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

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.
Introduction

While the pathogenesis of neurodegenerative diseases remains poorly understood, the involvement of the glutamatergic system and, specifically, of the N-methyl-D-aspartate receptor (NMDAR) in the pathogenesis of numerous neurodegenerative disorders is widely recognized (Hardingham and Bading, 2010).

N-Methyl-D-aspartate receptor are heteromultimeric channels comprised of three different subunit families (NR1, NR2A-D, NR3A-B; Meguro et al., 1992; Monyer et al., 1992; Dingledine et al., 1999). Different combinations of these subunits confer the pharmacological profile, gating properties, and Mg2+ sensitivity to the NMDAR complex (Sucher et al., 1995; Danysz and Parsons, 1998). Because of their properties, NMDARs are important to fast synaptic neurotransmission and synaptic plasticity (Cull-Candy et al., 2001). NMDAR activation requires the presence of glutamate and a co-agonist (glycine or D-serine) as well as the relief of the Mg2+ block through depolarization (Danysz and Parsons, 1998). Once open, NMDARs allow the passage of Ca2+ and, to a lesser extent, Na+ and K+ (fast synaptic transmission). Ca2+ influx through the NMDAR is also responsible for the persistent changes observed in long-term potentiation (LTP), the cellular mechanism underlying synaptic plasticity (Nicoll and Malenka, 1999; Cull-Candy et al., 2001), which is implicated in cognitive functions such as learning and memory.

One of the most devastating symptoms associated with neurodegenerative disorders is cognitive impairment, and damage to the hippocampal formation, the principal region associated with learning and memory, is linked to these disorders. The hippocampus is a complex network that consists of tightly regulated interactions between excitation [glutamatergic dentate granular cells, CA1, and CA3 pyramidal cells (PCs)] and inhibition [GABAergic interneurons (Ints); Woodson et al., 1989]. Inhibitory Ints play a crucial role in regulating the interactions between PCs (Klausberger et al., 2005; Klausberger and Somogyi, 2008; Isaacson and Scanziani, 2011; Kullmann, 2011), including population oscillations, plasticity, epileptic synchronization, hormonal effects, and cortical development. Palop and Mucke (2010) suggested that in Alzheimer’s disease (AD), dysfunction of Ints likely increases synchrony among excitatory principal cells and contributes to the destabilization of neuronal networks. In addition, using animal model studies, it has been hypothesized that in AD, the excitation-inhibition balance in hippocampal neuronal circuitry is shifted, resulting in over-excitation (Schmitt, 2005). Furthermore, memantine, an uncompetitive NMDAR antagonist clinically used for the treatment of mild to severe AD (2003 EU, USA), may restore balance between excitation and inhibition (Schmitt, 2005; Parsons et al., 2007). Very recently, Guadagna et al. (2012) suggested that, in mice, clinically relevant doses of memantine promote neuronal network synchronization in the hippocampus.

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