Biochemical and Biophysical Research Communications
Critical involvement of the orbitofrontal cortex in hyperlocomotion induced by NMDA receptor blockade in mice
Introduction
N-methyl-d-aspartate (NMDA) receptors play a critical role in excitatory neurotransmission in the central nervous system and are involved in learning, memory and synaptic development [1]. Alterations of NMDA receptor functions have been reported in several brain disorders such as schizophrenia and autism spectrum disorder [1], [2]. Noncompetitive NMDA receptor antagonists, such as phencyclidine, MK-801 and ketamine, produce psychotic symptoms similar to a clinical syndrome of schizophrenia, which has led researchers to propose a glutamate hypofunction model of schizophrenia [2], [3], [4]. In rodents, models of schizophrenia-like behaviors, such as hyperlocomotion, impaired social interaction and novel object recognition, induced by NMDA receptor antagonists are widely used to study the pathophysiology of schizophrenia, the mechanism of action of antipsychotic drugs, and the identification of novel treatments [5]. These behavioral abnormalities are more effectively ameliorated by atypical antipsychotics, such as clozapine, than typical antipsychotics [3], [5], [6]. Because NMDA receptors are widely expressed throughout the central nervous system and play a wide array of functions, it is important to understand the brain regions responsible for the effects of NMDA receptor antagonists and the role of each region. Previous studies have suggested the importance of several brain regions in NMDA receptor antagonist-induced psychotic behavior, including the medial prefrontal cortex [7], [8], [9]. However, the precise function of different regions remains to be fully elucidated.
A growing number of studies have investigated the mechanisms underlying brain dysfunction in animal models of psychiatric disorders [10], [11], [12]. For this purpose, we previously generated mice lacking pituitary adenylate cyclase-activating polypeptide [13], [14]. The mutant mice exhibited remarkable behavioral abnormalities related to psychiatric disorders [15], [16], [17] that were amenable to atypical antipsychotics [18], [19] and the selective metabotropic glutamate 2/3 receptor agonist [20]. We also revealed that prostaglandin D2 signaling mediated by the type 2 receptor DP2/CRTH2 is involved in MK-801-induced cognitive impairments, proposing a novel therapeutic mechanism for cognitive disorders [21]. More recently, we developed cell imaging tools to examine neuronal processes, such as a mouse embryonic stem cell line that expresses green fluorescent protein driven by the enhancer of Pet-1/Fev to assess serotonergic differentiation [22], and a lentiviral system for simultaneous neuron- and astrocyte-specific fluorescent labeling in vivo [23]. These studies aimed to address brain region-based mechanisms to help understand pathological processes implicating alterations of major neurotransmitters, including glutamate.
In line with these studies, here we examined the brain regions responsible for MK-801 action using Arc::dVenus reporter mice, in which the expression of dVenus, a destabilized form of the fluorescence protein Venus, is driven by the promoter of the immediate early gene Arc to detect neuronal activation [24]. In the present study, we identified the layer 2/3 of the medial part of the orbitofrontal cortex (OFC) as the brain region predominantly activated by MK-801 and examined its role in MK-801-induced hyperlocomotion.
Section snippets
Animals and drugs
The generation of Arc::dVenus transgenic mice was previously reported [24]. Wild-type C57BL/6J mice were purchased from SLC (Hamamatsu, Japan). Mice were maintained on a 12-h light–dark cycle (lights on at 8:00 a.m.) at a controlled room temperature (22 ± 1 °C). Water and food (CMF, Oriental Yeast, Osaka, Japan) were available ad libitum. Male mice were used at 8–11 weeks of age. All animal care and handling procedures were approved by the Animal Care and Use Committee of Osaka University. All
MK-801 induces dVenus expression predominantly in the OFC in Arc::dVenus mice
The brain regions whose activities are modulated by the NMDA receptor antagonist MK-801 were examined in sagittal sections of Arc::dVenus mice treated with MK-801 (0.5 mg/kg body weight). MK-801-dependent dVenus expression was predominantly observed in the OFC, located in the ventral part of the prefrontal cortex (Fig. 1). Other regions, including the retrosplenial cortex, also showed dVenus expression but they were not dependent on MK-801.
A detailed analysis in coronal sections revealed that
Discussion
The importance of the medial prefrontal cortex in NMDA receptor antagonist-induced psychotic behavior has been suggested by studies using lesion, local administration and electrophysiological experiments [7], [8], [9]. The medial prefrontal cortex can be divided into the following subregions: the anterior cingulate cortex, prelimbic cortex, infralimbic cortex and the medial part of the OFC, which can be differentiated based on efferent and afferent projection patterns [29]. Although studies
Conflict of interest
None.
Acknowledgments
We are grateful to Dr. Megumi Eguchi (Gifu University) for her support with the Arc::dVenus reporter mice. This work was supported in part by JSPS KAKENHI Grant Numbers JP26293020 (H.H.), JP26670122 (H.H.), JP15H01288 (H.H.), JP14J01466 (K.S.), JP15K14964 (A.K.); the JSPS Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers, Grant No. S2603 (H.H.); the JSPS Research Fellowships for Young Scientists (K.S.); the SRPBS from AMED (H.H.); and
References (34)
- et al.
Genetic animal models: focus on schizophrenia
Trends Neurosci.
(2001) - et al.
N-methyl-d-aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia?
Brain Res. Bull.
(2010) Calcium signaling dysfunction in schizophrenia: a unifying approach
Brain Res. Brain Res. Rev.
(2003)- et al.
Prostaglandin D2 signaling mediated by the CRTH2 receptor is involved in MK-801-induced cognitive dysfunction
Behav. Brain Res.
(2016) - et al.
Simultaneous neuron- and astrocyte-specific fluorescent marking
Biochem. Biophys. Res. Commun.
(2015) - et al.
In vivo and in vitro visualization of gene expression dynamics over extensive areas of the brain
Neuroimage
(2009) - et al.
Risperidone attenuates MK-801-induced hyperlocomotion in mice via the blockade of serotonin 5-HT 2A/2C receptors
Eur. J. Pharmacol.
(2007) - et al.
Dose-response characteristics of ketamine effect on locomotion, cognitive function and central neuronal activity
Brain Res. Bull.
(2006) - et al.
Diversity in NMDA receptor composition: many regulators, many consequences
Neuroscientist
(2013) - et al.
Glutamate synapses in human cognitive disorders
Annu. Rev. Neurosci.
(2015)
The role of serotonin in the NMDA receptor antagonist models of psychosis and cognitive impairment
Psychopharmacology (Berl.)
Clozapine, but not haloperidol, reverses social behavior deficit in mice during withdrawal from chronic phencyclidine treatment
Neuroreport
Prefrontal cortical involvement in phencyclidine-induced activation of the mesolimbic dopamine system: behavioral and neurochemical evidence
Psychopharmacology (Berl.)
NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons
J. Neurosci.
Local blockade of NMDA receptors in the rat prefrontal cortex increases c-Fos expression in multiple subcortical regions
Acta Neurobiol. Exp. (Wars.)
Inositol 1,4,5-trisphosphate receptor-mediated calcium release in Purkinje cells: from molecular mechanism to behavior
Cerebellum
NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease
Nat. Rev. Neurosci.
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