Synaptic modifications transform neural networks to function without oxygen

Amaral-Silva, Lara; Santin, Joseph M.

doi:10.1186/s12915-023-01518-0

Cited by 5 publications

(1 citation statement)

References 91 publications

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“…Rhythm-generating populations produce the rhythm that is transmitted to premotor and/or motor neurons facilitating their rhythmic activity. As such, respiratory-associated vagal motor neurons require presynaptic input to burst (Amaral-Silva and Santin, 2023a), functioning as one of the final motor outputs of the respiratory circuit. In preparations from hibernators, frequency of rhythmic respiratory motor output was largely insensitive to depression by muscimol and, albeit counterintuitively, depression by bicuculline.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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Caffeic acid recovers ischemia-induced synaptic dysfunction without direct effects on excitatory synaptic transmission and plasticity in mouse hippocampal slices

Fernandes

Lopes

Silva

et al. 2023

Neuroscience Letters

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Plasticity in the functional properties of NMDA receptors improves network stability during severe energy stress

Bueschke

Amaral-Silva

et al. 2023

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Brain energy stress leads to neuronal hyperexcitability followed by a rapid loss of function and cell death. In contrast, the frog brain switches into a state of extreme metabolic resilience that allows them to maintain motor function during hypoxia as they emerge from hibernation. NMDA receptors (NMDARs) are Ca2+-permeable glutamate receptors that typically drive the loss of homeostasis during hypoxia. Therefore, we hypothesized that hibernation leads to plasticity that reduces the role of NMDARs within neural networks to improve function during energy stress. To test this, we assessed a circuit with a large involvement of NMDAR synapses, the brainstem respiratory network of female bullfrogs,Lithobates catesbieanus. Contrary to our expectations, hibernation did not alter the role of NMDARs in generating network output, nor did it affect the amplitude, kinetics, and hypoxia sensitivity of NMDAR currents. Instead, hibernation strongly reduced NMDAR Ca2+permeability and enhanced desensitization during repetitive stimulation, with shifts in mRNA copy number for NMDAR subunits that modify receptor function. Under severe hypoxia, the normal NMDAR profile caused network hyperexcitability within minutes, which was mitigated by blocking NMDARs. After hibernation, the modified complement of NMDARs protected against hyperexcitability, as disordered output did not occur for at least one hour in hypoxia. These findings uncover state-dependence in the plasticity of NMDARs, whereby distinct changes to receptor function improve neural performance during energy stress without interfering with its normal role during healthy activity.

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Synaptic modifications transform neural networks to function without oxygen

Cited by 5 publications

References 91 publications

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

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

Caffeic acid recovers ischemia-induced synaptic dysfunction without direct effects on excitatory synaptic transmission and plasticity in mouse hippocampal slices

Plasticity in the functional properties of NMDA receptors improves network stability during severe energy stress

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