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

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.

RGS14 Regulation of Post-Synaptic Signaling and Spine Plasticity in Brain.

The regulator of G-protein signaling 14 (RGS14) is a multifunctional signaling protein that regulates post synaptic plasticity in neurons. RGS14 is expressed in the brain regions essential for learning, memory, emotion, and stimulus-induced behaviors, including the basal ganglia, limbic system, and cortex. Behaviorally, RGS14 regulates spatial and object memory, female-specific responses to cued fear conditioning, and environmental- and psychostimulant-induced locomotion. At the cellular level, RGS14 acts as a scaffolding protein that integrates G protein, Ras/ERK, and calcium/calmodulin signaling pathways essential for spine plasticity and cell signaling, allowing RGS14 to naturally suppress long-term potentiation (LTP) and structural plasticity in hippocampal area CA2 pyramidal cells. Recent proteomics findings indicate that RGS14 also engages the actomyosin system in the brain, perhaps to impact spine morphogenesis. Of note, RGS14 is also a nucleocytoplasmic shuttling protein, where its role in the nucleus remains uncertain. Balanced nuclear import/export and dendritic spine localization are likely essential for RGS14 neuronal functions as a regulator of synaptic plasticity. Supporting this idea, human genetic variants disrupting RGS14 localization also disrupt RGS14's effects on plasticity. This review will focus on the known and unexplored roles of RGS14 in cell signaling, physiology, disease and behavior.

Regulator of G Protein Signaling 14 protein expression profile in the adult mouse brain.

Regulator of G protein signaling 14 (RGS14) is a multifunctional signaling protein that serves as a natural suppressor of synaptic plasticity in the mouse brain. Our previous studies showed that RGS14 is highly expressed in postsynaptic dendrites and spines of pyramidal neurons in hippocampal area CA2 of the developing mouse brain. However, our more recent work with adult rhesus macaque brain shows that RGS14 is found in multiple neuron populations throughout hippocampal area CA1 and CA2, caudate nucleus, putamen, globus pallidus, substantia nigra, and amygdala in the adult rhesus monkey brain. In the mouse brain, we also have observed RGS14 protein in discrete limbic regions linked to reward behavior and addiction, including the central amygdala and the nucleus accumbens, but a comprehensive mapping of RGS14 protein expression in the adult mouse brain is lacking. Here, we report that RGS14 is more broadly expressed in mouse brain than previously known. Intense RGS14 staining is observed in specific neuron populations of the hippocampal formation, amygdala, septum, bed nucleus of stria terminalis and ventral striatum/nucleus accumbens. RGS14 is also observed in axon fiber tracts including the dorsal fornix, fimbria, stria terminalis, and the ventrohippocampal commissure. Moderate RGS14 staining is observed in various other adjacent regions not previously reported. These findings show that RGS14 is expressed in brain regions that govern aspects of core cognitive functions such as sensory perception, emotion, memory, motivation, and execution of actions, and suggests that RGS14 may serve to suppress plasticity and filter inputs in these brain regions to set the overall tone on experience-to-action processes.

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

RATIONALE: In rodents, exposure to novel environments or psychostimulants promotes locomotion. Indeed, locomotor reactivity to novelty strongly predicts behavioral responses to psychostimulants in animal models of addiction. RGS14 is a plasticity-restricting protein with unique functional domains that enable it to suppress ERK-dependent signaling as well as regulate G protein activity. Although recent studies show that RGS14 is expressed in multiple limbic regions implicated in psychostimulant- and novelty-induced hyperlocomotion, its function has been examined mostly in the context of hippocampal physiology and memory. OBJECTIVE: We investigated whether RGS14 modulates novelty- and cocaine-induced locomotion (NIL and CIL, respectively) and neuronal activity. METHODS: We assessed Rgs14 knockout (RGS14 KO) mice and wild-type (WT) littermate controls using NIL and CIL behavioral tests, followed by quantification of c-fos and phosphorylated ERK (pERK) induction in limbic regions that normally express RGS14. RESULTS: RGS14 KO mice were less active than WT controls in the NIL test, driven by avoidance of the center of the novel environment. By contrast, RGS14 KO mice demonstrated augmented peripheral locomotion in the CIL test conducted in either a familiar or novel environment. RGS14 KO mice exhibited increased thigmotaxis, as well as greater c-fos and pERK induction in the central amygdala and dorsal hippocampus, when cocaine and novelty were paired. CONCLUSIONS: RGS14 KO mice exhibited anti-correlated locomotor responses to novelty and cocaine, but displayed increased thigmotaxis in response to either stimuli which was augmented by their combination. Our findings also suggest RGS14 may reduce neuronal activity in limbic subregions by inhibiting ERK-dependent signaling.

Effects of early life stress on cocaine self-administration in post-pubertal male and female rhesus macaques.

RATIONALE: Early life stress (ELS), including childhood maltreatment, is a predictive factor for the emergence of cocaine use disorders (CUDs) in adolescence. OBJECTIVE: Accordingly, we examined whether post-pubertal male and female rhesus macaques that experienced infant maltreatment (maltreated, n = 7) showed greater vulnerability to cocaine self-administration in comparison with controls (controls, n = 7). METHODS: Infant emotional reactivity was measured to assess differences in behavioral distress between maltreated and control animals as a result of early life caregiving. Animals were then surgically implanted with indwelling intravenous catheters and trained to self-administer cocaine (0.001-0.3 mg/kg/infusion) under fixed-ratio schedules of reinforcement. Days to acquisition, and sensitivity to (measured by the EDMax dose of cocaine) and magnitude (measured by response rates) of the reinforcing effects of cocaine were examined in both groups. RESULTS: Maltreated animals demonstrated significantly higher rates of distress (e.g., screams) in comparison with control animals. When given access to cocaine, control males required significantly more days to progress through terminal performance criteria compared with females and acquired cocaine self-administration slower than the other three experimental groups. The dose that resulted in peak response rates did not differ between groups or sex. Under 5-week, limited-access conditions, males from both groups had significantly higher rates of responding compared with females. CONCLUSIONS: In control monkeys, these data support sex differences in cocaine self-administration, with females being more sensitive than males. These findings also suggest that ELS may confer enhanced sensitivity to the reinforcing effects of cocaine, especially in males.

A review of nonhuman primate models of early life stress and adolescent drug abuse.

Adolescence represents a developmental stage in which initiation of drug use typically occurs and is marked by dynamic neurobiological changes. These changes present a sensitive window during which perturbations to normative development lead to alterations in brain circuits critical for stress and emotional regulation as well as reward processing, potentially resulting in an increased susceptibility to psychopathologies. The occurrence of early life stress (ELS) is related to a greater risk for the development of substance use disorders (SUD) during adolescence. Studies using nonhuman primates (NHP) are ideally suited to examine how ELS may alter the development of neurobiological systems modulating the reinforcing effects of drugs, given their remarkable neurobiological, behavioral, and developmental homologies to humans. This review examines NHP models of ELS that have been used to characterize its effects on sensitivity to drug reinforcement, and proposes future directions using NHP models of ELS and drug abuse in an effort to develop more targeted intervention and prevention strategies for at risk clinical populations.