Histamine H₁ receptor knockout mice exhibit impaired spatial memory in the eight‐arm radial maze

Abstract

Background and purpose:In the mammalian brain, histaminergic neurotransmission is mediated by the postsynaptic histamine H1 and H2 receptors and the presynaptic H3 autoreceptor, which also acts as a heteroreceptor. The H1 receptor has been implicated in spatial learning and memory formation. However, pharmacological and lesion studies have revealed conflicting results. To examine the involvement of histamine H1 receptor in spatial reference and working memory formation, H1 receptor knockout mice (KO) were tested in the eight-arm radial maze. Previously, we found that the H1 receptor-KO mice showed reduced emotionality when confronted with spatial novelty. As it is known that emotions can have an impact on spatial learning and memory performance, we also evaluated H1 receptor-KO mice in terms of emotional behaviour in the light-dark box. Experimental approach: Mice lacking the H1 receptor and wild-type mice (WT) were tested for spatial reference and working memory in an eight-arm radial maze with three arms baited and one trial per day. Emotional behaviour was measured using the light-dark test. Key results: The H1 receptor-KO mice showed impaired spatial reference and working memory in the radial maze task. No significant differences between H1 receptor-KO and WT mice were observed in the light-dark test. Conclusions and implications:The spatial memory deficits of the H1 receptor-KO mice might be due to the reported changes in cholinergic neurochemical parameters in the frontal cortex and the CA1 subregion of the hippocampus, to impaired synaptic plasticity in the hippocampus, and/or to a dysfunctional brain reward/reinforcement system.

Memory retrieval of inhibitory avoidance requires histamine H 1 receptor activation in the hippocampus

“…This result strongly supports the notion that histamine signaling through H 1 receptors is essential for IA-LTM retrieval. Our results are in agreement with previous reports showing that the H 1 receptor is implicated in memory processes, because H 1 receptor KO mice showed impaired memory performance in the Barnes maze (49) and the radial maze task (50). Accordingly, long-term potentiation in the CA1 was significantly reduced in H 1 -KO compared with WT mice (49).…”

Therapeutics of Neurotransmitters in Alzheimer’s Disease

“…Interestingly, HDC and H1R knockout mice have also shown behavioral and neurochemical alterations [177, 179, 180]. Adult H1R deficient mice also exhibit the severe impairment in learning and memory, thus affecting both spatial and working memory [181, 182], novel objects [183], temporal order memory [184], and the retrieval of formed episodic memories [185]. However, in these H1R deficient mice, there is an increase in ACh concentrations in the frontal cortex and amygdala [183].…”

Neuronal histamine and cognitive symptoms in Alzheimer's disease

“…Both improvements and impairments in cognitive behavior have been reported after H1R antagonism depending on the reinforcement contingencies of the behavioral paradigm, motivational status and the stress-level experienced by the animal (for review see (Dere et al, 2010). Given that H1R antagonism can impair cognitive performance and given that H1R knockout mice show a dementia-like phenotype together with impaired neurogenesis (Ambree et al, 2014;Dere et al, 2008;Zlomuzica et al, 2013Zlomuzica et al, , 2009Zlomuzica et al, , 2008, it remains to be determined whether the possible beneficial effects of H1R antagonists on neuroinflammation would justify the concomitant adverse effects on cognition and adult neurogenesis in patients with Alzheimer's disease.…”

“…Adult H1R deficient mice exhibit a severe form of dementia that includes a global learning and memory impairment affecting both spatial and working memory (Ambree et al, 2014;Zlomuzica et al, 2009), novel objects-induced place preference , temporal order memory (Zlomuzica et al, 2013), and the formation and retrieval of episodic-like memories (Dere et al, 2008).…”