Classification of H₂O₂as a Neuromodulator that Regulates Striatal Dopamine Release on a Subsecond Time Scale

Abstract

Here we review evidence that the reactive oxygen species, hydrogen peroxide (H 2 O 2 ), meets the criteria for classification as a neuromodulator through its effects on striatal dopamine (DA) release. This evidence was obtained using fast-scan cyclic voltammetry to detect evoked DA release in striatal slices, along with whole-cell and fluorescence imaging to monitor cellular activity and H 2 O 2 generation in striatal medium spiny neurons (MSNs). The data show that (1) T he striatum is the largest component of the basal ganglia and receives dense dopamine (DA) innervation from midbrain DA neurons in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA).1 The primary targets of these DA afferents are medium spiny neurons (MSNs) that constitute over 90% of the striatal neuronal population and are the main output neurons of this region. Axons arising from midbrain DA neurons form symmetric synapses on MSNs, primarily on spine necks, adjacent to glutamatergic input to spine heads. 2,3 This architectural arrangement enables DA to modulate glutamate-induced MSN excitability with differential outcomes according to whether the target MSN also expresses DA D1 receptors (D1Rs) or DA D2 receptors (D2Rs); DA enhances MSN excitability and up-state MSN spiking via D1Rs and decreases these via D2Rs. 4 Thus, converging glutamatergic and dopaminergic afferents control striatal output at the level of individual spines to regulate motor and cognitive function.4−6 It is relevant to note that D1Rs and D2Rs are predominantly extrasynaptic, 7 so that rapid electrochemical measurements of extracellular DA concentration ([DA] o ) can provide a direct index of DA transmission (e.g., 8−10).The crucial role that DA plays in normal motor behavior has been illuminated by the findings that disturbances in DA function contribute to basal-ganglia circuit dysfunction and that DA depletion leads to the motor deficits of Parkinson's disease.11−13 Thus, elucidating factors that regulate DA release in the striatum is of relevance for understanding the role of DA in normal brain function, as well as for providing therapeutic insight for neuropathological conditions like Parkinson's disease.Our laboratory examines the regulation of striatal DA release using fast-scan cyclic voltammetry (FCV) with carbon-fiber microelectrodes. Because FCV detects dynamic changes in [DA] o with high temporal and spatial resolution, this technique is ideally suited to determine factors that influence the amplitude, duration, and sphere of influence of DA signaling.14−17 Basic factors that we have examined include the pattern of stimulation, Ca 2+ -dependence of DA release, inhibition of DA release by presynaptic DA autoreceptors, and DA clearance by the DA transporter (DAT); we have also examined the effect of a number of local neurotransmitters and neuromodulators that can act on DA axons either directly or indirectly to alter evoked [DA] o (for review, see ref 10).One unconventional and under-appreciated modulator of striatal DA rele...

Neurotoxic Agent-Induced Injury in Neurodegenerative Disease Model: Focus on Involvement of Glutamate Receptors

“…H 2 O 2 affects synaptic transmission and oxidative stress through the activation of NMDARs (Avshalumov and Rice, 2002). In striatal medium spiny neurons, the generation of AMPAR-dependent H 2 O 2 is one source of retrograde signals that can block the release of DA (Avshalumov et al, 2008). …”

Peroxide-Dependent MGL Sulfenylation Regulates 2-AG-Mediated Endocannabinoid Signaling in Brain Neurons

“…In those conditions, MGL sulfenylation might act as an intrinsic neuroprotective mechanism by potentiating 2-AG signaling at CB 1 receptors. Nevertheless, localized foci of heightened H 2 O 2 production (Mishina et al, 2011) might be sufficient to deactivate MGL even under physiological conditions, particularly at synapses that experience high-frequency synaptic activity and use glutamate as a neurotransmitter (Patel and Rice, 2012). In that context, MGL sulfenylation may strengthen endocannabinoid-mediated retrograde transmission by lowering the presynaptic degradation of 2-AG generated in postsynaptic spines.…”

“…A third cysteine (C242) located within the active site, in close proximity of the catalytic nucleophile S122, directly influences catalysis (Labar et al, 2010; Saario et al, 2005). These residues might be targeted by the second messenger, hydrogen peroxide (H 2 O 2 ), which modifies protein function (Patel and Rice, 2012) through reversible oxidation of cysteine’s thiol groups (-SH) to sulfenic acid (-SOH) (Dickinson and Chang, 2011; Lo Conte and Carroll, 2013). Because ionotropic glutamate receptors stimulate H 2 O 2 production (Patel and Rice, 2012) and H 2 O 2 influences the activities of several functionally important neuronal proteins (Rice, 2011), we hypothesized that peroxide-dependent sulfenylation of the regulatory cysteines, C201 and C208, might inhibit MGL and, by doing so, heighten 2-AG-mediated endocannabinoid signaling.…”

“…These residues might be targeted by the second messenger, hydrogen peroxide (H 2 O 2 ), which modifies protein function (Patel and Rice, 2012) through reversible oxidation of cysteine’s thiol groups (-SH) to sulfenic acid (-SOH) (Dickinson and Chang, 2011; Lo Conte and Carroll, 2013). Because ionotropic glutamate receptors stimulate H 2 O 2 production (Patel and Rice, 2012) and H 2 O 2 influences the activities of several functionally important neuronal proteins (Rice, 2011), we hypothesized that peroxide-dependent sulfenylation of the regulatory cysteines, C201 and C208, might inhibit MGL and, by doing so, heighten 2-AG-mediated endocannabinoid signaling. If confirmed experimentally, this mechanism would provide a presynaptic control point for 2-AG-mediated endocannabinoid signaling at central excitatory synapses.…”

Serotonin as a putative scavenger of hypohalous acid in the brain

“…Neutrophils are the major source of myeloperoxidase in the body and thus the recruitment and activation of these cells results in the deposition of this enzyme in the brain. The normal and inflamed brain produces significant amounts of hydrogen peroxide [54, 55], which in the presence of myeloperoxidase leads to the oxidation of chloride ions to HOCl [10]. The concurrence of myeloperoxidase and HOCl production has been established by measurements of the enzyme and 3-chlorotyrosine in the brain [12, 14, 16].…”