RGS14 modulates locomotor behavior and ERK signaling induced by environmental novelty and cocaine within discrete limbic structures

Foster, Stephanie L.; Lustberg, Daniel; Harbin, Nicholas H; Bramlett, Sara N; Hepler, John R.

doi:10.1007/s00213-021-05892-x

Cited by 8 publications

(12 citation statements)

References 110 publications

(169 reference statements)

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“…Image processing and analysis were performed using ImageJ software. The analysis pipeline included standardized background subtraction, intensity thresholding (Otsu method), and pixel intensity measurements within defined regions of interest cropped to the same size, as previously described (Foster et al, 2021;Lustberg et al, 2020b).…”

Section: Immunohistochemistry and Fluorescent Imagingmentioning

confidence: 99%

Norepinephrine and dopamine contribute to distinct repetitive behaviors induced by novel odorant stress in male and female mice

Lustberg

Liu²,

Iannitelli³

et al. 2022

Hormones and Behavior

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Section: Immunohistochemistry and Fluorescent Imagingmentioning

confidence: 99%

Norepinephrine and dopamine contribute to distinct repetitive behaviors induced by novel odorant stress in male and female mice

Lustberg

Liu²,

Iannitelli³

et al. 2022

Hormones and Behavior

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“…As mentioned, RGS14 is expressed in brain regions outside of the hippocampus in both primate (Squires, Montanez-Miranda, et al, 2018) and rodent (Foster et al, 2021) brain (Figures 2 and 3). In monkey brain, RGS14 was found throughout the rostro-caudal extent of structures of the basal ganglia, including the caudate nucleus and putamen, and in lower density in the NAc (Squires, Gerber, et al, 2018).…”

Section: Rgs14 Protein Expression Outside Of the Hippocampusmentioning

confidence: 66%

“…Studies done by us and our collaborators suggest an inhibitory effect of RGS14 in fear and anxiety processing in mice, evidenced by an increased thigmotaxis response to novelty stress in RGS14-KO mice and increased cue-conditioned freezing to a fearful stimulus in RGS14-KO females (Alexander et al, 2019;Foster et al, 2021).…”

Section: Possible Roles For Rgs14 In Anxiety Disordersmentioning

confidence: 79%

“…Strong immunoreactivity was observed in the caudate nucleus, putamen, substantia nigra pars reticulata, globus pallidus, and moderate staining in the amygdala and nucleus accumbens (NAc) (Squires, Gerber, et al, 2018). Recent findings show that RGS14 is also expressed in these same limbic structures and basal ganglia of rodents (Foster et al, 2021), and speculation about RGS14 roles in these brain regions and their relationship to the hippocampus will be discussed in depth below.…”

Section: Rgs1expression In Primate and Human Hippocampusmentioning

confidence: 97%

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RGS14 expression in CA2 hippocampus, amygdala, and basal ganglia: Implications for human brain physiology and disease

2022

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RGS14 is a multifunctional scaffolding protein that is highly expressed within postsynaptic spines of pyramidal neurons in hippocampal area CA2. Known roles of RGS14 in CA2 include regulating G protein, H‐Ras/ERK, and calcium signaling pathways to serve as a natural suppressor of synaptic plasticity and postsynaptic signaling. RGS14 also shows marked postsynaptic expression in major structures of the limbic system and basal ganglia, including the amygdala and both the ventral and dorsal subdivisions of the striatum. In this review, we discuss the signaling functions of RGS14 and its role in postsynaptic strength (long‐term potentiation) and spine structural plasticity in CA2 hippocampal neurons, and how RGS14 suppression of plasticity impacts linked behaviors such as spatial learning, object memory, and fear conditioning. We also review RGS14 expression in the limbic system and basal ganglia and speculate on its possible roles in regulating plasticity in these regions, with a focus on behaviors related to emotion and motivation. Finally, we explore the functional implications of RGS14 in various brain circuits and speculate on its possible roles in certain disease states such as hippocampal seizures, addiction, and anxiety disorders.

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“…Behavioral consequences of global RGS14 deletion in mice (RGS14 KO) include enhancement of spatial learning (Lee et al, 2010), sensitization to cued fear learning (Alexander et al, 2019), and locomotor sensitivity to cocaine (Foster et al, 2021). Apart from these behavioral findings, insights into RGS14 function come largely from cellular studies assessing RGS14 interacting partners and effects on cell signaling.…”

Section: Introductionmentioning

confidence: 99%

RGS14 is neuroprotective against seizure-induced mitochondrial oxidative stress and pathology in hippocampus

Harbin

Lustberg

Hurst

et al. 2023

Preprint

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RGS14 is a complex multifunctional scaffolding protein that is highly enriched within pyramidal cells (PCs) of hippocampal area CA2. There, RGS14 suppresses glutamate-induced calcium influx and related G protein and ERK signaling in dendritic spines to restrain postsynaptic signaling and plasticity. Previous findings show that, unlike PCs of hippocampal areas CA1 and CA3, CA2 PCs are resistant to a number of neurological insults, including degeneration caused by temporal lobe epilepsy (TLE). While RGS14 is protective against peripheral injury, similar roles for RGS14 during pathological injury in hippocampus remain unexplored. Recent studies show that area CA2 modulates hippocampal excitability, generates epileptiform activity and promotes hippocampal pathology in animal models and patients with TLE. Because RGS14 suppresses CA2 excitability and signaling, we hypothesized that RGS14 would moderate seizure behavior and early hippocampal pathology following seizure activity. Using kainic acid (KA) to induce status epilepticus (KA-SE) in mice, we show loss of RGS14 (RGS14 KO) accelerated onset of limbic motor seizures and mortality compared to wild type (WT) mice, and that KA-SE upregulated RGS14 protein expression in CA2 and CA1 PCs of WT. Utilizing proteomics, we saw loss of RGS14 impacted the expression of a number of proteins at baseline and after KA-SE, many of which associated unexpectedly with mitochondrial function and oxidative stress. RGS14 was shown to localize to the mitochondria in CA2 PCs of mice and reduce mitochondrial respiration in vitro. As a readout of oxidative stress, we found RGS14 KO dramatically increased 3-nitrotyrosine levels in CA2 PCs, which was greatly exacerbated following KA-SE and correlated with a lack of superoxide dismutase 2 (SOD2) induction. Assessing for hallmarks of seizure pathology in RGS14 KO, we observed worse neuronal injury in area CA3 (but none in CA2 or CA1), and a lack of microgliosis in CA1 and CA2 compared to WT. Together, our data demonstrates a newly appreciated neuroprotective role for RGS14 against intense seizure activity in hippocampus. Our findings are consistent with a model where, after seizure, RGS14 is upregulated to support mitochondrial function and prevent oxidative stress in CA2 PCs, limit seizure onset and hippocampal neuronal injury, and promote microglial activation in hippocampus.

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RGS14 modulates locomotor behavior and ERK signaling induced by environmental novelty and cocaine within discrete limbic structures

Abstract: AcknowledgmentsWe thank C. Strauss for helpful editing of the manuscript.

Cited by 8 publications

References 110 publications

Norepinephrine and dopamine contribute to distinct repetitive behaviors induced by novel odorant stress in male and female mice

Norepinephrine and dopamine contribute to distinct repetitive behaviors induced by novel odorant stress in male and female mice

RGS14 expression in CA2 hippocampus, amygdala, and basal ganglia: Implications for human brain physiology and disease

RGS14 is neuroprotective against seizure-induced mitochondrial oxidative stress and pathology in hippocampus

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