Elsevier

Neuropharmacology

Volume 44, Issue 8, June 2003, Pages 1013-1021
Neuropharmacology

Chronic AMPA receptor potentiator (LY451646) treatment increases cell proliferation in adult rat hippocampus

https://doi.org/10.1016/S0028-3908(03)00104-7Get rights and content

Abstract

Stress-induced neuronal atrophy and death in the hippocampus may play an important role in the etiology of clinical depression. Conventional antidepressants can stimulate hippocampal neurogenesis after chronic administration. AMPA receptor potentiators (ARPs) such as LY392098 and LY451616 are active in both the forced swim test and the tail suspension test, two behavioral despair procedures widely used to predict antidepressant efficacy. Unlike traditional antidepressants, this group of compounds does not affect extracellular concentrations of biogenic amines. In this study, we investigated the effect of LY451646 on progenitor cell proliferation in adult rat hippocampus. Male Sprague–Dawley rats (n = 4–5 per group) received either single or chronic (21 days) doses of LY451646 (0.025–0.5 mg/kg). Bromodeoxyuridine (BrdU) injections and immunohistochemistry were performed 30 min and 24 h after the last drug injection, respectively. Results show that chronic LY451646 treatment increased progenitor cell proliferation (~45%) in the dentate gyrus in a dose-dependent manner. This upregulation of BrdU labeling appeared as an increase in the number of cells arranged in clusters. Similarly, a significant increase in the number of cells in clusters was observed after a single injection of LY451646 (0.05 mg/kg), although the increase in total number of BrdU-positive cells (~30%) did not reach statistical significance. This is the first in vivo study showing the modulation of progenitor cell proliferation by an ARP. These findings suggest that the antidepressant-like activity of ARPs in animals may be attributed, at least in part, to the regulation of progenitor cell proliferation in the hippocampus.

Introduction

Recent studies suggest that neurons are generated throughout life in the brain of many animal species, including bird, rodent, monkey and human (Gould et al., 1999, Gross, 2000). This process is particularly prominent in the dentate gyrus of the hippocampus, which plays an important role in learning and memory. The newborn neurons originate from a population of continuously dividing progenitor cells in the subgranular zone (SGZ) of the dentate gyrus. Some of these proliferating cells migrate into the granule cell layer, differentiate, and express neuronal markers (Cameron et al., 1993).

Adult neurogenesis can be regulated by a number of stimuli. Positive stimuli include adrenalectomy, administration of ovarian steroid estrogen, lesion of the entorhinal cortex (source of glutamatergic input to the hippocampus) or NMDA receptor antagonists, serotonin, growth factors, certain forms of physical exercise, and enriched environment (Fuchs and Gould, 2000, Gould, 1999, Pencea et al., 2001). In contrast, conditions such as administration of adrenal steroids, glutamate, ovariectomy, lesion of serotonergic neurons, and various physical and psychological stress conditions negatively modulate the production of new neurons (Brezun and Daszuta, 1999, Fuchs and Gould, 2000).

Major and prolonged depression in humans has been associated with as much as a 19% reduction in hippocampal volume (Bremner et al., 2000). The persistence of hippocampal atrophy after the resolution of depression suggests the possibility of neuron loss (Sapolsky, 2000). Converging evidence indicates that disruption of the neurogenesis process may be an important mechanism by which stress facilitates depression (Duman et al., 1999, Sapolsky, 1996). Indeed, neurogenesis has been shown to decrease following chronic stress in animal models (Gould et al., 1997). In addition, whereas decreasing serotonin neurotransmission (which has been associated with depression) results in reduced neurogenesis (Brezun and Daszuta, 1999, Brezun and Daszuta, 2000), increased serotonergic transmission promotes hippocampal neurogenesis (Gould, 1999). The cAMP-CREB cascade and its downstream neurotrophic factor, brain derived neurotrophic factor (BDNF), have also been suggested as major mediators of antidepressant effects (Nibuya et al., 1995). Increased hippocampal BDNF protein has been reported in patients treated with antidepressants (Chen et al., 2001), and BDNF has been shown to promote cell proliferation, survival and/or differentiation in vitro and in vivo (Pencea et al., 2001). More importantly, recent studies have demonstrated that antidepressant treatment increases adult neurogenesis in the rat hippocampus (Duman et al., 2001, Malberg et al., 2000).

AMPA receptors, a subfamily of ionotropic glutamate receptors mediating the fast component of excitatory transmission, can be allosterically modulated by several classes of compounds. These compounds (so-called AMPA receptor positive modulators or AMPA receptor potentiators, ARPs) do not activate AMPA receptors themselves but slow the rate of receptor desensitization and/or deactivation in the presence of agonist (e.g. glutamate and AMPA) (Bleakman and Lodge, 1998, Borges and Dingledine, 1998). Studies have shown that the biarylpropylsulfonamide ARPs (LY392098 and LY 451616) are active in both the forced-swim test (FST) and the tail suspension test (TST) (Bai et al., 2001, Li et al., 2001), two behavioral despair models used to evaluate antidepressant-like drug activity. Unlike traditional antidepressants, this group of compounds does not affect the extracellular concentration of biogenic amines (Skolnick et al., 2001). However, these ARPs can upregulate the expression of BDNF mRNA and protein in primary neuronal cultures (Legutko et al., 2001), in rat entorhinal/hippocampal slice cultures (Lauterborn et al., 2000), and in rat hippocampus in vivo (Mackowiak et al., 2002).

Based on the neuropharmacology of the ARPs and the correlation between depression and hippocampal neurogenesis, the present studies were conducted to determine whether the ARP LY451646 influences progenitor cell proliferation in adult rat hippocampus.

Section snippets

Animals

Adult male Sprague–Dawley rats (275–300 g) were purchased from Harlan (Indianapolis, IN). Animals were housed in a vivarium for at least 1 week prior to use. The vivarium was maintained on a twelve-hour light/dark cycle (lights on/off at 06:00/18:00 h) and a constant room temperature with free access to rat chow and water. After 1 week of habituation in the vivarium, rats were subject to the treatments described below. All animal use procedures were performed in accordance with the National

Results

Incorporation of BrdU, a thymidine analogue, was used to label newly born or proliferating cells in the brain (Nowakowski et al., 1989). The effect of LY451646 on BrdU incorporation was investigated in the SGZ and hilus of the dentate gyrus (Fig. 2A). One day after repeated BrdU injections to normal rats, the SGZ and hilus contained a population of single BrdU-positive cells with round- to oval-shaped nuclei. A small number of irregularly shaped BrdU-labeled nuclei organized in clusters were

Discussion

The present study demonstrated that LY451646 administration increased progenitor cell proliferation in adult rat hippocampus. Both acute and chronic LY451646 treatments resulted in significantly more numerous and larger clusters of BrdU-positive cells. This suggests that LY451646 can stimulate single progenitor cells to give rise to a clonal population of immature daughter cells (Kuhn et al., 1996, Parent et al., 1997).

Both neuronal and glia progenitor cell populations, which exhibit limited

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