Elsevier

Neuroscience Research

Volume 57, Issue 2, February 2007, Pages 306-313
Neuroscience Research

Selective cognitive dysfunction in mice lacking histamine H1 and H2 receptors

https://doi.org/10.1016/j.neures.2006.10.020Get rights and content

Abstract

Previous pharmacological experiments provide conflicting findings that describe both facilitatory and inhibitory effects of neuronal histamine on learning and memory. Here, we examined learning and memory and synaptic plasticity in mice with a null mutation of gene coding histamine H1 or H2 receptor in order to clarify the role of these receptors in learning and memory processes. Learning and memory were evaluated by several behavioral tasks including object recognition, Barnes maze and fear conditioning. These behavioral tasks are highly dependent on the function of prefrontal cortex, hippocampus or amygdala. Object recognition and Barnes maze performance were significantly impaired in both H1 receptor gene knockout (H1KO) and H2 receptor gene knockout (H2KO) mice when compared to the respective wild-type (WT) mice. Conversely, both H1KO and H2KO mice showed better auditory and contextual freezing acquisition than their respective WT mice. Furthermore, we also examined long-term potentiation (LTP) in the CA1 area of hippocampus in H1KO and H2KO mice and their respective WT mice. LTP in the CA1 area of hippocampus was significantly reduced in both H1KO and H2KO mice when compared with their respective WT mice. In conclusion, our results demonstrate that both H1 and H2 receptors are involved in learning and memory processes for which the frontal cortex, amygdala and hippocampus interact.

Introduction

Neuronal histamine has been implicated in a variety of brain functions including learning and memory (Brown et al., 2001, Haas and Panula, 2003). Central histaminergic neurons are located exclusively in the tuberomammillary nucleus of posterior hypothalamus, from where they project diffusely to all regions of brain (Watanabe et al., 1984, Panula et al., 1984). Although histamine receptors distribution in the brain has been shown to considerably differ among species, high density of both postsynaptically located histamine H1 and H2 receptors has been found in the cortex, hypothalamus and other limbic regions including hippocampus and amygdala (Pollard and Bouthenet, 1992, Ryu et al., 1995). These brain regions are closely involved in cognition and emotion. Recent evidence has shown that activation of histamine receptor subtypes regulates neuronal intracellular signaling pathways, such as mitogen-activated protein kinases (MAPK) cascade, and modulates plastic changes, both of which are early cellular mechanisms likely to be involved in cognitive processes, such as memory consolidation (Brown et al., 1995, Drutel et al., 2001). Furthermore, many recent studies have demonstrated that histaminergic neuron system influences learning and memory by modulating cholinergic functions. Indeed, systemic and intracerebral administration of histaminergic agonists or antagonists has been shown to affect acetylcholine (ACh) release in the brain and modulate learning and memory (Passani et al., 2000a, Passani et al., 2000b, Bacciottini et al., 2001). Both in vitro (Arrang et al., 1995) and in vivo (Blandina et al., 1996) experiments demonstrated that histamine H3 antagonists increased the cholinergic tone in the cortex. Moreover, mice in which histidine decarboxylase (HDC), a histamine-forming enzyme, was genetically inactivated showed increased ACh content in the frontal cortex but reduced ACh levels in the neostriatum (Dere et al., 2004).

Although it is well known that sedative antihistamines induce cognitive decline in human through blockage of H1 receptor (Yanai et al., 1995, Okamura et al., 2000), both facilitatory and inhibitory effects of neuronal histamine on learning and memory have been described in animal behavioral studies. For instance, it was found that intracerebroventricular administration of histamine facilitates the retention of step-down inhibitory avoidance behavior (De Almeida and Izquierdo, 1986), while its depletion impairs the acquisition of active avoidance response (Kamei et al., 1993). Moreover, systemic administration of new potent and selective H3 receptor antagonists has been shown to improve cognitive performance and social interaction (Fox et al., 2003). These results suggest that activation of histaminergic neurotransmission improves learning and memory. Conversely, a negative influence of neuronal histamine on learning and memory has also been suggested. Particularly, it has been reported that bilateral lesion of the tuberomammillary nuclei improves performance in several learning and memory paradigm (Huston et al., 1997). In addition, a recent study using histidine decarboxylase gene knockout mice suggests that disruption of brain histamine synthesis can have both memory promoting and suppressive effects via distinct and independent mechanisms (Dere et al., 2003). Interestingly, we recently reported that blockage of histamine H1 receptor improves the impaired cognition by social isolation stress in mice (Dai et al., 2005). As learning and memory are complex processes that consist of related but dissociable events involving distinct brain regions, the contradictory results mentioned above suggest most likely that neuronal histamine affects learning and memory processes differently in different brain regions and conditions (Passani et al., 2000a, Passani et al., 2000b).

In this study, behavioral and electrophysiological studies were performed to examine learning and memory, and synaptic plasticity in mice with null mutation of the gene coding histamine H1 or H2 receptor subtype.

Section snippets

Animals

Histamine H1 receptor gene knockout (H1KO) and H2 receptor gene knockout (H2KO) mice were generated by homologous recombination as previously described (Inoue et al., 1996, Kobayashi et al., 2000). Male H1KO, H2KO mice and their respective wild-type (WT) mice weighting 25–35 g were used in this study. They were bred in our laboratory, and have been backcrossed eight times with C57BL mice. The mice were housed in groups of four to six mice in a temperature (22 ± 3 °C) and humidity (55 ± 10 °C)

Object recognition test

To examine H1KO and H2KO mice ability for cognition and memory, these mice were subjected to object recognition test, which is based on the spontaneous exploration of novel and familiar objects (Rothblat and Kromer, 1991, Dodart et al., 1997). Normal animals will spend more time exploring a novel object than a familiar one. Although both H1KO and H2KO mice tended to decrease locomotor activity during all trials when compared with their respective WT mice (data not shown), there was no genotype

Discussion

In this study, we examined learning and memory, and synaptic plasticity in mice with null mutation of the genes that encode histamine H1 and H2 receptor subtypes. A notable finding of the present study is that deletion of H1 and H2 receptor subtypes produces similar phenotypes that have both enhanced and deficient memory. H1KO and H2KO mice similarly showed enhanced learning and memory in the auditory and contextual fear conditioning tests, but impaired learning ability in the object

Acknowledgements

This work was supported in part by Grants-in-Aid for scientific research (#17390156; #14370027; #12557007) from the Japan Society of Promotion of Science (JSPS) and a 21st Century COE program (Bio-nano-technology) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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