Involvement of cholinergic and glutamatergic functions in working memory impairment induced by interleukin-1β in rats

doi:10.1016/S0014-2999(01)01374-7

European Journal of Pharmacology

Volume 430, Issues 2–3, 2 November 2001, Pages 283-288

https://doi.org/10.1016/S0014-2999(01)01374-7 Get rights and content

Abstract

Interleukin-1β at doses of 32 and 100 ng/side, injected bilaterally into the dorsal hippocampus of rats, significantly increased the working memory errors in a three-panel runway setup, whereas interleukin-1β at doses affecting working memory errors had no effect on the number of errors in the first trial or the latency. The increase in working memory errors induced by intrahippocampal administration of 100 ng/side interleukin-1β was significantly decreased by concurrent injection (300 ng/side) of the interleukin-1 receptor antagonist. The cholinesterase inhibitor physostigmine at a dose of 3.2 μg/side and d-cycloserine (1.0 and 10 μg/side), which is a partial agonist acting at the glycine binding site of the NMDA receptor/channel complex, reduced the increase in working memory errors induced by 100 ng/side interleukin-1β. These results suggest that interleukin-1β causes disruptions of septohippocampal cholinergic and glutamatergic transmission via its high-affinity receptor, which underlie the impairment of working memory.

Introduction

Interleukin-1β is well known as a proinflammatory cytokine, which shows numerous responses to infectious agents. In the brain, interleukin-1β and other cytokines are produced by astrocytes or microglias, and their receptors or binding sites are distributed in many regions. The interleukin-1 receptor is distributed in the CA1 and CA3 pyramidal cells and dentate gyrus granule cells of the hippocampus with high density Takao et al., 1990, Ban et al., 1991, Lechan et al., 1990, Cunningham et al., 1992.

Alzheimer's disease is characterized by the presence of senile plaques and neurofibrillary tangles accompanied by synaptic and neuronal loss (Coyle et al., 1983), underlying the cognitive impairments associated with dementia. The level of interleukin-1β is markedly increased in the hippocampus and frontal cortex in the brains of Alzheimer's disease patients (Cacabelos et al., 1994), suggesting that an increase in the level of interleukin-1β is related to the impairment of the cognitive function observed in Alzheimer's disease patients. The septohippocampal cholinergic system, known to be critical to the hippocampus and required for normal memory function (Smith, 1988), is extensively disrupted in the brains of Alzheimer's disease patients Davies and Maloney, 1976, Perry and Perry, 1977. It has also been reported that interleukin-1β decreased cholinergic transmission by blocking acetylcholine release from presynaptic cells (Rada et al., 1991). These results suggest that the impairment of memory function observed in Alzheimer's disease patients is due to an increase in interleukin-1β in the brain, which causes a decrease in cholinergic transmission. However, few behavioral studies have been designed to clarify the role of interleukin-1β in memory function. In the present study, we investigated, using the three-panel runway task, the effect of intrahippocampal administration of interleukin-1β on the working memory performance of rats, considered a model of working memory in humans, which is often disrupted in the early stage of Alzheimer's disease.

In addition to the cholinergic system, the glutamatergic system plays an important role in hippocampal memory, e.g., intrahippocampal administration of the muscarinic acetylcholine receptor antagonist scopolamine or selective and competitive N-methyl-d-aspartate (NMDA) receptor antagonists such as (±)-3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid produced a dose-dependent disruption of working memory performance in a three-panel runway task (Ohno et al., 1992), indicating that this behavior depended to some extent on the excitatory neurotransmission via not only muscarinic but also NMDA receptors in the hippocampus. Electrophysiologically, activation of the NMDA receptor is an absolute requirement for induction of long-term potentiation in the hippocampus, which models synaptic plasticity and is hypothesized to be a neurobiological mechanism underlying memory processes Collingridge and Briss, 1987, Bliss and Collingridge, 1993. Thus, to elucidate the functional interactions between interleukin-1β in the hippocampus and the cholinergic or glutamatergic neuronal activity involved in regulating the memory process, we examined the effects of cholinergic activation by the cholinesterase inhibitor physostigmine and of glutamatergic activation by d-cycloserine, a partial agonist at the glycine binding site on the NMDA receptor/channel complex, on the working memory performance changed by intrahippocampal injection of interleukin-1β.

Section snippets

Animals

Male Wistar-strain rats (8–10 weeks old) were obtained from Japan SLC. The initial free-feeding weights were 230–250 g, and the rats were placed on a deprivation schedule to maintain their weights at approximately 80% of the free-feeding level. The rats were housed in groups of four or five per cage at a constant temperature (23±2 °C), with a 12-h light–dark cycle (light period 07:00–19:00 h), and with water freely available. These experiments were conducted in accordance with the Guide for the

Results

As shown in Fig. 2, interleukin-1β at doses of 32 and 100 ng/side, administered bilaterally into the dorsal hippocampus, increased the number of working memory errors significantly and dose-dependently (P<0.05 and 0.01, respectively), although it had no effect on the number of errors in the first trial and latency. The increase in working memory errors induced by intrahippocampal administration of 100 ng/side interleukin-1β was significantly and dose-dependently reduced by concurrent injection

Discussion

The three-panel runway task allows us to assess hippocampus-dependent working memory processes in rats, since the working memory in this task is highly sensitive to disruption by dorsal hippocampal lesions (Kitajima et al., 1992). The present study demonstrated that interleukin-1β impaired working memory in rats when administered into the dorsal hippocampus and that the effect was prevented by concurrent injection of interleukin-1 receptor antagonist, interleukin-1 ra. These results indicate

Conclusion

The present study demonstrated that intrahippocampal administration of interleukin-1β induced impairment of working memory via the interleukin-1 receptor and this impairment was ameliorated by increases in cholinergic and glutamatergic transmission. Taken together, it is suggested that interleukin-1β-induced working memory impairment is due to decreases in these neural transmissions in the hippocampus.

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Involvement of cholinergic and glutamatergic functions in working memory impairment induced by interleukin-1β in rats

Abstract

Introduction

Section snippets

Animals

Results

Discussion

Conclusion

Neuroscience

Trends Neurosci.

Lancet

Jpn. J. Pharmacol.

Jpn. J. Pharmacol.

Brain Res.

Neuroscience

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Brain Res.

Brain Res.

Brain Res.