Original articleModification of AMPA receptor properties following environmental enrichment
Introduction
Over the past two decades, environmental stimulation and enrichment have been thought to give the positive effects on the brain and brain functions [1], [2]. Although environmental enrichment is a vague term, one standard definition of an environmental enrichment is ‘a combination of complex inanimate and social stimulation’ [3]. This definition implies that the relevance of single contributing factors cannot be easily isolated but there are good reasons to assume that it is the interaction of factors that is an essential element of an enriched environment, and not any single element that is hidden in the complexity [1]. In the animal experiments, previous reports demonstrated that environmental enrichment can produce structural, functional, and biochemical modifications in the brain such as increased neurogenesis [4], inhibition of spontaneous apoptosis [5], increase of synaptic density [6], increased spatial memory acquisition [7], and increased mRNA of nerve growth factor and neurotrophin-3 [8], [9]. Along these lines, we recently reported that enriched environment increases brain noradrenalin contents in mice [10].
It is possible that these changes, which occurred in the brain were induced by environmental enrichment, and may be related to synaptic plasticity. Kainate/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) excitatory amino acid receptors are thought to be involved in synaptic plasticity [11]. The function and expression of AMPA receptors are regulated by its subunit composition of GluR 1, 2, 3, and 4 [12]. Among the four subtypes of AMPA receptor, GluR2 and GluR4 play important roles in the brain. The GluR2 and GluR4 subunits are widely expressed [13] and is a critical subunit for the determination of AMPA receptor functions. Receptors lacking GluR2 subunits are known to be Ca2+-permeable [12], [14], [15], [16], suggesting that reduction of GluR2 subunit expression might enhance glutamate excitotoxicity within neurons due to increasing cytosolic Ca2+ [14], [15]. GluR2 subunit is also thought to be important for synaptic targeting and stabilization of AMPAs and the expression of hippocampal long term depression (LTD) by interacting with a number of intracellular proteins such as GRIP1, ABP, NSF, and PICK1 [17], [18]. Transient expression of GluR4 in rat hippocampus is important in the spontaneous electric activity [19].
In this study, we therefore examined the expression of GluR2 and GluR4 subunits of AMPA receptor in the condition of environmental enrichment.
Section snippets
Environmental enrichment and tissue preparation
At 4 weeks of age, male ICR mice (SEASCO, Saitama, Japan) were randomly assigned to either environmentally enriched housing (enriched animals; n=11) or regular cages (control; n=10). The control mice and the enriched mice were housed as described previously [10]. Briefly, the animals were maintained on a 12-h light/12-h dark schedule (lights on at 08:00 h) with water and food ad libitum. They were divided into two groups and reared for 40 days in control or enriched condition. In the control
Results
Fig. 1 shows the effect of enriched environment on the expression of GluR mRNA in the hippocampus detected by real-time PCR. As shown in the figure, GluR2 and GluR4 mRNA expression was significantly increased compared to the control group. Expression of GAPDH, an internal control, in the enriched group was not statistically different compared to control group.
The effects of enriched environment on the GluR2 protein expression in the hippocampus were shown in Fig. 2. Specific single bands were
Discussion
In this study, we demonstrated that both expressions of GluR2 and GluR4 in the hippocampus were significantly increased in the enriched animals compared to the control animals. These results indicate that environmental enrichment alters the expression of GluR2 and GluR4 and thus may regulate the functions of AMPA-type receptors, which might modify glutamatergic signal transduction.
Neuronal development can be modified by many factors such as genetical factor and exogenous factor. We demonstrated
Acknowledgements
This research was supported by Grant-in-Aid for the Japan Society for the Promotion of Science, and special coordination Funds of the Ministry of Education, Culture, Sports, Science and Technology. And we express our regret over the death of Dr Nobuo Okado.
References (27)
- et al.
Environmental enrichment and the brain
Prog Brain Res
(2002) - et al.
Social grouping cannot account for cerebral effects of enriched environments
Brain Res
(1978) - et al.
Changes in brain nerve growth factor levels and nerve growth factor receptors in rats exposed to environmental enrichment for one year
Neuroscience
(1999) - et al.
Expression of neurotrophin-3 mRNA in the rat visual cortex and hippocampus is influenced by environmental conditions
Neurosci Lett
(1996) - et al.
Environmental enrichment results in higher levels of nerve growth factor mRNA in the rat visual cortex and hippocampus
Behav Brain Res
(1998) - et al.
An enriched environment increases noradrenalin concentration in the mouse brain
Brain Res
(2002) - et al.
Regulation of AMPA receptors during sunaptic plasticity
Trends Neurosci
(2002) - et al.
The GluR2 (GluR-B) hypothesis: Ca2+-permeable AMPA receptors in neurological disorders
Trends Neurosci
(1997) - et al.
GluR2 knockdown reveals a dissociation between [Ca2+]i surge and neurotoxicity
Neurochem Int
(2003) - et al.
NSF binding to GluR2 regulates synaptic transmission
Neuron
(1998)
Synaptic transmission and plasticity in the absence of AMPA glutamate receptor GluR2 and GluR3
Neuron
Long term depletion of serotonin leads to selective changes in glutamate receptor subunits
Neurosci Res
Glutamate receptor mechanisms in human epileptic dysplastic cortex
Epilepsy Res
Cited by (64)
Differential impact of stress and environmental enrichment on corticolimbic circuits
2020, Pharmacology Biochemistry and BehaviorCitation Excerpt :EE also alters neurotransmission across the brain, under both basal and stress conditions. In the hippocampus, EE increases the expression of glutamate receptors, specifically α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (van Praag et al., 2000; Mlynarik et al., 2004; Gagné et al., 1998; Naka et al., 2005; Lee et al., 2003) and N-methyl-d-aspartate (NMDA) receptors (Lee et al., 2003; Andin et al., 2007). EE decreases glutamate transporter expression, which would also increase glutamate neurotransmission via decreased astrocytic uptake of glutamate in the synaptic cleft (Andin et al., 2007).
Therapeutic efficacy of environmental enrichment for substance use disorders
2020, Pharmacology Biochemistry and BehaviorEnvironmental enrichment: Evidence for an unexpected therapeutic influence
2015, Experimental NeurologyProtein profiles associated with context fear conditioning and their modulation by memantine
2014, Molecular and Cellular Proteomics