Calcium signaling in neuronal development

Abstract

The development of the nervous system involves the generation of a stunningly diverse array of neuronal subtypes that enable complex information processing and behavioral outputs. Deciphering how the nervous system acquires and interprets information and orchestrates behaviors will be greatly enhanced by the identification of distinct neuronal circuits and by an understanding of how these circuits are formed, changed, and/or maintained over time. Addressing these challenging questions depends in part on the ability to accurately identify and characterize the unique neuronal subtypes that comprise individual circuits. Distinguishing characteristics of neuronal subgroups include but are not limited to neurotransmitter phenotype, dendritic morphology, the identity of synaptic partners, and the expression of constellations of subgroup-specific proteins, including ion channel subtypes.

Figure 1.

Providing specificity for calcium signaling in neuronal differentiation. Calcium transients direct neuronal differentiation by regulating neurotransmitter phenotype, dendritic morphology, and axonal growth and guidance. Factors dictating intracellular calcium dynamics include the subcellular location of ion channels within the neuron and the neuron-specific constellation of ion channels and receptors expressed by individual cells. The location and identity of these channels and receptors influence the timing and frequency of calcium transients and determine whether the changes in calcium concentration occur in a global or localized fashion. Spatiotemporal patterns of calcium transients select the downstream mechanisms involved in neuronal differentiation. Calcium transients activate enzymes that transduce ionic signals into biochemical ones. These enzymes impact differentiation either through transcriptional mechanisms or by the regulation of cytoskeletal dynamics. Activation or repression of transcription factors controls neurotransmitter expression whereas cytoskeletal remodeling regulates axon and dendrite morphogenesis.

Figure 2.

Activity-dependent neurotransmitter specification at early stages of neuronal development. (A) Prior to synapse formation in the embryonic spinal cord, overexpression of voltage-gated sodium channels (Na_v) increases the incidence and frequency of calcium spikes that lead to a decrease in the number of neurons expressing excitatory transmitters (in green) and an increase in the number of neurons expressing inhibitory transmitters (in red). Overexpression of inward rectifier potassium channels (Kir) decreases calcium spiking and produces the opposite effect on transmitter specification. (B) Increasing the incidence and frequency of calcium spikes in the embryonic spinal cord leads to phosphorylation of the cJun transcription factor that binds to the promoter of the tlx3 selector gene and suppresses its expression; this results in a decrease in the number of glutamatergic neurons (in green) and an increase in the number of GABAergic neurons (in red). Suppressing spike production leads to dephosphorylation of cJun that no longer represses tlx3 expression; this results in an increase in the number of glutamatergic neurons and a decrease in the number of GABAergic neurons. (C) After synapse formation in the postembryonic brain, bright light illumination increases calcium spike activity that leads to an increase in the number of hypothalamic neurons that express dopamine (in red), which acts as an inhibitory transmitter. Dark exposure decreases calcium spike activity that leads to a decrease in the number of dopaminergic neurons.