Calcium and activity-dependent signaling in the developing cerebral cortex

Abstract

Calcium influx can be stimulated by various intra- and extracellular signals to set coordinated gene expression programs into motion. As such, the precise regulation of intracellular calcium represents a nexus between environmental cues and intrinsic genetic programs. Mounting genetic evidence points to a role for the deregulation of intracellular calcium signaling in neuropsychiatric disorders of developmental origin. These findings have prompted renewed enthusiasm for understanding the roles of calcium during normal and dysfunctional prenatal development. In this Review, we describe the fundamental mechanisms through which calcium is spatiotemporally regulated and directs early neurodevelopmental events. We also discuss unanswered questions about intracellular calcium regulation during the emergence of neurodevelopmental disease, and provide evidence that disruption of cell-specific calcium homeostasis and/or redeployment of developmental calcium signaling mechanisms may contribute to adult neurological disorders. We propose that understanding the normal developmental events that build the nervous system will rely on gaining insights into cell type-specific calcium signaling mechanisms. Such an understanding will enable therapeutic strategies targeting calcium-dependent mechanisms to mitigate disease.

Keywords: Calcium signaling; Cortical development; Neurodevelopmental disorders.

Fig. 1.

Overview of intracellular calcium signaling. Schematic highlighting ion channels and pumps mediating cytoplasmic calcium homeostasis and select calcium-dependent pathways that transduce calcium signals to the nucleus. Low resting cytosolic calcium levels are maintained by plasma membrane calcium ATPases (PMCA1-4, encoded by ATP2B1-4), which extrude calcium out of the cell and display low calcium efflux capacity but high calcium affinity, and pumps on the surface of the sarco/endoplasmic reticulum (SR/ER) and mitochondria (e.g., the SR/ER calcium ATPases SERCA1-3, encoded by ATP2A1-3), which transport calcium into intraorganellar stores. Large calcium elevations are countered by sodium calcium exchangers (NCX1-4, encoded by SLC8A1-4) on the plasma membrane and mitochondrial and ER membranes. Calcium-permeable channels mediating calcium influx from the extracellular space include voltage-gated calcium channels (VGCCs), N-methyl-D-aspartate receptors (NMDARs), α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs), transient receptor potential (TRP) channels and ORAI channels. VGCCs are activated by membrane depolarization, whereas ORAI channels allow calcium influx upon ER calcium store depletion. Successive release of calcium from the ER, mediated by IP3R or RyR, depletes ER calcium, which in turn activates STIM calcium sensors (STIM1 and STIM2) to promote their interaction with ORAI channels (ORAI 1-3) and subsequent calcium influx. Gap junctions in the plasma membrane allow for intercellular propagation of calcium signals, through direct transfer of ions or small molecules that are crucial for intracellular signaling (e.g. IP3). Calcium-sensitive proteins in the cytoplasm (e.g. calmodulin; CaM) undergo a conformational change upon calcium binding, initiating distinct signaling cascades to the nucleus that culminate in calcium-dependent transcription. Note that only select calcium-dependent transcription factors with reported roles in the developing nervous system are highlighted; other factors and organellar calcium stores (e.g. mitochondria, lysosomes, Golgi apparatus) are not depicted.

Fig. 2.

Calcium-dependent regulation of proliferation during corticogenesis. Calcium imaging and electrophysiological recordings performed on embryonic rodent cortical slice cultures demonstrate that radial glial cells (RGCs) in the ventricular zone (VZ) exhibit spontaneous and induced calcium rises. Purinergic signaling through metabotropic P2Y1 receptors initiates calcium transients that propagate across VZ cells. These calcium waves, which modulate proliferation, require gap junctions and IP3-mediated calcium release. RGC primary cilia protrude into the ventricles, where they are exposed to diffusible growth factors in the CSF that initiate calcium rises and also influence RGC division. Finally, depolarization mediated by GABA and glutamate acting on GABARs and AMPARs, respectively, controls proliferation by inducing calcium rises through VGCCs.

Fig. 3.

Calcium and excitatory neuroblast migration. Excitatory neuroblasts undergo radial migration along RGC fibers to reach their final laminar destination. Migratory neuroblasts exiting the VZ display high frequency spontaneous calcium transients. As they enter the SVZ, neuroblasts adopt a multipolar morphology and exhibit low amplitude calcium events. Calcium transients during neuroblast migration are largely mediated by extracellular agonists like BDNF, which activates TrkB, by neurotransmitter receptors (e.g. NMDARs, GABARs), and by downstream activation of VGCCs. Glutamate influences radial migration by inducing calcium influx primarily through NMDARs. Depolarization via GABARs and calcium influx via VGCCs also control radial migration. Emerging evidence suggests that calcium transients propagating through RGC fibers may also contribute to the regulation of neuroblast migration into the cortical plate.

Fig. 4.

Calcium and astrogliogenesis. Although microglia and embryonic oligodendrocytes originate largely outside of the cortex, RGCs (light purple) transition from making neurons to generating cortical astrocytes (green) during mid-to-late gestation in the rodent. This gliogenic switch begins at approximately embryonic day 17 in mice and continues postnatally. Activation of plasma membrane receptors [glycoprotein 130 (Gp130; Il6st), ciliary neurotrophic factor receptor (CNTFR) and leukemia inhibitory factor receptor (LIFR)] regulates Gfap transcription and astroglial differentiation via JAK/STAT signaling. In parallel, pituitary adenylate cyclase activating polypeptide (PACAP)-mediated activation of its receptor, PAC1R, generates cAMP-dependent calcium elevations. Calcium binds DREAM to promote expression of astrocyte-specific genes and astrogliogenesis.