Noradrenaline depresses spontaneous complex spikes activity of cerebellar Purkinje cells via α2-adrenergic receptor in vivo in mice

Sun, Na; Li, Bingxue; Hong, Ying-Ji; Bing, Yan-Hua; Qiu, De-Lai; Chu, Chun-Ping

doi:10.1016/j.neulet.2019.03.008

Cited by 9 publications

(13 citation statements)

References 26 publications

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“…We next dissected the effects of α1-AR blockers on NE-mediated inhibition of PCs (Figure 2A-F) ( 17 , 32 , 38 ). The general α1-AR blocker Praz reliably recovered PC SS firing to 81% of reference levels after NE-mediated inhibition (Figure 2E, G-J) and successfully restored PC regularity (Figure 2I).…”

Section: Resultsmentioning

confidence: 99%

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Cerebellar α1_D-adrenergic receptors mediate stress-induced dystonia in tottering^tg/tgmice

Bohne,

Josten,

Rambuschek

et al. 2023

Preprint

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Episodic ataxia type 2 (EA2) is an inherited neurological disorder, where patients suffer from chronic ataxia and severe episodes of motor dysfunction exhibited as dystonia. Despite other factors, physical and emotional stress triggers those episodes reliably in both human and mice. We used the well-established EA2 mouse model tottering to explore the cerebellar adrenergic receptor (AR) involvement in stress-induced dystonic attacks. We found that α1-ARs, but not α2-ARs, on cerebellar Purkinje cells (PCs) are activated by norepinephrine (NE) from the locus coeruleus (LC), differentially expressed and required for initiation of dystonia. Moreover, pharmacological blockade and shRNA-induced knock down of cerebellar α1D-ARs was sufficient to effectively prevent stress-induced dystonia in homozygous totteringtg/tgmice but had no impact on ataxia amelioration.In vivorecordings and live calcium (Ca2+) imaging of PCs demonstrated that α1D-AR blockade successfully protects PCs from NE-mediated erratic firing patterns through decreased release of calcium from intracellular stores, thus preventing stress-induced dystonia. Furthermore, chemogenetic inhibition of the LC-NE pathway alleviated the frequency and symptoms of stress-induced dystonia. Together, our data show the modulatory effects of NE on dystonia severity and suggest a predominant role of cerebellar α1D-ARs in the formation of stress-induced dystonia in totteringtg/tgmice and, thereby providing a potential new therapeutic target to treat stress-induced dystonia in EA2.

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Section: Resultsmentioning

confidence: 99%

“…During stressful conditions, norepinephrine (NE) is released from the LC, innervating the whole brain. In the cerebellum, PCs are the main target of LC synapses ( 14 ), receiving predominantly inhibitory input though α- and β-adrenergic receptors (ARs) ( 15–17 ), resulting in long-lasting inhibition of PCs ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

Cerebellar α1_D-adrenergic receptors mediate stress-induced dystonia in tottering^tg/tgmice

Bohne,

Josten,

Rambuschek

et al. 2023

Preprint

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“…Morphological studies have shown that both α-ARs and β-ARs are present in the cerebellar cortex ( McCune et al, 1993 ). We previously found that NA regulates spontaneously complex spikes activity of cerebellar PCs via activation of α2-ARs in vivo in mice ( Sun et al, 2019 ). Our results in this study show that cerebellar surface perfusion of NA produces a concentration-dependent inhibition of synaptic transmission convey sensory information in the cerebellar GL.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, activation of α2-ARs by NA decreased the probability of transmitter release at climbing fiber–PC synapses, which in turn suppressed the climbing fiber-evoked dendritic calcium transients and controlled the induction of synaptic plasticity at parallel fiber–PC synapses by modulating dendritic calcium influx ( Carey and Regehr, 2009 ). We previously found that NA-activated presynaptic α2-AR regulated climbing fiber–PC synaptic transmission via the PKA signaling pathway, suggesting that the NAergic fibers from the nucleus of the LC might regulate the output behavior of PC by suppressing the information transmission from the inferior olivary nucleus to the cerebellar cortex in vivo in mice ( Sun et al, 2019 ; Cui et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Effect of Noradrenaline on the Facial Stimulation-Evoked Mossy Fiber-Granule Cell Synaptic Transmission in Mouse Cerebellar Cortex

Jin

Zhang

et al. 2021

Front. Neurosci.

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Noradrenaline is an important neuromodulator in the cerebellum. We previously found that noradrenaline depressed cerebellar Purkinje cell activity and climbing fiber–Purkinje cell synaptic transmission in vivo in mice. In this study, we investigated the effect of noradrenaline on the facial stimulation-evoked cerebellar cortical mossy fiber–granule cell synaptic transmission in urethane-anesthetized mice. In the presence of a γ-aminobutyrateA (GABAA) receptor antagonist, air-puff stimulation of the ipsilateral whisker pad evoked mossy fiber–granule cell synaptic transmission in the cerebellar granular layer, which expressed stimulus onset response, N1 and stimulus offset response, N2. Cerebellar surface perfusion of 25 μM noradrenaline induced decreases in the amplitude and area under the curve of N1 and N2, accompanied by an increase in the N2/N1 ratio. In the presence of a GABAA receptor blocker, noradrenaline induced a concentration-dependent decrease in the amplitude of N1, with a half-maximal inhibitory concentration of 25.45 μM. The noradrenaline-induced depression of the facial stimulation-evoked mossy fiber–granule cell synaptic transmission was reversed by additional application of an alpha-adrenergic receptor antagonist or an alpha-2 adrenergic receptor antagonist, but not by a beta-adrenergic receptor antagonist or an alpha-1 adrenergic receptor antagonist. Moreover, application of an alpha-2 adrenergic receptor agonist, UK14304, significantly decreased the synaptic response and prevented the noradrenaline-induced depression. Our results indicate that noradrenaline depresses facial stimulation-evoked mossy fiber–granule cell synaptic transmission via the alpha-2 adrenergic receptor in vivo in mice, suggesting that noradrenaline regulates sensory information integration and synaptic transmission in the cerebellar cortical granular layer.

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“…27 NE, acting through α2Rs, inhibits glutamate release from climbing fibers [28][29][30] and reduces complex spike activity in Purkinje cells. 31 This reduces Ca 2+ transients and thus afterhyperpolarization of Purkinje cells, leading to an increased frequency of single spike firing. 30 However, the indirect inhibitory effects of NE through molecular layer GABAergic interneurons overwhelm the direct excitatory effects of NE on single spike firing of Purkinje cells.…”

Section: Complexity Of Noradrenergic Modulation Of Cerebellar Cortica...mentioning

confidence: 99%

What Is the Role of Norepinephrine in Cerebellar Modulation and Stress-Induced Episodic Ataxia?

Benarroch

2023

Neurology

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The cerebellum receives noradrenergic input from the locus ceruleus (LC).1-3 The LC input to the cerebellar cortex is diffuse and targets mainly the molecular layer but also the Purkinje and granule cell layers.4,5 Norepinephrine (NE), acting through different adrenoceptor subtypes localized presynaptically and postsynaptically in the various components of the cerebellar circuit, has a complex modulatory effect on the tonic firing of Purkinje cells, which control the output of the cerebellum through the cerebellar nuclei (Figure). Purkinje cell activity is determined both by their intrinsic ion conductances and by synaptic influences from excitatory inputs from the mossy-parallel fiber and climbing fiber systems and inhibitory inputs from molecular layer interneurons.6,7 The components of the cerebellar cortex circuit express different α1-adrenergic, α2-adrenergic, and β-adrenergic receptor (adrenoceptors [ARs]) subtypes, with a distinct distribution.8,9 Given the multiple modulatory effects of NE in the cerebellar circuit, activation of LC and NE release in the cerebellum, for example, in response to stress, may directly or indirectly affect Purkinje cell activity and thus cerebellar output. Stress is an important trigger of episodic movement disorders due to channelopathies, including episodic ataxias (EAs).10 A common feature in several ataxic disorders is impaired tonic pacemaking firing of Purkinje cells.11-14 A recent study in the tottering mouse model of EA2 provides a mechanism by which stress, through the activation of LC-NE input to the cerebellum, can trigger episodic ataxia.15 This study supports the role of NE signaling and downstream effects on tonic firing of Purkinje cells and provides potential therapeutic approaches to treat this disorder. Furthermore, these results also provide a potential link between stress and other episodic movement disorders.

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Noradrenaline depresses spontaneous complex spikes activity of cerebellar Purkinje cells via α2-adrenergic receptor in vivo in mice

Cited by 9 publications

References 26 publications

Cerebellar α1_D-adrenergic receptors mediate stress-induced dystonia in tottering^tg/tgmice

Cerebellar α1_D-adrenergic receptors mediate stress-induced dystonia in tottering^tg/tgmice

Effect of Noradrenaline on the Facial Stimulation-Evoked Mossy Fiber-Granule Cell Synaptic Transmission in Mouse Cerebellar Cortex

What Is the Role of Norepinephrine in Cerebellar Modulation and Stress-Induced Episodic Ataxia?

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Noradrenaline depresses spontaneous complex spikes activity of cerebellar Purkinje cells via α2-adrenergic receptor in vivo in mice

Cited by 9 publications

References 26 publications

Cerebellar α1D-adrenergic receptors mediate stress-induced dystonia in totteringtg/tgmice

Cerebellar α1D-adrenergic receptors mediate stress-induced dystonia in totteringtg/tgmice

Effect of Noradrenaline on the Facial Stimulation-Evoked Mossy Fiber-Granule Cell Synaptic Transmission in Mouse Cerebellar Cortex

What Is the Role of Norepinephrine in Cerebellar Modulation and Stress-Induced Episodic Ataxia?

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Cerebellar α1_D-adrenergic receptors mediate stress-induced dystonia in tottering^tg/tgmice

Cerebellar α1_D-adrenergic receptors mediate stress-induced dystonia in tottering^tg/tgmice