How voltage-gated calcium channels gate forms of homeostatic synaptic plasticity - PubMed (original) (raw)

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How voltage-gated calcium channels gate forms of homeostatic synaptic plasticity

C Andrew Frank. Front Cell Neurosci. 2014.

Abstract

Throughout life, animals face a variety of challenges such as developmental growth, the presence of toxins, or changes in temperature. Neuronal circuits and synapses respond to challenges by executing an array of neuroplasticity paradigms. Some paradigms allow neurons to up- or downregulate activity outputs, while countervailing ones ensure that outputs remain within appropriate physiological ranges. A growing body of evidence suggests that homeostatic synaptic plasticity (HSP) is critical in the latter case. Voltage-gated calcium channels gate forms of HSP. Presynaptically, the aggregate data show that when synapse activity is weakened, homeostatic signaling systems can act to correct impairments, in part by increasing calcium influx through presynaptic CaV2-type channels. Increased calcium influx is often accompanied by parallel increases in the size of active zones and the size of the readily releasable pool of presynaptic vesicles. These changes coincide with homeostatic enhancements of neurotransmitter release. Postsynaptically, there is a great deal of evidence that reduced network activity and loss of calcium influx through CaV1-type calcium channels also results in adaptive homeostatic signaling. Some adaptations drive presynaptic enhancements of vesicle pool size and turnover rate via retrograde signaling, as well as de novo insertion of postsynaptic neurotransmitter receptors. Enhanced calcium influx through CaV1 after network activation or single cell stimulation can elicit the opposite response-homeostatic depression via removal of excitatory receptors. There exist intriguing links between HSP and calcium channelopathies-such as forms of epilepsy, migraine, ataxia, and myasthenia. The episodic nature of some of these disorders suggests alternating periods of stable and unstable function. Uncovering information about how calcium channels are regulated in the context of HSP could be relevant toward understanding these and other disorders.

Keywords: CaV1 channels; CaV2 channels; VGCCs; calcium channelopathies; homeostatic synaptic plasticity; neurotransmitter release; synaptic growth; synaptic scaling.

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Figures

Figure 1

Figure 1

Mammalian CaV1 and CaV2 channels play central roles in forms of homeostatic plasticity. These two cartoons attempt to synthesize knowledge of mammalian pre- and postsynaptic homeostatic plasticity mechanisms involving CaV1 and CaV2 calcium channels in preparations like cultured hippocampal neurons. The cartoons are not intended to depict a single synaptic preparation or universally conserved mechanism, though some molecular responses may be widely conserved. (A) Homeostatic potentiation of synapse function. Inhibition of synaptic activity or postsynaptic CaV1 calcium influx results in multiple changes, including postsynaptic signaling through molecules like adenylate cyclase 1 (AC1) or guanylate kinase-associated protein (GKAP) to drive activating mechanisms, such as glutamate receptor insertion. Trans-synaptic signaling controlled by factors like Target of Rapamycin (TOR) and Brain-Derived Neurotrophic Factor (BDNF) can trigger enhanced presynaptic release probability. From a variety of systems there is evidence for enhanced presynaptic calcium influx through CaV2—which may require diminishment of cyclin-dependent kinase 5 (CDK5) function—as well as an enhanced readily releasable pool of presynaptic vesicles. (B) Homeostatic downscaling of synapse function. Synaptic activation (e.g., through GABA receptor blockade) and/or enhanced postsynaptic calcium influx through CaV1 results in the activation of diverse pathways, such as those mediated by calcium/calmodulin-dependent kinases (CaMK), as well as the Protein Phosphatase 1 (PP1) inhibitor, I-2. This can result in removal of excitatory glutamate receptors from the synapse. Presynaptically, there is evidence of diminished calcium influx through CaV2, and thus, diminished evoked presynaptic release.

Figure 2

Figure 2

Invertebrate models of CaV-directed homeostatic plasticity. Inspection of the Drosophila melanogaster NMJ has provided a wealth of information regarding the roles VGCCs and associated molecules play in homeostatic plasticity, as has examination of C. elegans preparations, such as the ventral nerve cord (VNC) or the NMJ. (A) Drosophila NMJ. Pharmacological or genetic impairment of postsynaptic glutamate receptors triggers a retrograde signaling process that results in enhanced presynaptic Cac/CaV2 function and increased neurotransmitter release. Additionally, Cac/CaV2, α2δ, and Dmca1D/CaV1 all affect synaptic bouton development or maturation at the NMJ. (B) C. elegans synapses. At the C. elegans VNC, the coordinated functions of UNC-2/CaV2, EGL-19/CaV1, UNC-36/α2δ and UNC-43/CaMKII ensure proper coupling of GLR-1 glutamate receptor density to developmental growth.

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