Rebound from Inhibition: Self-Correction against Neurodegeneration?

Abstract

Neural networks play a critical role in establishing constraints on excitability in the central nervous system. Several recent studies have suggested that network dysfunction in the brain and spinal cord are compromised following insult by a neurodegenerative trigger and might precede eventual neuronal loss and neurological impairment. Early intervention of network excitability and plasticity might therefore be critical in resetting hyperexcitability and preventing later neuronal damage. Here, the behavior of neurons that generate burst firing upon recovery from inhibitory input or intrinsic membrane hyperpolarization (rebound neurons) is examined in the context of neural networks that underlie rhythmic activity observed in areas of the brain and spinal cord that are vulnerable to neurodegeneration. In a non-inflammatory rodent model of spongiform neurodegenerative disease triggered by retrovirus infection of glia, rebound neurons are particularly vulnerable to neurodegeneration, likely due to an inherently low calcium buffering capacity. The dysfunction of rebound neurons translates into a dysfunction of rhythmic neural circuits, compromising normal neurological function and leading to eventual morbidity. Understanding how virus infection of glia can mediate dysfunction of rebound neurons, induce hyperexcitability and loss of rhythmic function, pathologic features observed in neurodegenerative disorders ranging from epilepsy to motor neuron disease, might therefore suggest a common pathway for early therapeutic intervention.

Inhibitory basal ganglia nuclei differentially innervate pedunculopontine nucleus subpopulations and evoke opposite motor and valence behaviors.

“…Post-inhibitory rebound firing has been observed in the PPN as well as other brainstem structures 48,[50][51][52][53][54][55] and is associated with greater excitability, temporal encoding, and generation of oscillatory activity 56 . Indeed, we found that the rostral and caudal cholinergic PPN neurons exhibited an increase in action potential firing after inhibition (2way ANOVA, p=0.0154; Tukey test, %Frequency Pre vs. Post Stimulation Rostral p=0.0013, Pre vs Post Caudal p<0.0012; Figure 2K).…”

Ventral pallidum GABA and glutamate neurons drive approach and avoidance through distinct modulation of VTA cell types

“…DA release in dmsh NAc was inhibited by stimulation of VP glutamate terminals in VTA, and here too, a rebound of DA release was observed. Rebound activation of DA neurons has been observed before and may signal the termination of an aversive stimulus [91][92][93] or function as a mechanism to reset and restore coherent activity in neuronal ensembles [94][95][96] .…”

Astrocyte Infection Is Required for Retrovirus-Induced Spongiform Neurodegeneration Despite Suppressed Viral Protein Expression

“…Whether these cells fully integrate and establish themselves as part of the tripartite synapse on dendrites and cell bodies remains to be determined. However, given the ability of astrocytes to modulate neuronal voltage-gated calcium channels (Mazzanti and Haydon, 2003), and regulate neuronal excitability (Fellin et al, 2006, 2007; Gourine et al, 2010; Halassa and Haydon, 2010), their infection could explain the elevated intracelluar calcium levels in rebound neurons associated with hyperexcitability and loss of rebound firing noted in FrCasE-induced spongiosis (Li et al, 2014; Sivaramakrishnan and Lynch, 2017). Further dissection of this process in the simple MLV-based system, using these new visualization tools will accelerate our understanding of how retroviruses cause neurodegeneration.…”