Kazutaka Ikeda

Impairment of motor coordination, Purkinje cell synapse formation, and cerebellar long-term depression in GluRδ2 mutant mice

Of the six glutamate receptor (GluR) channel subunit families identified by molecular cloning, five have been shown to constitute either the AMPA, kainate, or NMDA receptor channel, whereas the function of the delta subunit family remains unknown. The selective localization of the delta 2 subunit of the GluR delta subfamily in cerebellar Purkinje cells prompted us to examine its possible physiological roles by the gene targeting technique. Analyses of the GluR delta 2 mutant mice reveal that the delta 2 subunit plays important roles in motor coordination, formation of parallel fiber-Purkinje cell synapses and climbing fiber-Purkinje cell synapses, and long-term depression of parallel fiber-Purkinje cell synaptic transmission. These results suggest a close relationship between synaptic plasticity and synapse formation in the cerebellum.

Cloning and expression of the ε4 subunit of the NMDA receptor channel

The primary structure of a novel subunit of the mouse NMDA (N‐methyl‐d‐aspartate) receptor channel, designated ε4, has been revealed by cloning and sequencing the cDNA. The ε4 subunit shares high amino acid sequence identity with the ε1, ε2 and ε3 subunits of the mouse NMDA. receptor channel, thus constituting the ε subfamily of the glutamate receptor channel. Expression from cloned cDNAs of the ε4 subunit together with the ζ1 subunit in Xenopus oocytes yields Functional NMDA receptor channels. The ε4/ζ1 heteromeric channel exhibits high apparent affinities for agonists and low sensitivities to competitive antagonists. The ε4 subunit is thus distinct in Functional properties from the ε1, ε2 and ε3 subunits, and contributes further diversity of the NMDA receptor channel.

Reduced spontaneous activity of mice defective in the ε4 subunit of the NMDA receptor channel

In an attempt to examine the functional significance of the molecular diversity of theN-methyl-d-aspartate (NMDA) receptor channel, we generated mutant mice defective in the e4 subunit by gene targeting technique. The e4 subunit mutant mice grew and mated normally. No e4 subunit protein was detected in the homozygous mutant mice, and the amount of the e4 subunit protein of 155 kDa was reduced in the heterozygous mice. The expressions of the other NMDA receptor channel subunit mRNAs were not appreciably affected by the mutation. The mutant mice exhibited no obvious histological abnormalities in the various brain regions and in the formation of whisker-related neuronal patterns (barrels, barreloids and barrelettes). In an open field test, however, the e4 subunit mutant mice showed a reduced spontaneous activity. No significant difference was found between the heterozygous and mutant mice in motor activity and anxiety tests. These results suggest that the e4 subunit of the NMDA receptor channel plays a role in vivo in controlling the spontaneous behavioral activity.

Comparison of the Three Mouse G‐Protein‐Activated K+ (GIRK) Channels and Functional Couplings of the Opioid Receptors with the GIRKI Channela

The opioid, dopamine and serotonin receptors are crucial molecules in drug addictions. Previous studies of signal transduction pathways from these receptors have shown that their activation alters membrane conductances for K+ and Ca*+ and levels of second messengers such as CAMP and inositol 1,4,5-triphosphate, each through G-protein activation, and ultimately results in the activation or inhibition of neural firing and of neurotransmitter release. In the signal transduction from these receptors, the G-protein-activated K+ channel (GIRK channel), a member of a family of inward-rectifier K+ channels, is considered to play an important r ~ l e . ~ , ~ Recent molecular biological studies have revealed the presence of at least three GIRK channels in the brain, GIRK1, GIRK2 and GIRK3 channels.5-* However, details of these GIRK channels including those regarding their in vivo relationships among each other and their functional coupling with various receptors remain largely unknown.

Early manifestation of depressive‐like behavior in transgenic mice that express dementia with Lewy body‐linked mutant β‐synuclein

We previously generated transgenic (Tg) mice that expressed P123H β‐synuclein (βS), a dementia with Lewy body‐linked mutant βS. Notably, these mice recapitulated neurodegenerative features of Lewy body disease, reflected by motor dysfunction, greater protein aggregation, and memory impairment. Since recent studies suggested that non‐motor symptoms, such as depression, might be manifested in the prodromal stage of Lewy body disease, the main objective of the present study was to investigate the early expression of behavior in P123H βS Tg mice.

A pharmacogenetics approach to pain management

Opioid analgesics are widely used as effective analgesics for the treatment of moderate‐to‐severe pain. However, the analgesic efficacy of opioids is well known to vary widely among individuals, and effective pain treatment is hampered by vast individual differences. Although these differences in opioid requirements have been attributed to various factors, genetic factors are becoming increasingly relevant to the development of genome science.

Association between rs2275913 single-nucleotide polymorphism of the interleukin-17A gene and perioperative analgesic use in cosmetic orthognathic surgery

Interleukin‐17A (IL‐17A) plays an essential role in tissue inflammation by inducing proinflammatory cytokine and chemokine production and is related to innate immune reactions. IL‐17A also contributes to neuroinflammation, neuropathic pain, and mechanical hypersensitivity after peripheral nerve injury in rodents. To clarify the contribution of IL‐17A to pain‐related phenotypes in humans, we investigated the association between pain‐related phenotypes and the rs2275913 single‐nucleotide polymorphism (SNP) of the IL‐17A gene, which has been reported to be associated with rheumatoid arthritis, ulcerative colitis, and some cancers.

Gamma-aminobutyric acid transaminase genetic polymorphism is a candidate locus for responsiveness to opioid analgesics in patients with cancer pain: An exploratory study

Cancer pain impairs not only physical functions but also social functions and roles. Consequently, the overall health‐related quality of life of patients with cancer pain deteriorates. Opioid analgesics are recommended for treating moderate to strong cancer pain. Advances in human genome research have fueled a growing interest to understand individual differences in responsiveness to opioid analgesics. This study aimed to explore and identify novel loci for genes predisposing an individual to opioid analgesic responsiveness.

Reward-enhancing effect of methylphenidate is abolished in dopamine transporter knockout mice: A model of attention-deficit/hyperactivity disorder

Attention‐deficit/hyperactivity disorder is a heterogeneous neurobiological disorder that is characterized by inattention, impulsivity, and an increase in motor activity. Although methylphenidate has been used as a medication for decades, unknown is whether methylphenidate treatment can cause drug dependence in patients with attention‐deficit/hyperactivity disorder. This study investigated the reward‐enhancing effects of methylphenidate using intracranial self‐stimulation in an animal model of attention‐deficit/hyperactivity disorder, dopamine transporter knockout mice.

Association between the rs7583431 single nucleotide polymorphism close to the activating transcription factor 2 gene and the analgesic effect of fentanyl in the cold pain test

Activating transcription factor 2 (ATF2) is a member of the leucine zipper family of DNA binding proteins and is widely distributed in tissues. Several recent studies have demonstrated that this protein is involved in mechanisms that are related to pain and inflammation. However, unclear is whether polymorphisms of the ATF2 gene, which encodes the human ATF2 protein, influence pain or analgesic sensitivity. This study examined associations between the analgesic effect of fentanyl in the cold pressor‐induced pain test and polymorphisms in the ATF2 gene in 355 Japanese subjects.