This Week in The Journal

Teresa Esch

Copine-6 Regulates Spontaneous Vesicle Release

Pei Liu, Mikhail Khvotchev, Ying C. Li, Natali L. Chanaday, and Ege T. Kavalali

When action potentials reach axon terminals, calcium channels open and intracellular calcium levels rise. This causes synaptic vesicles docked at the plasma membrane to fuse, resulting in a burst of neurotransmitter release. Vesicles occasionally fuse to the synaptic membrane in the absence of spikes, however. These so-called spontaneous fusion events were long assumed to involve the same protein machinery as evoked fusion; but accumulating evidence suggests this is not the case. For example, altering expression of some vesicle-associated proteins affects spontaneous, but not evoked release. Moreover, some neuromodulators selectively enhance spontaneous release. This suggests spike-independent vesicle fusion has important physiological functions that can be upregulated or downregulated as needed. Indeed, spontaneous release appears to be important for synaptic development and homeostatic plasticity, and it can affect excitability of postsynaptic cells (Kavalali, 2015 Nat Rev Neurosci 16:5). Hence, efforts to identify additional endogenous regulators of spontaneous release are ongoing.

The frequency of spontaneous fusion events was higher after copine-6 was knocked down (red) than in controls (blue). See Liu et al. for details.

The vesicle-membrane protein synaptobrevin2 is involved in most spontaneous release events and all evoked release. Therefore, Liu et al. screened for proteins that interact with synaptobrevin2, hypothesizing that such proteins might influence whether synaptobrevin2-expressing vesicles fuse in the absence of spikes. One protein they identified was copine-6, which contains two phospholipid-binding C2 domains. This was intriguing because another protein with double C2 domains was previously shown to be involved selectively in spontaneous fusion.

Overexpressing copine-6 in rat hippocampal neuron cultures did not significantly alter evoked release probability or kinetics, but it reduced the frequency of spontaneous release events. Chelating calcium or knocking out synaptobrevin2 blocked this effect. Conversely, overexpressing a mutant form of synaptobrevin2 that cannot bind to copine-6 increased spontaneous release, as did knocking down copine-6.

These and additional results suggest that copine-6 limits spontaneous release of vesicles in the presence of calcium by binding to synaptobrevin2 and other vesicle-associated proteins. Thus, copine-6 might help ensure that vesicles are released synchronously when an action potential arrives. By regulating copine-6 levels or activity, cells might modulate spontaneous release to promote or impede homeostatic plasticity or synapse development. Future work should explore endogenous regulation of copine-6 and its role in these processes.

ΔFosB in Nucleus Accumbens Modulates Aggression

Hossein Aleyasin, Meghan E. Flanigan, Sam A. Golden, Aki Takahashi, Caroline Menard, et al.

(see pages 5913–5924)

Aggression is often necessary to secure food, mates, and/or offspring. It can also be rewarding. Indeed, animals (including people) sometimes seek opportunities to fight. For example, sexually experienced male mice that have been victorious in confrontations with conspecifics will perform specific actions to gain the opportunity to fight again. Furthermore, mice that have dominated an intruder in one chamber of a cage spend more time in that chamber than in one in which they had no social encounter. And like other reward-directed behaviors, aggression is associated with activation of the nucleus accumbens (NAc).

Aleyasin et al. now show that, like other rewards, aggression is linked to increased expression of the transcription factor ΔFosB in NAc medium spiny neurons (MSNs). Specifically, ΔFosB levels in NAc were higher in male mice that showed aggression toward intruders than in nonaggressive males. Moreover, the higher the ΔFosB level, the quicker aggressors were to attack. Importantly, overexpressing ΔFosB in NAc increased the duration of attacks and increased the victory rate of aggressors, whereas suppressing ΔFosB transcription reduced the number and duration of attacks. Overexpressing ΔFosB did not turn nonaggressive mice into aggressors, however. And despite promoting attacks in aggressive mice, ΔFosB overexpression reduced aggressors' preference for a conflict-paired context. An explanation for this paradoxical result emerged when ΔFosB levels were manipulated in each of the two MSN populations independently. In aggressors, ΔFosB levels were elevated selectively in MSNs that express D1 dopamine receptors (D1-MSNs), and overexpressing ΔFosB selectively in these neurons increased attack duration without affecting place preference. In contrast, overexpressing ΔFosB selectively in D2-MSNs had no effect on attack duration, but it induced aversion toward the conflict-paired chamber.

These results suggest that D1- and D2-MSNs have different roles in aggressive behavior, but both roles involve increases in ΔFosB. Specifically, increases in ΔFosB levels in D1-MSNs promote aggressive behaviors, whereas increases of ΔFosB in D2-MSNs make aggression less rewarding. Of course, ΔFosB is not the only factor regulating aggression, as demonstrated by the failure to induce aggression in nonaggressive mice. Nonetheless, identifying which ΔFosB targets contribute to aggression should help to elucidate the neural mechanisms underlying these behaviors.