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Bidirectional Influence of Sodium Channel Activation on NMDA Bidirectional influence of sodium channel activation on NMDA receptor–dependent cerebrocortical neuron structural plasticity Joju Georgea, Daniel G. Badenb, William H. Gerwickc, and Thomas F. Murraya,1 aDepartment of Pharmacology, Creighton University School of Medicine, Omaha, NE 68178; bCenter for Marine Science, University of North Carolina, Wilmington, NC 28409; and cCenter for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, La Jolla, CA 92093 Edited by William A. Catterall, University of Washington School of Medicine, Seattle, WA, and approved October 16, 2012 (received for review July 31, 2012) Neuronal activity regulates brain development and synaptic plastic- NMDA receptors (NMDARs) and downstream signaling path- ity through N-methyl-D-aspartate receptors (NMDARs) and calcium- ways (9, 10). Previous studies have indicated that changes in in- + + dependent signaling pathways. Intracellular sodium ([Na ]i)also tracellular sodium concentration ([Na ]i) produced in soma and + exerts a regulatory influence on NMDAR channel activity, and [Na ]i dendrites as a result of neuronal activity may play a role in ac- may, therefore, function as a signaling molecule. In an attempt to tivity-dependent synaptic plasticity. Synaptic stimulation causes fl + mimic the in uence of neuronal activity on synaptic plasticity, we [Na ]i increments of 10 mM in dendrites and of up to 35–40 mM used brevetoxin-2 (PbTx-2), a voltage-gated sodium channel (VGSC) in dendritic spines (11). In hippocampal neurons, intracellular fi + + gating modi er, to manipulate [Na ]i in cerebrocortical neurons. [Na ] increments greater than 5–10 mM have been demonstrated The acute application of PbTx-2 produced concentration-dependent to increase NMDAR-mediated whole-cell currents and single- + 2+ increments in both intracellular [Na ] and [Ca ]. Pharmacological channel activity by increasing both channel open probability and 2+ evaluation showed that PbTx-2–induced Ca influx primarily in- mean open time (12). volved VGSC activation and NMDAR-mediated entry. Additionally, + In the present study, we used brevetoxin-2 (PbTx-2), a voltage- PbTx-2 robustly potentiated NMDA-induced Ca2 influx. PbTx-2–ex- + gated sodium channel (VGSC) gating modifier, to manipulate [Na ]i posed neurons showed enhanced neurite outgrowth, increased in immature cerebrocortical neurons in an effort to mimic neuronal fi dendritic arbor complexity, and increased dendritic lopodia den- activity. Brevetoxins interact with neurotoxin site 5 on the α subunit of fl sity. The appearance of spontaneous calcium oscillations, re ecting VGSCs (13, 14) and augment sodium influx by shifting the activation synchronous neuronal activity, was accelerated by PbTx-2 treat- potential to more negative values and inhibiting channel inactivation ment. Parallel to this response, PbTx-2 increased cerebrocortical neu- (15). We have shown previously that in cerebrocortical neurons, ron synaptic density. PbTx-2 stimulation of neurite outgrowth, den- + PbTx-2 elevates [Na ]i and augments NMDAR whole-cell currents dritic arborization, and synaptogenesis all exhibited bidirectional by increasing both channel open probability and mean open time concentration–response profiles. This profile paralleled that of – without affecting the resting membrane potential (16). PbTx-2 NMDA, which also produced bidirectional concentration response treatment affects neurite outgrowth in day in vitro (DIV)-1 cere- profiles for neurite outgrowth and synaptogenesis. These data are brocortical neurons in a bidirectional pattern (16). We hypothesized consistent with the hypothesis that PbTx-2–enhanced neuronal plas- that the effects of PbTx-2 on structural plasticity in cerebrocortical ticity involves NMDAR-dependent signaling. Our results demon- neurons may be mediated by NMDAR-dependent mechanisms strate that PbTx-2 mimics activity-dependent neuronal structural + + subsequent to an increase in [Na ]i. Here, we show that acute plasticity in cerebrocortical neurons through an increase in [Na ]i, + 2+ + application of PbTx-2 causes Na and Ca influx, with the [Na ]i up-regulation of NMDAR function, and engagement of downstream fi Ca2+-dependent signaling pathways. These data suggest that VGSC increment being suf cient to up-regulate NMDAR function. fi Furthermore, we demonstrate that PbTx-2 treatment enhances gating modi ers may represent a pharmacologic strategy to regu- fi late neuronal plasticity through NMDAR-dependent mechanisms. dendritic arborization, lopodia formation, and synaptogenesis. We also demonstrate that PbTx-2 exposure engages downstream 2+ neuronal connectivity | ion flux activity-dependent mechanisms involving Ca -calmodulin kina- ses (CaMKs), ERK, cAMP response element binding protein (CREB), and BDNF signaling pathways. Taken together, our evelopment of the nervous system involves both a pre- results indicate that PbTx-2 mimics activity-dependent synaptic Ddetermined genetic program that controls the general or- plasticity by potentiating NMDAR function with downstream + ganization of the brain and activity-dependent mechanisms that engagement of Ca2 -dependent signaling mechanisms. modulate several developmental processes, including dendritic elaboration, spine formation, synapse formation, and synapse Results elimination (1). Neuronal activity is one of the essential extra- fi fl PbTx-2, a Sodium Channel Gating Modi er, Increases Intracellular cellular signals that in uences dendritic arborization (2). During Sodium and Calcium Influx in DIV-1 Cerebrocortical Neurons. To development, dendrites are first decorated by filopodia (3) that + determine the extent to which PbTx-2 can elevate [Na ]i in im- are considered to be precursors of spines (4, 5). During initial mature DIV-1 cerebrocortical neurons, we imaged individual development, synapses emerge at contacts between axons and dendritic filopodia (6, 7) that may mature into excitatory spine synapses in later development. Previous studies have demon- Author contributions: J.G. and T.F.M. designed research; J.G. performed research; D.G.B. strated that neuronal activity and activity-dependent gene tran- and W.H.G. contributed new reagents/analytic tools; J.G. and T.F.M. analyzed data; and scription have profound effects on synaptogenesis (8). J.G. and T.F.M. wrote the paper. The N-methyl-D-aspartate (NMDA) type of glutamate receptor The authors declare no conflict of interest. mediates many of the effects of neuronal activity on structural This article is a PNAS Direct Submission. plasticity. The development and structural remodeling of den- 1To whom correspondence should be addressed. E-mail: [email protected]. drites and spines depend on actin cytoskeletal reorganization, and This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. cytoskeletal dynamics are regulated by calcium influx through 1073/pnas.1212584109/-/DCSupplemental. 19840–19845 | PNAS | November 27, 2012 | vol. 109 | no. 48 www.pnas.org/cgi/doi/10.1073/pnas.1212584109 Downloaded by guest on October 4, 2021 + (Fig. 1C). To delineate the Ca2 -influx pathways triggered by 2+ PbTx-2, a pharmacological evaluation of the [Ca ]i response to 100 nM PbTx-2 was performed. Neurons were pretreated with the antagonists TTX (VGSC), amino-5-phosphonopentanoic acid (D-APV) (NMDAR), or nifedipine (L-type voltage-gated calcium channel) before PbTx-2 challenge (Fig. 1D). TTX (1 μM) com- pletely blocked the response to PbTx-2, whereas D-APV (100 μM), but not nifedipine (1 μM), significantly reduced PbTx-2–in- + duced Ca2 influx. A pharmacological evaluation of PbTx-2 in- + duced Ca2 influx at the population level using neurons loaded with Fluo3-AM yielded similar results (Fig. S3). These experi- + ments indicate that PbTx-2–induced Ca2 influx requires VGSC activation and primary cell entry through the calcium-permeable NMDAR. Given the ability of PbTx-2 exposure to augment NMDAR channel function (12, 16), we next evaluated the ability of + PbTx-2 treatment to affect NMDA-induced Ca2 influx at the single-cell level in DIV-1 neurons. NMDA alone produced a con- 2+ centration-dependent elevation of [Ca ]i (Fig. 1E) with an EC50 of 444.1 nM (95% CI, 24 nM to 8.2 μM). In the presence of a con- centration of PbTx-2 (30 nM) that alone produced a modest 2+ 2+ transient increase in [Ca ]i, the NMDA-induced Ca influx was robustly potentiated. The NMDA concentration–response curve displayed a leftward shift [NMDA plus PbTx-2: EC50, 12 nM (95% Fig. 1. PbTx-2, a sodium channel gating modifier, increases intracellular CI, 4.7–30.2 nM)] and an increased maximum response (Emax)in sodium and calcium levels in DIV-1 cerebrocortical neurons. (A) PbTx-2 = – + fl the presence of PbTx-2 [NMDA: Emax 0.013 (95% CI, 0.011 concentration-dependent elevation of [Na ]i.SBFI uorescence data are = – expressed as maximum changes in (340/380) ratio divided by the baseline 0.016); NMDA plus PbTx-2: Emax 0.025 (95% CI, 0.022 0.028)]. + fi fi ratio (ΔR/R0). Right ordinate depicts the calibrated [Na ]i corresponding to These ndings con rm the ability of PbTx-2 treatment to en- SBFI fluorescence ratio. Data shown are from a representative experiment hance NMDAR function in cerebrocortical neurons. (n = 20–30 cells) repeated three times. (B) Pretreatment with TTX (1 μM) blocked 100 nM PbTx-2–induced increase in SBFI fluorescence. TTX and PbTx- PbTx-2–Enhanced Neurite Outgrowth Exhibits a Bidirectional Profile + 2 addition indicated by arrows. A representative trace is shown. (C)Ca2 Similar to that of NMDA. We have shown previously that the effect imaging with Fura-2 AM showed PbTx-2 concentration-dependent incre- of PbTx-2 on neurite outgrowth exhibited a bidirectional concen- 2+ fl ments in [Ca ]i. Data are expressed as maximum change in uorescence – fi 2+ tration response pro le and that this effect was primarily de- ratio (340/380) divided by baseline ratio. Right ordinate indicates [Ca ]i fl pendent on NMDARs (16). Lipton and Nakanishi (18) have derived from calibration of the Fura-2 uorescence. PbTx-2 EC50 value: 360 fi nM (95% CI, 133-969 nM). Data shown are from a representative experiment similarly described an inverted-U pro le for the relationship be- (n = 20–30 cells) repeated four times.
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