as AMPA-, NMDA-, or

kainite-types. AMPA receptors determine synaptic

strength, whereas NMDA receptors induce synaptic plas-

ticity. Kainate receptors play multiple roles in regulating

synaptic transmission and plasticity. mGluRs are G

protein- coupled receptors that modulate postsynaptic sig-

naling by the type I mGluRs through Gq signaling and

modulate glutamate release via the type II and III mGluRs

acting via Gi/o signaling. Combinatory action among the

glutamate receptors coordinates synaptic transmission

and synaptic plasticity. Disruption of receptor activities

causes various neurological disorders including epilepsy,

mental retardation, and neurodegenerative diseases, and

controlling glutamate receptor activities is used as a thera-

peutic strategy for these disorders. This chapter covers

topics of glutamate receptors and their auxiliary

subunits.

Keywords

30.1 Glutamatergic Pathways andSynaptic Transmission

Neurons communicate with each other at synapses through the release and uptake of neurotransmitters. One major excitatory neurotransmitter in the vertebrate brain is glutamate. In the cerebellum, glutamate is used as a neurotransmitter at various synapses such as mossy ber to granule cells, parallel ber to Golgi cells, parallel ber to stellate cells, parallel ber to Basket cells, parallel ber to Purkinje cells, and climbing ber to Purkinje cells (Ito 2006; Jakab and Hamori

1988). Synaptic transmission is initiated when glutamate is

released from the presynaptic terminals upon depolarization of the terminals by the arrival of an action potential. Subsequently, glutamate binds to and activates glutamate receptors at pre- and postsynaptic membranes. At each synapse, unique classes of glutamate receptors are expressed and localized to mediate characteristic synaptic properties.

30.2 Glutamate Receptors

The various subtypes of metabotropic and ionotropic glutamate receptors are illustrated in Fig. 30.1 (Hollmann and Heinemann 1994; Nakanishi 1992; Wisden and Seeburg

1993).

Glutamate receptor · Synapse · Metabotropic glutamate receptor · AMPA receptor · Kainate receptor · NMDA receptor

S. Tomita (*) Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA

Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA e-mail: Susumu.Tomita@yale.edu

© 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_30

30.2.1 Metabotropic Glutamate Receptors (mGluRs)

mGluRs are classic G protein-coupled receptors (GPCRs) that contain a conserved seven transmembrane domain and play major roles in modulating intracellular second messenger signaling. Upon glutamate binding, type I (1/5) mGluR activates protein kinase C (PKC) and inositol triphosphate (IP3) signaling through Gq-mediated phospholipase C (PLC) activation. Subsequently, the phosphorylation of PKC sub-

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S. Tom it a

Fig. 30.1 Glutamate receptor complex. Glutamate receptors are classied as metabotropic and ionotropic receptors. mGluRs mediates various G protein signaling dependent on mGluR isoforms. Each ionotropic receptor is a heterotetramer with distinct auxiliary subunits that modu-

strates or an increase in intracellular calcium (Ca2+) mediated via IP3 receptors modulates postsynaptic functions. Type II (2/3) and III (4/6/7/8) mGluRs couple with Gi/o to reduce cAMP levels through Gi/o-mediated adenylate cyclase inhibition. In addition, type II/III mGluRs are primarily localized on presynaptic membranes where these receptors modulate neurotransmitter release.

mGluRs are implicated in various neurological diseases, including depression, schizophrenia, pain, epilepsy, and neurodegenerative diseases (Bear etal. 2004; Niswender and Conn

2010). The disruption of mGluR expression is associated with

multiple neurological diseases. For example, mGluR1 knockout mice show severe ataxia (Aiba etal. 1994). In addition, the disruption of mGluR functions is observed in Fragile X mental retardation, and mGluR5 knockout mice show mental retardation-like phenotypes (Bear et al. 2004; Dolen et al. 2007). Therefore, mGluRs are recognized as a therapeutic target for the treatment of various neurological disorders.

30.2.2 Ionotropic Glutamate Receptors

(iGluRs)

iGluRs are glutamate-gated cationic channels and are further classied pharmacologically as AMPA-, NMDA-, and kainate- sensitive glutamate receptors (Fig.30.1) (Hollmann and Heinemann 1994; Nakanishi 1992; Wisden and Seeburg

late receptor properties and/or localization. AMPA receptor (AMPAR) interacts with transmembrane AMPA receptor regulatory protein (TARP) and kainate receptor (KAR) interacts with Neuropilin and Tolloid-like protein (Neto)

1993). The AMPA and kainate receptors can be activated by

glutamate at the neuron resting potential of approximately

−70 mV. In contrast, at the resting potential, magnesium (Mg2+) binds to the NMDA receptor to block the channel pore preventing a response to glutamate. Upon membrane depolarization by repetitive stimulation, Mg2+ is removed from the NMDA receptor, enabling activation of the receptor. The activated NMDA receptor possesses high Ca2+ conductivity, which is implicated in synaptic plasticity. All iGluR subunits have three transmembrane domains with 1 pore-loop, and a tetramer of these receptors forms a glutamate- gated cationic channel. In the brain, several iGluRs contain auxiliary subunits that stably bind to the receptors and modulate receptor localization and/or channel properties including pharmacology and activity.

30.2.2.1 AMPA Receptors (AMPARs)

AMPARs are composed of four subunits (GluA1–4), and all AMPARs can form homotetramers. However, in hippocampal and other neurons, AMPARs form heteromeric Ca2+impermeable channels of GluA2 with GluA1/3/4 (Sommer and Seeburg 1992). Importantly, GluA2 is subjected to RNA editing and the resulting protein has an R (glutamine) instead of a Q (arginine) in the pore-loop. This R/Q editing affects the ion permeability as GluA2(R) is Ca2+ impermeable, whereas GluA2(Q) is Ca2+ permeable. Several neurons, including cerebellar stellate cells, express Ca2+-permeable

30 Glutamatergic Pathways andReceptors

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AMPARs, indicating that GluA2 is absent in these AMPARs (Liu and Cull-Candy 2000). Furthermore, to add to the complexity of this system, each subunit has splicing isoforms, termed the ip/op isoforms, and the splicing site is located on the extracellular domain and modulates receptor kinetics (Sommer and Seeburg 1992).

In the brain, AMPARs contain auxiliary subunits (e.g., TARPs, GSG1L, CNIHs, and CKAMPs/Shisas) (Jackson and Nicoll 2011; Jacobi and von Engelhardt 2021; Kamalova and Nakagawa 2021; Schwenk etal. 2012; Yan and Tomita 2012). TARPs have six isoforms (γ-2/3/4/5/7/8) that display distinct expression patterns in the brain. CNIHs, GSG1L, and CKAMPs/Shisa express broadly in the brain. Auxiliary subunits interact with AMPARs to modulate receptor properties, pharmacology, and localization. For example, no synaptic AMPAR activity is observed in the cerebellar granule cells and in Purkinje cells with disruptive expression of TARPγ-2 and both γ-2/7, respectively (Hashimoto etal. 1999; Yamazaki etal. 2010), indicating essential roles of TARPs in synaptic AMPAR activity. Furthermore, AMPARs expressed in heterologous cells do not respond to kainic acid, whereas both native AMPAR in the brain and AMPAR co-expressed with TARPs respond to kainic acid (Tomita etal. 2005). To study AMPAR in the brain, the incorporation of TARPs and other auxiliary subunits into the receptors is required.

30.2.2.2 NMDA Receptors (NMDARs)

NMDAR is a heteromer of GluN1 and GluN2/3 that has high Ca2+ permeability. Due to the blockage of the channel pore by Mg+ at the resting potential, both glutamate binding and Mg2+ removal by membrane depolarization are required for NMDAR activation. Ca2+ inux through NMDAR plays critical roles in synaptic plasticity. In long-term potentiation (LTP), postsynaptic Ca2+ through NMDAR activates calmodulin (CaM) kinase II to increase synaptic AMPARs.

30.3 Glutamate Pathways inGlia Cells

In addition to neurons, glia cells also express glutamate receptors, which are activated by glutamate released from presynaptic terminals or ambient glutamate in the extracellular space to help glia function and development (Volterra and Meldolesi 2005). In the cerebellum, the Bergmann glia engulfs the parallel ber—Purkinje cell synapses to form a tripartite synapse in the cerebellum (Palay and Chan-Palay 1974). At this tripartite synapse, Bergmann glia expresses AMPAR subunits, GluA1, and GluA4. Elimination of both GluA1 and GluA2 from Bergmann glia cells changes synaptic transmission at the parallel ber-Purkinje cell synapses and synapse development (Saab et al. 2012), suggesting signicant roles of glutamate receptors in glia.

30.4 Concluding Remarks

At excitatory synapses in the cerebellum, glutamate binds to various types and classes of glutamate receptors. Each of these receptors shows distinct expression, localization, and properties, and combinatory receptor activity causes excitatory synaptic transmission. Furthermore, glutamate receptor disruption causes various neurological disorders. For example, the disruption of NMDAR or both AMPAR and KAR causes mouse lethality, whereas TARPγ-2 disruption causes severe ataxia phenotypes. Furthermore, genome-wide association study (GWAS) ndings have identied mutations in these receptor components in various neurological disorders, including schizophrenia, epilepsy, and ataxia; therefore, glutamate receptor complex components are considered to be drug targets for neurological disorders.

30.2.2.3 Kainate Receptors (KARs)

KARs have ve isoforms (GluK1–5). GluK1–3 form a homo-tetramer; however, GluK4/5 cannot form a tetramer and require GluK1–3 to function as a heterotetramer. Similar to AMPARs, GluK1–3 can be subjected to Q/R editing to alter Ca2+ permeability. Unlike AMPARs, KARs localize at both pre- and post-synapses (Lerma 2006; Nicoll and Schmitz 2005). At pre-synapses, KARs function as autoreceptors to modulate glutamate release, and at postsynapses, KARs function as membrane depolarizers, similar to AMPARs. Furthermore, KARs and AMPARs play redundant roles at post-synapses (Yan et al. 2013). In addition, KARs display distinctly slow kinetics, which are determined by Neto1/2 auxiliary subunits (Copits and Swanson 2012; Tomita and Castillo 2012). Neto1/2 interacts with KARs and slows the decay kinetics of synaptic KARs without changes in KAR localization.

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Norepinephrine intheCerebellum

https://t.me/medicina_free

HavenK.Predale, DanielJ.Chandler, andBarryD.Waterhouse

Abstract

Although the presence of norepinephrine (NE) in the

mammalian cerebellum was initially controversial, there

is now substantial evidence of a role for the NE system in

modulating the response properties of individual cerebel-

lar neurons to synaptic inputs rather than transmitting

moment-to-moment details of modality-specic informa-

tion. As a result of these cellular actions, the noradrener-

gic system is capable of regulating cerebellar circuit

functions within the context of ongoing voluntary and

reex motor activities and in a manner appropriate to the

behavioral state of the organism. The evidence for this

mode of operation derives from extensive anatomical,

physiological, and pharmacological investigations over a

period of more than 50years. This chapter summarizes

those studies and the development of this concept.

Implications for developmental disorders and pathologi-

cal conditions involving the cerebellum are also

discussed.

Keywords

Norepinephrine · Locus coeruleus · Noradrenergic

Neurotransmitter · Neuromodulation · Cerebellum

Purkinje cells · Coeruleo-cerebellar pathway

31.1 Anatomical Considerations

Early uorescent histochemical (Andén etal. 1967) and biochemical (Iversen and Glowinski 1966) studies provided the rst evidence of norepinephrine (NE)-containing bers within the cerebellar cortex. Later anatomical, physiological,

H. K. Predale · D. J. Chandler · B. D. Waterhouse (*) Department of Cell Biology and Neuroscience, Rowan University School of Osteopathic Medicine, Stratford, NJ, USA e-mail: predal25@rowan.edu; chandlerd@rowan.edu;

waterhouse@rowan.edu

and pharmacological experiments (Bloom etal. 1971; Hoffer etal. 1971, 1973; Siggins etal. 1971a, b) conrmed the exis- tence of a prominent NE pathway from the brainstem nucleus locus coeruleus (LC) to all regions of the cerebellar cortex and deep cerebellar nuclei (Olson and Fuxe 1971). The LC is a small, bilateral nucleus located in the brainstem, ventral to the cerebellum and lateral to the fourth ventricle that contains approximately 45,000–50,000 neurons in the adult human and about 3000 neurons in rodent (Poe etal. 2020; Swanson 1976; Von Coelln et al. 2004; Liu et al. 2013). Within the cerebellar cortex, NE bers arising from LC terminate primarily in the inner portion of the molecular, granule, and Purkinje cell layers, with no contact made in the cerebellar white matter (Bloom etal. 1971). The deep cerebellar nuclei also receive noradrenergic input from LC, presumably from collaterals of axons ascending to the cortex (Carlson etal. 2021). The LC-cerebellar pathway arises from NE-containing cell bodies that are distributed throughout the rostral-caudal extent of the ipsilateral and contralateral nucleus (see Fig.31.1). In early studies, electrical stimulation of the LC resulted in the suppression of Purkinje cell spontaneous discharge, further supporting the existence of an input pathway from LC to the cerebellum (Siggins etal.

1971a). Aside from LC afferents, there is evidence that a

subset of Purkinje neurons is capable of synthesizing catecholamine transmitter (Locke etal. 2020).

Because of the small number of LC neurons in the brainstem, and the broad expanse of cerebellar tissue, it must be assumed that individual LC cells give rise to axons that collateralize extensively throughout the cerebellum. Currently, we know little about the branching patterns and distribution of LC-NE axon collaterals within the cerebellum or elsewhere in the brain. Such information would provide new insight regarding the topographic specicity of interactions between LC output and cerebellar operations.

Immunohistochemical studies using antibodies against tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis, further conrmed the existence of cat-

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Fig. 31.1 Enhanced green uorescent protein (EGFP)+NE-containing cells in the ipsi- (at right) and contralateral (at left) LC nucleus following retrograde delivery of the canine adenovirus encoding Cre recombinase (CAV2-CMV-Cre) from the medial nucleus of the mouse cerebellum. Mice were heterozygous for En1

Dre

, Dbh

Flpo

, and the

echolamine afferents to the cerebellum in both rat (Kimoto etal. 1978) and mouse (Landis et al. 1975). Although TH labeling can also be a biomarker for dopamine cell bodies and bers, studies using antibodies against dopamine have revealed only a limited distribution of dopaminergic bers in the cerebellum (Nelson et al. 1997) indicating that NE remains the dominant catecholamine transmitter in the cerebellum. Recent work by Flace etal. indicates that dopaminergic innervation of the lobules in the cerebellar cortex and deep cerebellar nuclei varies among different species (Flace etal. 2021).

Traditionally, the cerebellum has been viewed as a motor control center; engaged in planning movement, providing for on-line correction of movements in progress, and exerting a major inuence on balance, posture, and eye movements. It achieves its role in motor control through massive connections with the primary motor cortex, brainstem, and spinal cord. However, substantial evidence indicates that a large portion of the cerebellar circuitry is dedicated to non-motor functions (Stoodley and Schmahmann 2010; Strick et al.

2009; Schmahmann 2019; Schmahmann etal. 2019). Studies

on strokes in humans showed that motor decits resulted from stroke-induced damage in the anterior lobe of the cerebellum, but not from insult to the posterior or occulonodular lobes (Schmahmann et al. 2009). Additional stroke studies noted that the posterior lobe of the cerebellum appears to be necessary for learned fear (Sacchetti et al.

2009). Finally, recent studies in mice (Carlson etal. 2021;

Locke et al. 2018, 2020) have shown that catecholaminecontaining Purkinje cells and catecholamine regulated output from the lateral nucleus of cerebellum can modulate cognitive behaviors. Taken together, these reports conrm

RC::RFLTG indicator allele (Jensen Laboratory, NIEHS). LC-NE neurons are labeled constitutively with tdTomato (red uorescence) and switch to EGFP (green uorescence) after Cre recombination (Plummer etal. 2020, eNeuro)

the existence of non-motor regions of the cerebellum and catecholaminergic inuence over non-motor cerebellar functions. Nevertheless, the specic role of the LC-NE system in regulating non-motor operations of the cerebellum has yet to be fully detailed.

31.2 Physiology ofNE inCerebellum—Cellular Actions

NE was initially viewed as an inhibitory transmitter in the cerebellum. However, later studies demonstrated differential effects of NE on spontaneous and evoked discharge of Purkinje neurons that are best described as neuromodulatory (Freedman etal. 1977; Moises etal. 1979, 1990). NE suppresses Purkinje cell spontaneous discharge but reduces mossy ber- or climbing ber evoked excitation to a lesser extent or not all, yielding a net increase in signal to noise ratio, i.e., the ratio of the change in stimulus evoked versus spontaneous discharge. In addition, NE augments inhibitory responses of Purkinje neurons to afferent pathway stimulation (Freedman etal. 1976, 1977). Thus, NE is capable of producing a relative or absolute enhancement of stimulusdriven activity in the primary output cells of the cerebellar cortex. Beyond these actions, a “gating” effect has been observed whereby Purkinje cells exhibiting little or no response to peripheral stimuli become responsive to such inputs in the presence of NE (cf. Fig.5—Moises etal. 1990). Collectively, the evidence indicates that NE can produce a spectrum of effects on spontaneous and evoked discharge of Purkinje neurons, all of which serve to regulate the responsiveness of these cells to synaptically driven inputs. It is

31 Norepinephrine intheCerebellum

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important to note that despite anatomical evidence of noradrenergic innervation of the deep cerebellar nuclei (Olson and Fuxe 1971), the effect of NE release on response properties of cells in the deep cerebellar nuclei has not been elucidated.

Further tests showed that NE’s neuromodulatory action on inhibitory transmission to Purkinje cells was specic for GABA. For example, Moises et al. (1979) showed that glycine- induced inhibition of Purkinje cell ring was not enhanced by NE application, and Yeh etal. (1981) showed that NE did not enhance Purkinje cell inhibition elicited by direct application of taurine or beta-alanine, inhibitory amino acids that are structurally similar to GABA. Despite these demonstrations of specicity for GABA, NE can also enhance Purkinje neuron responses to the excitatory amino acid transmitter glutamate (Moises etal. 1979). Importantly, the facilitating effects of NE on amino acid evoked responses in Purkinje neurons have been demonstrated in waking animals (West and Woodward 1984) suggesting these actions are indeed physiologically relevant.

Activation of the noradrenergic input pathway from the LC results in modulatory actions similar to those observed following local application of NE to Purkinje neurons. For example, phasic patterns of LC electrical stimulation that mimic physiologic discharge along the coeruleo-cerebellar pathway result in prominent modulation of Purkinje neuron responses to excitatory and inhibitory synaptic inputs; both climbing ber and parallel ber excitation as well as inhibition mediated by local inhibitory interneurons [cf. Fig.5— Moises et al. (1981), cf. Fig. 2—Moises et al. (1983)]. In addition, LC stimulation increases the probability of Purkinje cell discharge in response to otherwise sub-threshold activation of the climbing ber input pathway [cf. Fig.5—Moises et al. (1981)]. As in other brain regions (Berridge and Waterhouse 2003; Waterhouse and Navarra 2019), these LC-NE modulatory effects follow an inverted-U function (Moises etal. 1981) suggesting that state-dependent uctuations in LC output can adjust cerebellar circuit operations across a dynamic range, one that is capable of optimizing or minimizing function as behavioral contingencies change.

31.3 Noradrenergic Receptors

inCerebellum

The net effect of NE on cerebellar network properties not only depends on the cellular type on which it acts, but also the receptor expression and localization, and concurrent excitatory or inhibitory afferent drive impinging on the neuron. Three main subtypes of adrenergic receptors exist: α1, β, and α2, each of which is coupled to a distinct intracellular signaling pathway that produces unique effects on cellular physiology. While NE was originally characterized as an

inhibitory transmitter in cerebellum, it is now quite apparent that it functions as a neuromodulator, altering the response properties of target neurons by facilitating the actions of other transmitters. The net impact of the LC-NE system on cerebellar circuit function derives from the constellation of actions mediated by individual receptor sub-types.

Βeta Receptor Activation Suppresses Purkinje Cell Discharge and Augments GABA-Mediated Inhibitory Action It has been very clearly demonstrated that NE

reduces the spontaneous ring rate of cerebellar Purkinje neurons (Bickford-Wimer etal. 1991), and potentiates the inhibitory response of these neurons to GABAergic neurotransmission (Cheun and Yeh 1992, 1996; Llano and Gerschenfeld 1993). Furthermore, the decline in the spontaneous ring rate of Purkinje neurons is very tightly correlated with NE efux (Bickford-Wimer et al. 1991). These inhibitory responses are mediated by β-receptor activation (Cheun and Yeh 1992, 1996; Llano and Gerschenfeld 1993; Saitow and Konishi 2000; Saitow etal. 2000). Microiontophoretic application of the β agonist isoproterenol mimics the effect of NE administration on the ring rate of Purkinje neurons and GABA-mediated inhibition, while α-adrenergic drugs have no effect (Cheun and Yeh 1992; Llano and Gerschenfeld

1993; Lin etal. 1991).

The transmembrane β receptor is Gs protein coupled and activates protein kinase A (PKA)-dependent intracellular signaling cascades to phosphorylate various proteins, ultimately increasing the sensitivity of the neuron to afferent inhibitory inputs. A proposed molecular mechanism by which this occurs is phosphorylation of an intracellular domain of the GABA receptor itself, which produces a conformational change that increases GABA-dependent chloride currents to hyperpolarize the neuron (Cheun and Yeh

1992; Sweetnam etal. 1988; Kirkness etal. 1989). As such,

the discharge properties of Purkinje cells are sensitive to manipulations that target the downstream signaling cascade of β activation: for example, forskolin, a potent activator of adenylate cyclase, increases the frequency of inhibitory postsynaptic currents (IPSC) in cerebellar Purkinje and stellate cells (Llano and Gerschenfeld 1993; Kondo and Marty

1997), while 8-bromo-cAMP, a membrane permeant analog

of cAMP resistant to degradation by cAMP phosphodiesterase, mimics the effect of NE application on GABAergic inhibition of Purkinje neurons (Cheun and Yeh 1992).

The Αlpha 1 Receptor Suppresses Purkinje Cell Discharge Via a Presynaptic Mechanism In the cerebel-

lum, the cellular localization of α1 adrenergic receptors remains somewhat inconclusive. α1 Receptors have been reported primarily on Bergmann glial cells (Herold et al.

2005). Due to the regulatory role that glia play in neuronal

transmitter release and uptake, metabolism, morphology, and

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H. K. Predale et al.

connectivity, activation of glial α1 receptors may account for some of the changes in neuronal discharge properties that are associated with α1 receptor stimulation (Kulik etal. 1999; Hirono and Obata 2006). However, there is also evidence that α1 receptors are located presynaptically on interneurons, and their activation causes release of intracellular calcium to increase the frequency of inhibitory postsynaptic currents in Purkinje cells, leading to neuronal inhibition (Hirono and Obata 2006). Importantly, this effect can be suppressed by blocking phospholipase C, but not PKA, suggesting that it is an effect independent of β receptor signaling. Despite the apparent widespread distribution of this receptor on both neuronal and non-neuronal cells, its activation consistently increases the frequency and amplitude of both spontaneous and evoked inhibitory postsynaptic potentials, likely due to an increase of presynaptic GABA release (Kulik etal. 1999; Hirono and Obata 2006). Therefore, both α1 and β receptors inhibit tonic Purkinje discharge. Although these effects are likely mediated by distinct cellular and molecular mechanisms, they act synergistically to modulate the signal-tonoise ratio of Purkinje neurons.

Activation of the α2 Receptor Suppresses Inhibition of Purkinje Cells Presynaptically α2 Receptors are located

presynaptically on interneurons within the cerebellar cortex (Hirono and Obata 2006). Like the other adrenergic receptors, the α2 receptor spans the membrane and is coupled to an intracellular G protein signaling cascade. However, unlike the other adrenergic receptors, its activation stimulates Gi proteins, which leads to opposing intracellular actions of β receptor activation and reducing intracellular cAMP concentration, inhibiting voltage-gated calcium channels, and activating inward rectifying potassium channels. Furthermore, activation of this adrenergic receptor subtype decreases the amplitude of hyperpolarization-activated nonselective cation currents, which inhibits the release of both glutamate and GABA from terminals by decreasing the ring rate of presynaptic interneurons (Hirono and Obata 2006; Hirono etal.

2008). This is achieved by suppressing spike generation at

both dendrites and somata (Hirono and Obata 2006), thereby decreasing the ability of neurons to propagate action potentials and release transmitter onto postsynaptic Purkinje neurons. Therefore, the ultimate effect of presynaptic α2 receptor activation is a net disinhibition of Purkinje cell discharge. This receptor appears to be necessary to ne-tune motor coordination. Interestingly, genetically altered mice who do not express a subtype of the α2 receptor display impaired motor coordination (Lahdesmaki etal. 2002), which may be due in part to the lack of the receptor within cerebellum.

While it is valuable to identify individual receptor mechanisms responsible for NE actions, one must consider the combined effect of LC activation and NE release in the context of global cerebellar function and whole animal behavior.

In this context, it is important to remember that under physiologic conditions, noradrenergic receptors do not operate independently, but rather are all subject to simultaneous activation by NE release according to their afnity for NE;

α2a>α1>β. It is important to note that to date there is no

evidence of differential expression of adrenergic receptors across the cerebellum. Based upon the distribution of DBHpositive bers, the assumption is that adrenergic receptors are present in both the cortex and deep cerebellar nuclei. Studies to date suggest the β, α1, and α2 adrenergic receptors act both pre- and postsynaptically to synergistically modulate cerebellar network properties and subsequent motor behaviors. One additional caveat is that variances in receptor sensitivity and expression could most certainly dictate the net outcome of NE release on cerebellar operations.

31.4 Functional Implications

Impact of the LC-NE System on Motor and Non-motor Functions of the Cerebellum The cerebellum through its

afferent and efferent connections serves both motor and nonmotor functions (Strick etal. 2009; Schmahmann 2019). The role of NE in regulating these functions is clear in some cases but speculative in many others. Several reexes mediated by the cerebellum are modulated by NE, indicating that the effects of NE on individual neuron and neural network properties impact signicantly the motor-related output of the cerebellum. For example, the vestibular ocular reex (VOR) relies on output from the occulus of the cerebellum to stabilize images on the retina during a head movement by proportionately rotating the eyes in the direction opposite to that of head movement. It has been shown experimentally that β receptor agonists and antagonists are capable of increasing and decreasing, respectively, the ability of this reex to keep a visual stimulus stabilized on the retina (van Neerven etal. 1990).

Anatomical studies have clearly demonstrated input–output connections between the cerebellum and cognitive centers of the brain (Strick et al. 2009; Schmahmann 2019). Recently, Carlson etal. demonstrated LC projections and LC-mediated release of catecholamines, presumably NE, in the lateral nucleus of the mouse cerebellum (Carlson etal.

2021). Following selective depletion of catecholamine bers

in the lateral nucleus, these authors observed decits in tasks that measure sensorimotor integration, associative fear learning, response inhibition, and working memory; but not in tasks assessing motor coordination, vestibular function, or gait. These ndings conrm a role for the LC-NE system in non-motor cerebellar-mediated functions.

The above ndings suggest a role for NE in moment-tomoment regulation of cerebellar operations. Thus, as LC output waxes and wanes across the waking cycle, NE release in

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