Korean J Physiol Pharmacol.  2015 Nov;19(6):523-531. 10.4196/kjpp.2015.19.6.523.

Enhancement of GluN2B Subunit-Containing NMDA Receptor Underlies Serotonergic Regulation of Long-Term Potentiation after Critical Period in the Rat Visual Cortex

• Joo K
• Rhie DJ
• Jang HJ

• KMID: 2070792
• DOI: http://doi.org/10.4196/kjpp.2015.19.6.523

Abstract

Serotonin [5-hydroxytryptamine (5-HT)] regulates synaptic plasticity in the visual cortex. Although the effects of 5-HT on plasticity showed huge diversity depending on the ages of animals and species, it has been unclear how 5-HT can show such diverse effects. In the rat visual cortex, 5-HT suppressed long-term potentiation (LTP) at 5 weeks but enhanced LTP at 8 weeks. We speculated that this difference may originate from differential regulation of neurotransmission by 5-HT between the age groups. Thus, we investigated the effects of 5-HT on apha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-, gamma-aminobutyric acid receptor type A (GABA(A)R)-, and N-methyl-D-aspartic acid receptor (NMDAR)-mediated neurotransmissions and their involvement in the differential regulation of plasticity between 5 and 8 weeks. AMPAR-mediated currents were not affected by 5-HT at both 5 and 8 weeks. GABA(A)R-mediated currents were enhanced by 5-HT at both age groups. However, 5-HT enhanced NMDAR-mediated currents only at 8 weeks. The enhancement of NMDAR-mediated currents appeared to be mediated by the enhanced function of GluN2B subunit-containing NMDAR. The enhanced GABA(A)R- and NMDAR-mediated neurotransmissions were responsible for the suppression of LTP at 5 weeks and the facilitation of LTP at 8 weeks, respectively. These results indicate that the effects of 5-HT on neurotransmission change with development, and the changes may underlie the differential regulation of synaptic plasticity between different age groups. Thus, the developmental changes in 5-HT function should be carefully considered while investigating the 5-HT-mediated metaplastic control of the cortical network.

Keyword

5-HT; AMPA receptor; GABA(A) receptor; Metaplasticity; Serotonin

MeSH Terms

Animals
Critical Period (Psychology)*
Humans
Long-Term Potentiation*
N-Methylaspartate*
Plastics
Rats*
Receptors, AMPA
Receptors, GABA
Receptors, GABA-A
Serotonin
Synaptic Transmission
Visual Cortex*
N-Methylaspartate
Plastics
Receptors, AMPA
Receptors, GABA
Receptors, GABA-A
Serotonin

Figure

• 

  Fig. 1 Opposite effects of 5-HT on LTP induction at 5 and 8 weeks. TBS was applied to layer 4 to induce LTP of fEPSP recorded at layer 2/3. (A) LTP induced by TBS (open circle) was inhibited by 5-HT (10 µM, closed circle) at 5 weeks. Left panel plots the amplitude of fEPSPs normalized to the baseline fEPSPs. Left upper traces show average recordings taken from representative experiments at the indicated time periods. Right panel shows individual data (symbols) and averages (thick lines) of the amplitude of fEPSPs, which were measured 30 to 40 min after TBS. ##p<0.01 vs. baseline, *p<0.05 between groups linked by lines. (B) At 8 weeks, LTP could not be induced by TBS (open diamond). However, LTP was reinstated by 5-HT (closed diamond). ##p<0.01 vs. baseline, ***p<0.001 between groups linked by lines. (C) Application of the NMDAR antagonist D-AP5 (+APV) inhibited the LTPs with control ACSF at 5 weeks (open circle) and with 5-HT at 8 weeks (closed diamond).

• 

  Fig. 2 Effects of 5-HT on AMPAR-, GABAAR-, and NMDAR-mediated currents in layer 2/3 pyramidal neurons at 5 and 8 weeks. (A) AMPAR currents were evoked by electrical stimulation of the underlying layer 4 and were recorded with K-gluconate-based pipette solution at -70 mV holding potential. (A1) Effect of 5-HT on AMPAR currents at 5 weeks. Left panel shows traces from a representative recording. Right panel shows individual data (symbols) and averages (thick lines) of the amplitude of AMPAR currents, which were measured before and 7 min after 5-HT application. (A2) Effect of 5-HT on AMPAR currents at 8 weeks. (B) GABAAR currents were recorded with CsCl-based pipette solution at -70 mV holding potential. Amplitude of GABAAR currents were compared before and 7 min after 5-HT application. (B1) Effect of 5-HT on GABAAR currents at 5 weeks. (B2) Effect of 5-HT on GABAAR currents at 8 weeks. **p<0.01 between groups linked by lines. (C) NMDAR currents were recorded with K-gluconate-based pipette solution at -70 mV holding potential in low Mg2+ (0.4 mM) ACSF. Area under the current was compared before and 7 min after 5-HT application. (C1) Effect of 5-HT on NMDAR currents at 5 weeks. (C2) Effect of 5-HT on NMDAR currents at 8 weeks.

• 

  Fig. 3 Importance of GluN2B subunit in the 5-HT-mediated enhancement of NMDAR currents. After 7 min application of ifenprodil, CP-101,606, and PPDA, which are known as preferential blockers of GluN2B, GluN2B and GluN2C/D subunits, respectively, 5-HT was added to the ACSF for 7 min. (A) 5-HT had no effect on NMDAR currents in the presence of ifenprodil (3 µM). Left panel shows traces of NMDAR currents at the baseline condition, after ifenprodil application, and after 5-HT application from a representative recording. Right panel shows individual data (symbols) and averages (thick lines) of the changes in the area under the NMDAR currents. (B) 5-HT had no effect on NMDAR currents in the presence of CP-101,606 (3 µM). (C) 5-HT enhanced NMDAR currents in the presence of PPDA (300 nM). *p<0.05, **p<0.01 and ***p<0.001 between groups linked by lines.

• 

  Fig. 4 Effects of 5-HT receptor antagonists on 5-HT enhancement of NMDAR currents and 5-HT receptor agonists on NMDAR currents at 8 weeks. (A) The 5-HT1A receptor antagonist NAN-190 (A1) or the 5-HT2 receptor antagonist mesulergine (A2) were co-applied with 5-HT. Area under the current was compared before and 7 min after the application of each drug combination. Left panel shows traces from a representative recording. Right panel shows individual data (symbols) and averages (thick lines) of the changes in area under the current. **p<0.01 between groups linked by lines. (B) Effects of the 5-HT1A receptor agonist DPAT (B1) or the 5-HT2 receptor agonist DOI (B2) on NMDAR currents.

• 

  Fig. 5 Effects of kinases inhibitors on 5-HT enhancement of NMDAR currents at 8 weeks. (A) 5-HT was applied in the presence of the PKA inhibitor PKI in pipette. Area under the current was compared before and 7 min after the application of 5-HT. Left panel shows traces from a representative recording. Right panel shows individual data (symbols) and averages (thick lines) of the changes in area under the current. **p<0.01 between groups linked by lines. (B) 5-HT was applied in the presence of the PKC inhibitor chelerythrine in pipette. (C) 5-HT was applied in the presence of the tyrosine kinases inhibitor genistein in pipette. (D) 5-HT was applied in the presence of the CaMKII inhibitor KN-93 in pipette.

• 

  Fig. 6 Effects of bicuculline and ifenprodil on 5-HT modulation of GABAAR and NMDAR currents. The effects of 5-HT on GABAAR and NMDAR currents at 5 and 8 weeks, respectively, were assessed first, and then bicuculline and ifenprodil were applied. (A) Bicuculline (300 nM) can negate the effect of 5-HT on GABAAR currents at 5 weeks. Left panel shows traces of GABAAR currents at the baseline condition, after 5-HT application, and after bicuculline application from a representative recording. Right panel shows individual data (symbols) and averages (thick lines) of the changes in the amplitude of GABAAR currents. **p<0.01 and ***p<0.001 between groups linked by lines. (B) Ifenprodil (1 µM) can negate the effect of 5-HT on NMDAR currents at 8 weeks. Left panel shows traces of NMDAR currents at the baseline condition, after 5-HT application, and after ifenprodil application from a representative recording. Right panel shows individual data (symbols) and averages (thick lines) of the changes in the area under the NMDAR currents.

• 

  Fig. 7 Reversal of the 5-HT regulation of LTP by bicuculline and ifenprodil. For clear comparison, data for 5-HT were reproduced from Fig. 1. (A) 5-HT suppression of LTP at 5 weeks (closed circle) was rescued by the application of bicuculline (300 nM) (open circle). (B) 5-HT enhancement of LTP at 8 weeks (closed diamond) was vanished by the application of both bicuculline and ifenprodil (1 µM, open diamond) or ifenprodil alone (grey diamond). ##p<0.01, ###p<0.001 vs. baseline, **p<0.01 between groups linked by lines.

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