αCaMKII Is Required for Amphetamine-Induced Serotonin Release

Thomas Steinkellner, Therese R. Montgomery, Tina Hofmaier, Oliver Kudlacek, Jae-Won Yang, et al.

(see pages 8258–8271)

Amphetamines are a large family of psychostimulants that includes plant alkaloids (e.g., ephedrine and cathinone), as well as synthetic derivatives used therapeutically (e.g., Ritalin) or recreationally (e.g., ecstasy). Like most abuse-prone drugs, amphetamines activate dopaminergic reward signaling. They do this by targeting molecules involved in dopamine reuptake, vesicular packaging, and degradation, which ultimately results in dopamine being released into the synaptic cleft by reverse action of the plasmalemmal dopamine transporter (DAT). Because amphetamines target these same pathways in noradrenergic and serotonergic neurons, they also promote release of these monoamines. Furthermore, because different amphetamine derivatives have different affinities for different monoamine transporters, their psychoactive effects vary. For example, 3,4 methylenedioxymethamphetamine (MDMA, ecstasy) has a relatively high affinity for the serotonin transporter (SERT), and thus many of its psychoactive properties result from increasing serotonin release.

An unsettled question regarding amphetamine actions is how they cause monoamine transporters to work in reverse. Under normal conditions, cytosolic monoamine concentrations are low because the molecules are quickly packaged into vesicles or degraded by monoamine oxidase (MAO). Because amphetamines block the actions of vesicular transporters and MAO, cytoplasmic monoamine concentrations rise. This may be sufficient to allow the molecules to bind to unoccupied inward-facing binding sites on plasmalemmal transporters and then be released extracellularly when the transporter returns to the outward-facing conformation. There are problems with this model, however, prompting some researchers to hypothesize that modification of the transporter is required for significant reverse transport to occur. Indeed, amphetamines promote phosphorylation of DAT by calmodulin kinase IIα (αCaMKII), and this phosphorylation enhances reverse transport of dopamine. Whether SERT is similarly regulated has been unclear, however.

Steinkellner et al. now show that αCaMKII is present in serotonergic neurons and it closely associates with SERT in transfected cells. Moreover, inhibiting αCaMKII reduced amphetamine-induced serotonin efflux in a cell line, and MDMA-induced serotonin release was lower in αCaMKII-deficient mice than in controls. Finally, αCaMKII-deficient mice had a blunted locomotor response to MDMA. These data suggest that αCaMKII-mediated phosphorylation of SERT contributes to the physiological effects of SERT-preferring amphetamine derivatives, and they further support the hypothesis that transporter modification is an essential component of amphetamine action.

Norepinephrine and KCl Activate Distinct Sets of Stem Cells

Dhanisha J. Jhaveri, Imogen O'Keeffe, Gregory J. Robinson, Qiong-Yi Zhao, Zong Hong Zhang, et al.

(see pages 8132–8144)

The adult hippocampus contains a large population of neural stem cells (NSCs), most of which are in a quiescent state, rarely undergoing mitosis. Various stimuli—including physical exercise, induction of long-term potentiation, depolarization, and norepinephrine—have been shown to activate quiescent cells, so they proliferate more rapidly. This increases the generation of new neurons, which can become integrated into hippocampal circuits.

Adult neurogenesis is important for learning and memory, and it also accompanies effective antidepressant treatment. Do the neurons that contribute to these different functions come from the same NSC population? Given that memory and mood functions are thought to be somewhat segregated to the septal and temporal regions, respectively, of the hippocampus, and given that the neuronal maturation rate varies across the same axis (Piatti et al., 2011, J Neurosci 31:7715), it is conceivable that different NSC populations give rise to functionally distinct neurons.

Jhaveri et al. tested the first part of this hypothesis—that multiple populations of NSCs are present in mouse adult hippocampus—by examining proliferation of single isolated NSCs under different conditions in vitro. Few NSCs (∼11%) proliferated in control conditions, but treatment of cells with norepinephrine or KCl increased this proportion to ∼48% or ∼29%, respectively. Importantly, treating cells with KCl and norepinephrine together produced an approximately additive effect: ∼77% of cells proliferated. This strongly suggests that the treatments activated separate populations of cells. In further support of this conclusion, the effects of KCl and norepinephrine were blocked by different treatments: treating isolated NSCs with GABA blocked norepinephrine-induced proliferation without affecting KCl-induced proliferation, whereas treating mice with the stress hormone corticosterone reduced only KCl-induced proliferation. Finally, the proportion of precursors activated by different treatments varied along the septal–temporal axis of the hippocampus: more norepinephrine-responsive NSCs were isolated from the septal region than from the temporal region, while the temporal region had a greater proportion of KCl-responsive than norepinephrine-responsive NSCs.

Altogether, the authors provide convincing evidence that the adult hippocampus contains at least two populations of NSCs. Further characterizing these populations, their activators, and the fates of their progeny will be exciting avenues for future research.