Abstract
Ca2+/calmodulin-dependent kinase II (CaMKII) regulates synaptic plasticity in multiple ways, supposedly including the secretion of neuromodulators like brain-derived neurotrophic factor (BDNF). Here, we show that neuromodulator secretion is indeed reduced in mouse α- and βCaMKII-deficient (αβCaMKII double-knockout [DKO]) hippocampal neurons. However, this was not due to reduced secretion efficiency or neuromodulator vesicle transport but to 40% reduced neuromodulator levels at synapses and 50% reduced delivery of new neuromodulator vesicles to axons. αβCaMKII depletion drastically reduced neuromodulator expression. Blocking BDNF secretion or BDNF scavenging in wild-type neurons produced a similar reduction. Reduced neuromodulator expression in αβCaMKII DKO neurons was restored by active βCaMKII but not inactive βCaMKII or αCaMKII, and by CaMKII downstream effectors that promote cAMP-response element binding protein (CREB) phosphorylation. These data indicate that CaMKII regulates neuromodulation in a feedback loop coupling neuromodulator secretion to βCaMKII- and CREB-dependent neuromodulator expression and axonal targeting, but CaMKIIs are dispensable for the secretion process itself.
Highlights
Neuropeptides and neuromodulators are secreted via Ca2+-dependent fusion of dense-core vesicles (DCVs) found in axons and dendrites of most neurons in the brain
We discovered that the reduced secretion of neuromodulators was entirely due to a decreased neuropeptide/neuromodulator content in synapses and a decreased number of DCVs entering the axons of DKO neurons
Hippocampal neuron cultures were infected with Cre-recombinase (DKO) or an inactive form of Cre [36] (WT) on the day of plating (Fig 1A), producing complete knockout of both α and βCaMKII at DIV17 (Fig 1B)
Summary
Neuropeptides and neuromodulators are secreted via Ca2+-dependent fusion of dense-core vesicles (DCVs) found in axons and dendrites of most neurons in the brain. Upon binding to their receptors, the secreted molecules modulate synaptic function [1, 2] and synaptic plasticity. One of the well-documented examples is how brain-derived neurotrophic factor (BDNF) facilitates long-term potentiation (LTP) and learning [3, 4]. The mechanism by which molecules like BDNF are secreted from DCVs is still a poorly defined element. DCV exocytosis is strictly Ca2+-dependent and requires higher frequency stimulation than synaptic.
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