scholarly journals 1,25-Dihydroxyvitamin D modulates L-type voltage-gated calcium channels in a subset of neurons in the developing mouse prefrontal cortex

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Helen Gooch ◽  
Xiaoying Cui ◽  
Victor Anggono ◽  
Maciej Trzaskowski ◽  
Men Chee Tan ◽  
...  
Keyword(s):  
Risk Factors ◽  
Vitamin D ◽  
Prefrontal Cortex ◽  
Calcium Channels ◽  
Brain Maturation ◽  
Genome Wide Association Studies ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Enhanced Activity ◽  
Activity Dependent

Abstract Schizophrenia has been associated with a range of genetic and environmental risk factors. Here we explored a link between two risk factors that converge on a shared neurobiological pathway. Recent genome-wide association studies (GWAS) have identified risk variants in genes that code for L-type voltage-gated calcium channels (L-VGCCs), while epidemiological studies have found an increased risk of schizophrenia in those with neonatal vitamin D deficiency. The active form of vitamin D (1,25(OH)2D) is a secosteroid that rapidly modulates L-VGCCs via non-genomic mechanisms in a range of peripheral tissues, though its non-genomic effects within the brain remain largely unexplored. Here we used calcium imaging, electrophysiology and molecular biology to determine whether 1,25(OH)2D non-genomically modulated L-VGCCs in the developing prefrontal cortex, a region widely implicated in schizophrenia pathophysiology. Wide-field Ca2+ imaging revealed that physiological concentrations of 1,25(OH)2D rapidly enhanced activity-dependent somatic Ca2+ levels in a small subset of neurons in the developing PFC, termed vitamin D-responsive neurons (VDRNs). Somatic nucleated patch recordings revealed a rapid, 1,25(OH)2D-evoked increase in high-voltage-activated (HVA) Ca2+ currents. Enhanced activity-dependent Ca2+ levels were mediated by L-VGCC but not associated with any changes to Cacna1c (L-VGCC pore-forming subunit) mRNA expression. Since L-VGCC activity is critical to healthy neurodevelopment, these data suggest that suboptimal concentrations of 1,25(OH)2D could alter brain maturation through modulation of L-VGCC signalling and as such may provide a parsimonious link between epidemiologic and genetic risk factors for schizophrenia.

scholarly journals Ca2+ entry through NaV channels generates submillisecond axonal Ca2+ signaling

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Naomi AK Hanemaaijer ◽  
Marko A Popovic ◽  
Xante Wilders ◽  
Sara Grasman ◽  
Oriol Pavón Arocas ◽  
...  
Keyword(s):  
Calcium Channels ◽  
High Speed ◽  
Initial Segment ◽  
Hek 293 ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
293 Cells ◽  
Axonal Initial Segment ◽  
Nav Channels ◽  
Activity Dependent

Calcium ions (Ca2+) are essential for many cellular signaling mechanisms and enter the cytosol mostly through voltage-gated calcium channels. Here, using high-speed Ca2+ imaging up to 20 kHz in the rat layer five pyramidal neuron axon we found that activity-dependent intracellular calcium concentration ([Ca2+]i) in the axonal initial segment was only partially dependent on voltage-gated calcium channels. Instead, [Ca2+]i changes were sensitive to the specific voltage-gated sodium (NaV) channel blocker tetrodotoxin. Consistent with the conjecture that Ca2+ enters through the NaV channel pore, the optically resolved ICa in the axon initial segment overlapped with the activation kinetics of NaV channels and heterologous expression of NaV1.2 in HEK-293 cells revealed a tetrodotoxin-sensitive [Ca2+]i rise. Finally, computational simulations predicted that axonal [Ca2+]i transients reflect a 0.4% Ca2+ conductivity of NaV channels. The findings indicate that Ca2+ permeation through NaV channels provides a submillisecond rapid entry route in NaV-enriched domains of mammalian axons.

Effect of Divalent Cations on AMPA-Evoked Extracellular Alkaline Shifts in Rat Hippocampal Slices

1999 ◽  
Vol 82 (4) ◽  
pp. 1902-1908 ◽  
Author(s):  
S. E. Smith ◽  
M. Chesler
Keyword(s):  
Carbonic Anhydrase ◽  
Calcium Channels ◽  
Divalent Cations ◽  
Hippocampal Slices ◽  
Strong Base ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Alkaline Shift ◽  
Ca1 Area ◽  
Activity Dependent

The generation of activity-evoked extracellular alkaline shifts has been linked to the presence of external Ca2+ or Ba2+. We further investigated this dependence using pH- and Ca2+-selective microelectrodes in the CA1 area of juvenile, rat hippocampal slices. In HEPES-buffered media, alkaline transients evoked by pressure ejection of RS-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) averaged ∼0.07 unit pH and were calculated to arise from the equivalent net addition of ∼1 mM strong base to the interstitial space. These alkaline responses were correlated with a mean decrease in [Ca2+]o of ∼300 μM. The alkalinizations were abolished reversibly in zero-Ca2+ media, becoming indiscernible at a [Ca2+]o of 117 ± 29 μM. Addition of as little as 30–50 μM Ba2+ caused the reappearance of an alkaline response. In approximately one-fourth of slices, a persistent alkaline shift of ∼0.03 unit pH was observed in zero-Ca2+ saline containing EGTA. In HEPES media, addition of 300 μM Cd2+, 100 μM Ni2+, or 100 μM nimodipine inhibited the alkaline shifts by roughly one-half, one-third, and one-third, respectively, whereas Cd+ and Ni2+ in combination fully blocked the response. In bicarbonate media, by contrast, Cd+ and Ni2+blocked only two-thirds of the response. In the presence of bicarbonate, Ni2+ caused an unexpected enhancement of the alkalinization by ∼150%. However, when the extracellular carbonic anhydrase was blocked by benzolamide, addition of Ni2+reduced the alkaline shift. These results suggested that Ni2+ partially inhibited the interstitial carbonic anhydrase and thereby increased the alkaline responses. These data indicate that an activity-dependent alkaline shift is largely dependent on the entry of Ca2+ or Ba2+ via voltage-gated calcium channels. However, sizable alkaline transients still can be generated with little or no external presence of these ions. Implications for the mechanism of the activity-dependent alkaline shift are discussed.

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