Inhibitory and excitatory neuromodulation by hydrogen peroxide: translating energetics to information

Abstract

Historically, brain neurochemicals have been broadly classified as energetic or informational. However, increasing evidence implicates metabolic substrates and byproducts as signalling agents, which blurs the boundary between energy and information, and suggests the introduction of a new category for 'translational' substances that convey changes in energy state to information. One intriguing example is hydrogen peroxide (H 2 O 2 ), which is a small, readily diffusible molecule. Produced during mitochondrial respiration, this reactive oxygen species, can mediate dynamic regulation of neuronal activity and transmitter release by activating inhibitory ATP-sensitive K + (K ATP ) channels, as well as a class of excitatory non-selective cation channels, TRPM2. Studies using ex vivo guinea pig brain slices have revealed that activity-generated H 2 O 2 can act via K ATP channels to inhibit dopamine release in dorsal striatum and dopamine neuron activity in the substantia nigra pars compacta. In sharp contrast, endogenously generated H 2 O 2 enhances the excitability of GABAergic projection neurons in the dorsal striatum and substantia nigra pars reticulata by activating TRPM2 channels. These studies suggest that the balance of excitation vs. inhibition produced in a given cell by metabolically generated H 2 O 2 will be dictated by the relative abundance of H 2 O 2 -sensitive ion channel targets that receive this translational signal.

Striatal dopamine neurotransmission: Regulation of release and uptake

“…A variety of heteroreceptors and the D2 autoreceptor can also regulate Ca 2+ currents in DA axons [178] (see Section 1.4.1). The specific Ca 2+ channels required for somatodendritic DA release remain uncertain [179], given that the release process can be triggered in very low extracellular Ca 2+ concentrations [180]; contributing factors, including intracellular Ca 2+ stores [181], are discussed elsewhere [182]. …”

“…The effects of ionotropic glutamate-receptor activation on DA release are most likely indirect given that DA terminals lack these receptors [258,259]. Studies by Margaret Rice’s group suggest that glutamatergic regulation of DA release in CPu is indirect and mediated by AMPA receptors on striatal medium spiny neurons, as reviewed elsewhere [182,260]. Briefly, AMPA receptor-dependent activation of striatal spiny neurons enhances mitochondrial H 2 O 2 generation [261].…”

“…Notably, most studies of AMPA receptor/H 2 O 2 modulation of DA release were conducted in guinea-pig striatal slices using FCV. Although endogenous H 2 O 2 also suppresses evoked DA release in rat striatum in vivo [264], this modulation may differ in other species, including mice [182]. Another indirect means of glutamatergic regulation of DA release in striatum is via effects on ChIs, which powerfully regulate DA release (see Section 1.4.4).…”

Laccase-mediated catalyzed fluorescent reporter deposition for live cell imaging

“…[29] Even at lower concentrations,h ydrogen peroxide is recognized to alter cell signaling, [30] particularly in sensitive cells like neurons. [31] These effects are highly dependent on the specific conditions and identity of the cells in question. [32] The diversity of effects over ar ange of concentrations makes it difficultt op redict what might happen upon addition of hydrogenp eroxide to any given cell line.…”

Coupling cellular metabolism to neuronal signalling

“…The authors conclude by highlighting the need for more research on this topic to better define how the brain expends energy on non-signalling tasks. Lee and colleagues from New York University School of Medicine examine the emerging idea that ROS lie at the hub of a number of signalling pathways in the brain (Lee et al 2015). The authors focus on the role of hydrogen peroxide (H 2 O 2 ) which the Rice lab has shown to be an endogenous modulator of dopamine release in the striatum (Chen et al 2001).…”