Molecular profiling of CO2/pH-sensitive neurons in the locus coeruleus of bullfrogs reveals overlapping noradrenergic and glutamatergic cell identity

Amaral-Silva, Lara; Santin, Joseph M.

doi:10.1016/j.cbpa.2023.111453

Cited by 5 publications

(2 citation statements)

References 59 publications

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“…There is ample evidence to indicate that the noradrenergic system plays a key role in the regulation of epileptogenesis and convulsions ( 14 , 15 ). Norepinephrine (NE) is generally synthesized and released from noradrenergic nerve endings in the locus coeruleus (LC) ( 16 , 17 ). Abnormal NE secretion causes an increase in tonic/clonic seizures in mice genetically prone to epileptic seizures ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

Adrenergic receptor system as a pharmacological target in the treatment of epilepsy (Review)

Ozdemir

2024

Med Int

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Epilepsy is a complex and common neurological disorder characterized by spontaneous and recurrent seizures, affecting ~75 million individuals worldwide. Numerous studies have been conducted to develop new pharmacological drugs for the effective treatment of epilepsy. In recent years, numerous experimental and clinical studies have focused on the role of the adrenergic receptor (AR) system in the regulation of epileptogenesis, seizure susceptibility and convulsions. α 1 -ARs (α 1A , α 1B and α 1D ), α 2 -ARs (α 2A , α 2B and α 2C ) and β-ARs (β 1 , β 2 and β 3 ), known to have convulsant or anticonvulsant effects, have been isolated. Norepinephrine (NE), the key endogenous agonist of ARs, is considered to play a crucial role in the pathophysiology of epileptic seizures. However, the effects of NE on different ARs have not been fully elucidated. Although the activation of some AR subtypes produces conflicting results, the activation of α 1 , α 2 and β receptor subtypes, in particular, produces anticonvulsant effects. The present review focuses on NE and ARs involved in epileptic seizure formation and discusses therapeutic approaches.

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Section: Introductionmentioning

confidence: 99%

Adrenergic receptor system as a pharmacological target in the treatment of epilepsy (Review)

Ozdemir

2024

Med Int

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“…To investigate plasticity of the GABA system in the adult respiratory network, we took advantage of an extreme model of respiratory neuroplasticity—hibernation in the American bullfrog. These animals use lungs for gas exchange and contain all salient components of the respiratory network, including a respiratory rhythm generator (Wilson et al, 2002; Baghdadwala et al, 2015; Baghdadwala et al, 2016), central chemoreceptors (Amaral-Silva and Santin, 2023b; Burton and Santin 2020; Santin and Hartzler, 2013), and conserved nuclei for sensory integration (Hanamori et al, 1987; Wang et al, 1999). However, during hibernation they may spend up to several months under water without access to air using only skin to breathe.…”

Section: Introductionmentioning

confidence: 99%

Hibernation reduces GABA signaling in the brainstem to enhance motor activity of breathing at cool temperatures

Saunders,

Santin

2023

Preprint

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The respiratory network must produce consistent output throughout an animal's life. Although respiratory motor plasticity is well appreciated, how plasticity mechanisms are organized to give rise to robustness following perturbations that disrupt breathing is less clear. During underwater hibernation, respiratory neurons of bullfrogs remain inactive for months, providing a large disturbance that must be overcome to restart breathing. As a result, motoneurons upregulate excitatory synapses to promote the drive to breathe. Reduced inhibition often occurs in parallel with increased excitation, yet the loss of inhibition can destabilize respiratory motor output. Thus, we hypothesized that GABAergic inhibition would decrease following hibernation, but this decrease would be expressed differentially throughout the network. We confirmed that respiratory frequency was under control of GABAAR signaling, but after hibernation, it became less reliant on inhibition. The loss of inhibition was confined to the respiratory rhythm-generating centers: non-respiratory motor activity and large seizure-like bursts were similarly triggered by GABAA receptor blockade in controls and hibernators. Supporting reduced presynaptic GABA release, firing rate of respiratory motoneurons was constrained by a phasic GABAAR tone, but after hibernation, this tone was decreased despite the same postsynaptic receptor strength as controls. Thus, selectively reducing inhibition in respiratory premotor networks promotes stability of breathing, while wholesale loss of GABAARs causes non-specific hyperexcitability throughout the brainstem. These results suggest that different parts of the respiratory network select distinct strategies involving either excitation (motoneurons) or inhibition (rhythm generator) to minimize pathological network states when engaging plasticity that protects the drive to breathe.

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Anatomical distribution of µ-opioid receptors, neurokinin-1 receptors, and vesicular glutamate transporter 2 in the mouse brainstem respiratory network

Furdui,

da Silveira Scarpellini,

Montandon

2024

Journal of Neurophysiology

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µ-Opioid receptors (MORs) are responsible for mediating both the analgesic and respiratory effects of opioids drugs. By binding to MORs in brainstem regions involved in controlling breathing, opioids produce respiratory depressive effects characterized by slow and shallow breathing, with potential cardiorespiratory arrest and death during overdose. To better understand the mechanisms underlying opioid-induced respiratory depression, thorough knowledge of the regions and cellular subpopulations that may be vulnerable to modulation by opioids is needed. Using in situ hybridization, we determined the distribution and co-expression of Oprm1 (gene encoding MORs) mRNA with glutamatergic ( Vglut2) and neurokinin-1 receptor ( Tacr1) mRNA in medullary and pontine regions involved in breathing control and modulation. We found that >50% of cells expressed Oprm1 mRNA in the preBötzinger Complex (preBötC), nucleus tractus solitarius (NTS), nucleus ambiguus (NA), locus coeruleus (LC), Kölliker-Fuse nucleus (KF), and the lateral and medial parabrachial nuclei (LBPN and MPBN, respectively). Among Tacr1 mRNA-expressing cells, >50% co-expressed Oprm1 mRNA in the preBötC, NTS, NA, Bötzinger Complex (BötC), LC, raphe magnus nucleus, KF, LPBN, and MPBN, whereas among Vglut2 mRNA-expressing cells, >50% co-expressed Oprm1 mRNA in the preBötC, NTS, NA, BötC, LC, KF, LPBN, and MPBN. Taken together, our study provides a comprehensive map of the distribution and co-expression of Oprm1, Tacr1, and Vglut2 mRNA in brainstem regions that control and modulate breathing and identifies Tacr1 and Vglut2 mRNA-expressing cells as subpopulations with potential vulnerability to modulation by opioids.

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Molecular profiling of CO2/pH-sensitive neurons in the locus coeruleus of bullfrogs reveals overlapping noradrenergic and glutamatergic cell identity

Cited by 5 publications

References 59 publications

Adrenergic receptor system as a pharmacological target in the treatment of epilepsy (Review)

Adrenergic receptor system as a pharmacological target in the treatment of epilepsy (Review)

Hibernation reduces GABA signaling in the brainstem to enhance motor activity of breathing at cool temperatures

Anatomical distribution of µ-opioid receptors, neurokinin-1 receptors, and vesicular glutamate transporter 2 in the mouse brainstem respiratory network

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