Selective pharmacological modulation of pyramidal neurons and interneurons in the CA1 region of the rat hippocampus

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Abstract

The hippocampus is a complex network tightly regulated by interactions between excitatory and inhibitory neurons. In neurodegenerative disorders where cognitive functions such as learning and memory are impaired this excitation-inhibition balance may be altered. Interestingly, the uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist memantine, currently in clinical use for the treatment of Alzheimer's disease, may alter the excitation-inhibition balance in the hippocampus. However, the specific mechanism by which memantine exerts this action is not clear. To better elucidate the effect of memantine on hippocampal circuitry, we studied its pharmacology on NMDAR currents in both pyramidal cells (PCs) and interneurons (Ints) in the CA1 region of the hippocampus. Applying whole-cell patch-clamp methodology to acute rat hippocampal slices, we report that memantine antagonism is more robust in PCs than in Ints. Using specific NMDAR subunit antagonists, we determined that this selective antagonism of memantine is attributable to specific differences in the molecular make-up of the NMDARs in excitatory and inhibitory neurons. These findings offer new insight into the mechanism of action and therapeutic potential of NMDA receptor pharmacology in modulating hippocampal excitability. © 2013 Martina, Comas and Mealing.

Figures

  • FIGURE 1 | Excitatory (PCs) and inhibitory (Ints) neurons recorded in the CA1 region of the hippocampus. (A) CA1 PCs and Ints were patch-clamped with a pipette solution containing Lucifer Yellow (2 mM). The location of neurons in the slices was visualized by superimposition of the reflected light image of the hippocampal slice and of the Lucifer yellow fluorescence signal (left panel). The right panel shows reconstructed confocal images of two PCs (yellow) and three Ints (green) recorded in the CA1 sp and sr, respectively. (B,C) Confocal images of one PC (B) and one Int (C) of CA1 pyramidal layer and stratum radiatum, respectively. (B) Right
  • FIGURE 2 | Effect of memantine on NMDAR currents in PCs and Ints in the CA1 region of the hippocampus. NMDAR currents were recorded from individual PCs and Ints voltage-clamped at V m=−70 mV. (A,B) Time-course of memantine-induced reduction on the NMDAR current amplitude in PCs and Ints, respectively. In PCs, bath application of 100 nM, 1 µM, 10 µM, 20 µM, 100 µM, 300 µM, 500 µM, and 1 mM memantine reduced the amplitude of the NMDAR currents by 0% (n=3), 27.28±13.26% (n=5), 52.66±3.52% (n=14), 60.55±2.93% (n=7), 73.82±3.48% (n=7), 87.8±2.42% (n=8), 98.04±1.69% (n=3), and 100% (n=3), respectively. In Ints, bath application of 100 nM, 1 µM, 10 µM, 20 µM, 100 µM, 300 µM, 500 µM memantine reduced the
  • FIGURE 3 | Effect of memantine on NMDAR currents recorded in presence of Mg2+ at Vm =−30, in PCs and Ints in the CA1 region of the hippocampus. (A–C) Time-course of memantine-induced reduction on the NMDAR current amplitude in PCs and Ints, respectively. Normalized NMDAR current amplitudes (%) are plotted as a function of time for memantine concentrations of 100 nM (full square), 10 µM (empty circle), 300 µM (full circle). Each point (one every min) is the average of six points (stimulations every 10 s). The
  • FIGURE 4 | NMDAR deactivation kinetics in PCs and Ints. (A,B)
  • Table 2 | Decay time-constants of the NMDAR currents in PCs and Ints.
  • Table 3 | Decay time-constants of the NVP-AAM077-, Ro25-6981, and NVP-AAM077+Ro-6981-resistant NMDAR currents in PCs.
  • Table 4 | Decay time-constants of the NVP-AAM077-, Ro25-6981, and NVP-AAM077+Ro-6981-resistent NMDAR currents in Ints.
  • FIGURE 5 | Effect of memantine on NVP-AAM077- and Ro25-6981-resistent NMDAR currents in PCs and Ints. NMDAR currents were recorded from individual PCs and Ints voltage-clamped at V m=−70 mV. (A,B) Time-course of the NVP-AAM077, Ro25-6981 memantine-induced reduction on NMDAR current amplitude in PCs (empty circle) and Ints (full circle). Normalized NMDAR current amplitudes (%) are plotted as a function of time. Each point (one every min) is the average of six points (stimulation

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Martina, M., Comas, T., & Mealing, G. A. R. (2013). Selective pharmacological modulation of pyramidal neurons and interneurons in the CA1 region of the rat hippocampus. Frontiers in Pharmacology, 4 MAR. https://doi.org/10.3389/fphar.2013.00024

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