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ABSTRACT: It has been reported earlier that interactions between Cav2.1α1 and calcium/calmodulin-dependent protein kinase II (CaMKII) in the presynaptic fraction and between the NMDA receptor subunit
NR2B and CaMKII in the postsynaptic density (PSD) fraction are important for neuronal function. Cav2.1α1, CaMKII, and NR2B are predominantly expressed in the hippocampus. To examine the above interactions and CaMKII activity in
the hippocampal presynapse and PSD of Rolling Nagoya mice carrying a mutation in Cav2.1α1 subunit, we performed immunoprecipitation and Western blot analyses. In the presynapse, the interaction between Cav2.1α1 and CaMKII and the phosphorylation of CaMKII (at Thr286) and its substrate Synapsin I (at Ser603) were decreased in mutant
mice compared to wild-type mice. In the PSD, a similar pattern was observed for the interaction between NR2B and CaMKII and
the phosphorylation of CaMKII (at Thr286) and its substrate AMPA receptor subunit glutamate receptor 1 (at Ser831) between
mutant and wild-type mice. Our data indicate that disruption of the interaction between Cav2.1α1 and CaMKII may down-regulate presynaptic CaMKII activity and that Rolling Nagoya mice would be a useful model for examining presynaptic function.
Keywords
Rolling Nagoya mice-Interaction between Cav2.1α1 and CaMKII-Presynaptic CaMKII activity-Immunoprecipitation-Western blot
Journal of Molecular Neuroscience 04/2012; 41(2):223-229. · 2.50 Impact Factor
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ABSTRACT: The role of the P/Q-type voltage-gated Ca(2+) channels (VGCCs) in release of neurotransmitters involved in nociception is not fully understood. Rolling mouse Nagoya (tg(rol)), a P/Q-type channel mutant mouse, expresses P/Q-type VGCC whose activation curve has a higher half activation potential and a smaller slope factor than the wild type channel. We previously reported that tg(rol) mice showed hypoalgesic responses to noxious stimuli. In this study, we examined the VGCC current in dorsal root ganglion (DRG) neurons by the whole-cell patch-clamp method. Both ω-agatoxin IVA (0.1 μM) and ω-conotoxin GVIA (1 μM) inhibited the VGCC current by about 40-50% in both the homozygous tg(rol) (tg(rol)/tg(rol)) and wild type (+/+) mice. The voltage-activation relationships of the total VGCC current and the ω-agatoxin IVA-sensitive component in the tg(rol)/tg(rol) mice shifted positively compared to the +/+ mice, whereas that sensitive to the ω-conotoxin GVIA was not different between the two genotypes. The time constant of activation of the VGCC current at -20 mV was longer in the tg(rol)/tg(rol) mice than in the +/+ mice. These changes in the properties of the VGCC in the tg(rol)/tg(rol) mouse may reduce the amount of the released neurotransmitters and account for the hypoalgesic responses.
Neuroscience Research 04/2012; 73(3):199-206. · 2.25 Impact Factor
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ABSTRACT: Heterozygous rolling Nagoya (rol/+) mice with a Ca(V)2.1α₁ mutation show normal Y-maze behavior. Intra-accumbens injection of N-methyl-d-aspartate (NMDA; 0-2.0 μg/side) induced similar spontaneous alternations in wild-type and rol/+ mice; injections of NMDA receptor antagonist MK-801 (0.5 μg/side) or Ca(V)2.1 inhibitor levetiracetam (0.1 μg/side) did not affect controls but decreased spatial cognition in rol/+ mice, suggesting that Ca(V)2.1-mediated NMDA receptor signaling in the nucleus accumbens is involved in short-term spatial learning.
Behavioural brain research 04/2011; 218(2):353-6. · 3.22 Impact Factor
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ABSTRACT: The ganglioside GM3 synthase (SAT-I), encoded by a single-copy gene, is a primary glycosyltransferase for the synthesis of complex gangliosides. Although its expression is tightly controlled during early embryo development and postnatal development and maturation in the brain, the physiological role of ganglioside GM3 in the regulation of neuronal functions has not been elucidated. In the present study, we examined motor activity, cognitive and emotional behaviors, and drug administration in juvenile GM3-knockout (GM3-KO) mice. GM3-KO male and female mice showed hyperactivity in the motor activity test, Y-maze test, and elevated plus maze test. In the Y-maze test, there was significantly less spontaneous alternation behavior in GM3-KO male mice than in wild-type mice. In the elevated plus maze test, the amount of time spent on the open arms by GM3-KO male mice was significantly higher than that of sex-matched wild-type mice. In contrast, there was no significant difference between GM3-KO and wild-type female mice in these tests. Thus, juvenile GM3-KO mice show gender-specific phenotypes resembling attention-deficit hyperactivity disorder (ADHD), namely hyperactivity, reduced attention, and increased impulsive behaviors. However, administration of methylphenidate hydrochloride (MPH) did not ameliorate hyperactivity in either male or female GM3-KO mice. Although these data demonstrate the involvement of ganglioside GM3 in ADHD and the ineffectiveness of MPH, the first-choice psychostimulant for ADHD medication, our studies indicate that juvenile GM3-KO mice are a useful tool for neuropsychological studies.
Biochemical and Biophysical Research Communications 02/2011; 406(4):524-8. · 2.48 Impact Factor
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ABSTRACT: Heterozygous rolling Nagoya (rol/+) mice carrying Ca(V)2.1 alpha(1) mutation demonstrated normal behavior in Y maze test. Similar spontaneous alternation patterns were noted in wild-type and rol/+ mice injected with N-methyl-D-aspartate (NMDA; 0-50mg/kg, sc). Systemic injection of NMDA receptor blocker (MK-801; 0.05 mg/kg, ip) or intrahippocampal injection of MK-801 (0.5 microg/side), which had no effect in wild-type controls, decreased spatial cognition in rol/+ mice. These results indicate that Ca(V)2.1 alpha(1) mutation probably through decrease in Ca(2+) influx lowers the threshold for learning impairment. The combination subthreshold pharmacological and genetic approach is useful to study functional pathways in neuronal circuits.
Behavioural brain research 11/2010; 213(1):121-5. · 3.22 Impact Factor
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ABSTRACT: Ca(V)2.1 is highly expressed in the nervous system and plays an essential role in the presynaptic modulation of neurotransmitter release machinery. Recently, the antiepileptic drug levetiracetam was reported to inhibit presynaptic Ca(V)2.1 functions, reducing glutamate release in the hippocampus, although the precise physiological role of Ca(V)2.1-regulated synaptic functions in cognitive performance at the system level remains unknown. This study examined whether Ca(V)2.1 mediates hippocampus-dependent spatial short-term memory using the object location and Y-maze tests, and perirhinal cortex-dependent nonspatial short-term memory using the object recognition test, via a combined pharmacological and genetic approach. Heterozygous rolling Nagoya (rol/+) mice carrying the Ca(V)2.1alpha(1) mutation had normal spatial and nonspatial short-term memory. A 100mg/kg dose of levetiracetam, which is ineffective in wild-type controls, blocked spatial short-term memory in rol/+ mice. At 5mg/kg, the N-methyl-D-aspartate (NMDA) receptor blocker (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), which is ineffective in wild-type controls, also blocked the spatial short-term memory in rol/+ mice. Furthermore, a combination of subthreshold doses of levetiracetam (25 mg/kg) and CPP (2.5mg/kg) triggered a spatial short-term memory deficit in rol/+ mice, but not in wild-type controls. Similar patterns of nonspatial short-term memory were observed in wild-type and rol/+ mice when injected with levetiracetam (0-300 mg/kg). These results indicate that Ca(V)2.1-mediated NMDA receptor signaling is critical in hippocampus-dependent spatial short-term memory and differs in various regions. The combination subthreshold pharmacological and genetic approach presented here is easily performed and can be used to study functional signaling pathways in neuronal circuits.
European journal of pharmacology 10/2010; 645(1-3):113-8. · 2.59 Impact Factor
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ABSTRACT: Ca(V)2.1, which is highly expressed in the nervous system, plays an essential role in presynaptic neurotransmitter release. Although recent data suggest that the antiepileptic drug levetiracetam (LEV) inhibits presynaptic Ca(V)2.1 activity, the precise physiological role of Ca(V)2.1/LEV-regulated emotional performance has not been elucidated. We examined whether Ca(V)2.1/LEV mediates emotional behavior using a combined pharmacologic and genetic approach. Heterozygous rolling Nagoya (rol/+) mice carrying the Ca(V)2.1alpha(1) mutation demonstrated normal emotional behavior. Exposure to 75mg/kg LEV, which had no effect in wild-type controls, reduced anxiety in elevated plus maze and light-dark exploration tests and reduced depression in forced swimming and tail suspension behavioral tests in rol/+ mice. Similar behavioral patterns in motor activity were noted in wild-type and rol/+ mice injected with 0-150mg/kg LEV. The phosphorylation of tryptophan hydroxylase at serine-58 and serotonin concentration were increased in the brainstems of rol/+ mice injected with 75mg/kg LEV but not in those of wild-type controls. These results indicate that Ca(V)2.1/LEV mediates serotonin signaling leading to alterations in emotion. Our results also indicate that a combination of subthreshold pharmacologic and genetic approaches can be used to study functional signaling pathways in neuronal circuits.
Pharmacology Biochemistry and Behavior 09/2010; 96(3):294-300. · 2.53 Impact Factor
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ABSTRACT: Many neuropharmacological agents modulate the activity and conformation of heptahelical G protein-coupled receptors and activate ligand-specific signaling pathways. The hallucinogenic chemical 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI), a serotonin receptor 2A (5-HT2AR) agonist, evokes extracellular signal-regulated kinase 1/2 (ERK1/2) signaling and head-twitch behavior. We previously reported that the senescence accelerated-prone mouse 6 (SAMP6) exhibited altered emotional behavior and increased levels of a serotonin-biosynthesizing enzyme compared to the senescence accelerated-resistant mouse 1 (SAMR1); however, the mechanism underlying the relationship between specific receptor signaling and behavioral phenotypes was unclear. In this study, we performed head-twitch tests and examined the total and phosphorylated levels of ERK1/2 and cAMP-responsive element-binding protein (CREB) in the bilateral somatosensory cortex to assess the differences between SAMP6 and SAMR1 using DOI. Although DOI dose-dependently increased the head-twitch response in both strains, the responses of SAMP6 given 0.3 and 1.0 mg/kg DOI were significantly greater than those of SAMR1 given DOI at the same doses. Although no dose-dependent increase in total ERK1/2 and total CREB expression was detected in response to DOI, the levels of phospho-ERK1/2 and -CREB increased in both strains. The phospho-ERK1/2 and -CREB levels in SAMP6 given 0.3 and 1.0 mg/kg DOI were significantly higher than those in SAMR1 given DOI at the same doses. These results indicate that SAMP6 increases DOI-dependent ERK1/2-CREB signaling leading to more head-twitch responses than SAMR1, and that SAMP6 could provide a useful model for examining the relationship between 5-HT2AR regulatory signaling and behavioral phenotypes.
Experimental Animals 01/2010; 59(4):441-7. · 0.92 Impact Factor
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ABSTRACT: Senescence-accelerated mouse prone 6 (SAMP6) is a model of senile osteoporosis. From 10 to 22 wk of age, SAMP6 mice were heavier than age-matched AKR/J and SAMR1 mice. Body mass indices of 10- and 25-wk-old SAMP6 mice were higher than those of age-matched AKR/J and SAMR1 mice, indicating obesity in the SAMP6 animals. We compared the blood biochemical values among SAMP6, SAMR1, and AKR/J mice to assess whether the SAMP6 strain has abnormal obesity-related parameters. Plasma glucose, triglyceride, insulin, and leptin levels were higher in 10-wk-old SAMP6 mice than in age-matched SAMR1 and AKR/J mice, whereas plasma glucagon and adiponectin levels in 25-wk-old SAMP6 were lower compared with those in age-matched SAMR1 and AKR/J. Total cholesterol levels in SAMR1 and SAMP6 mice at 10 and 25 wk of age were higher than those in AKR/J mice. Hepatic lipid levels were higher in 10- and 25-wk-old SAMP6 mice compared with age-matched AKR/J and SAMR1 animals. These results indicate that SAMP6 mice exhibit obesity and hyperlipidemia, suggesting that the SAMP6 strain is a potential tool for the study of hyperlipidemia.
Comparative medicine 10/2009; 59(5):431-6. · 1.05 Impact Factor
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ABSTRACT: Rolling Nagoya mice show ataxia and carry a mutation in the Cacna1a gene, which encodes the pore-forming alpha1 subunit of the Cav2.1 channels. Because an impaired motor function has not been examined during neonatal stages in detail, we employed a battery of tests including assessments of body weight gain, righting reflex, negative geotaxis, hind-limb suspension, and tail suspension using neonatal wild-type, heterozygous, and homozygous rolling mice. We found deterioration of body weight gain after postnatal day 8 (P8) in the homozygous mice, as well as a longer latency time to complete the righting reflex and the negative geotaxis tests after P8. Additionally, the homozygous rolling mice exhibited lower pulling and holding attempts after P8 in the hind-limb suspension test. The mice heterozygous and homozygous for the rolling mutation exhibited muscle fatigue after P10 and P8, respectively, following movement execution tests administered immediately after the first trial, suggesting that gene dosage plays an important role in determining when muscle weakness occurs. The homozygous rolling mice showed hind-limb clasping or touching after P14 during the hind-limb and tail suspension tests. Our results indicate that the gait abnormality of neonatal rolling Nagoya would be due to the combination of muscle weakness and neuronal dysfunction and that the rolling mice could be a useful model for delineating neonatal motor deficiencies.
Behavioural brain research 10/2009; 207(2):273-9. · 3.22 Impact Factor
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ABSTRACT: It has been reported earlier that interactions between Ca(v)2.1alpha(1) and calcium/calmodulin-dependent protein kinase II (CaMKII) in the presynaptic fraction and between the NMDA receptor subunit NR2B and CaMKII in the postsynaptic density (PSD) fraction are important for neuronal function. Ca(v)2.1alpha(1), CaMKII, and NR2B are predominantly expressed in the hippocampus. To examine the above interactions and CaMKII activity in the hippocampal presynapse and PSD of Rolling Nagoya mice carrying a mutation in Ca(v)2.1alpha(1) subunit, we performed immunoprecipitation and Western blot analyses. In the presynapse, the interaction between Ca(v)2.1alpha(1) and CaMKII and the phosphorylation of CaMKII (at Thr286) and its substrate Synapsin I (at Ser603) were decreased in mutant mice compared to wild-type mice. In the PSD, a similar pattern was observed for the interaction between NR2B and CaMKII and the phosphorylation of CaMKII (at Thr286) and its substrate AMPA receptor subunit glutamate receptor 1 (at Ser831) between mutant and wild-type mice. Our data indicate that disruption of the interaction between Ca(v)2.1alpha(1) and CaMKII may down-regulate presynaptic CaMKII activity and that Rolling Nagoya mice would be a useful model for examining presynaptic function.
Journal of Molecular Neuroscience 08/2009; 41(2):223-9. · 2.50 Impact Factor
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ABSTRACT: Senescence-accelerated mouse prone 6 (SAMP6) mice exhibit increased expression of NMDA receptor NR2B subunit (NR2B) and improved short-term memory compared with senescence-accelerated mouse resistance 1 (SAMR1) mice. The Thr286 phosphorylation of alpha calcium/calmodulin-dependent protein kinase II (CaMKII) has a crucial role in plasticity and learning among multiple downstream signaling pathways linked to the NMDA receptor. To examine the relationship between CaMKII activity and spatial learning in SAMP6, the authors employed western blot analysis and behavioral analyses (object location and delayed spatial win-shift eight-arm radial-maze tests). The levels of Thr286 and Ser831 phosphorylation of CaMKII and AMPA receptor subunit glutamate receptor 1 (CaMKII substrate), respectively, were increased in hippocampus of SAMP6 compared with SAMR1. SAMP6 showed faster hippocampal-dependent spatial memory formation than SAMR1 in both the object location and win-shift eight-arm radial-maze tests. Our results indicate that increased CaMKII activity influences the NR2B/CaMKII signal pathway and cognitive function in SAMP6.
Behavioral Neuroscience 07/2009; 123(3):527-32. · 2.62 Impact Factor
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ABSTRACT: Voltage-dependent Ca(2+) channels (VDCCs) play important roles in physiological functions and pathological processes of the nervous system. Given that the precise regulation of Ca(2+) signaling is important for neuronal processes such as action potential generation, transmitter release, and synaptic plasticity, alterations in Ca(2+) current through VDCCs affect the functions of neurons and circuits. Central nervous system (CNS) diseases, including pain, epilepsy, seizure, anxiety, depression, dementia, and stroke, are characterized by an altered balance between excitatory and inhibitory neuronal functions. An efficient way of controlling such diseases is to block or modulate VDCC function. An effective strategy to reduce the likelihood of adverse effects is to develop agents that selectively control the VDCC isoform/subunit involved in the mechanism of the disease in question. This review provides an overview of knowledge on VDCCs, traditional and newly developed therapeutic fields, clinical fields, and the diverse medicinal chemistry of traditional and newly developed VDCC blockers in the CNS based on the scientific and patent literature.
Recent patents on CNS drug discovery. 07/2009; 4(2):96-111.
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ABSTRACT: Although rolling Nagoya mice exhibit ataxia and carry a mutation in the alpha1 subunit of the Cav2.1 channel regulating neurotransmitter release, heterozygous mice have not received a great deal of attention. Given the pivotal role of Cav2.1 channels in controlling neurotransmitter release, age-dependent alterations in Cav2.1 channel function may result in aberrant synaptic signaling, leading to motor dysfunction. To examine age-related motor alterations in heterozygous mice, we used a battery of tests (e.g., motor activity, footprint, traction, wire suspension, balance beam, rotating rod, hind-limb extension analysis) in 2- and 22-month-old mice and examined expression patterns of the alpha1 gene in their cerebellum. No significant difference was observed between 2-month-old heterozygous and wild-type mice in the any of the behavioral tests or in the alpha1 expression levels. Although 22-month-old heterozygous and wild-type mice exhibited no significant difference in motor activity, footprint, or traction tests, 22-month-old heterozygous mice showed deficits in the wire hanging, balance beam, and rotating rod tests. Additionally, 22-month-old heterozygous mice displayed clasping behavior in the hind-limb extension test. Expression analysis showed that wild-type Cav2.1alpha(1) mRNA was lower in aged mice than in young mice and that mutant-type Cav2.1alpha(1) mRNA was higher in aged mice than in young mice. These findings suggest that heterozygous mice show age-related motor changes due to mutant-type Cav2.1 and that heterozygous mice may represent a new model for examining motor function.
Brain research 06/2009; 1279:50-7. · 2.46 Impact Factor
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ABSTRACT: Aged heterozygous Rolling Nagoya mice carrying Cav2.1alpha1 mutation show deficits with regard to spatial short-term memory using hippocampus-related object location test, but not with regard to nonspatial memory using perirhinal cortex-related object recognition test. In hippocampus, wild-type Cav2.1alpha1 mRNA exhibited lower expression and mutant-type expression was higher in aged heterozygous mice. In perirhinal cortex, there were no significantly different expressions. Alteration of age-dependent expressions of Cav2.1 channels differs in different regions with related effects on behavioral performances.
Behavioural brain research 06/2009; 204(1):241-5. · 3.22 Impact Factor
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ABSTRACT: Although rolling mouse Nagoya, a Ca(v)2.1α(1) mutant, exhibits ataxia and elevated serotonin concentrations, heterozygous mice have not been examined in detail. Patients with heterozygous mutations in this orthologous gene exhibit neurological disorders. To examine the emotional behavior of heterozygous mice, we used behavioral tasks and examined Ca(v)2.1α(1) message levels, tryptophan hydroxylase expression patterns, and monoamine concentrations in 2- and 22-month-old mice. Reduced anxiety in the elevated plus maze, light-dark exploration, and marble-burying behavioral tests and reduced depression in the forced swimming and tail suspension tests were observed in 22-month-old heterozygous mice compared to aged-matched wild-type mice. The levels of mutant-type Ca(v)2.1α(1) message, phosphorylation of tryptophan hydroxylase, and serotonin increased in the brainstems of 22-month-old heterozygous mice. No difference was observed between 2-month-old heterozygous and wild-type mice in these analyses. These findings suggest that heterozygous mice show age-related emotional changes due to alterations in the serotonin system associated with mutant-type Ca(v)2.1α(1), and that heterozygous mice may represent a novel model to delineate the interaction between Ca(v)2.1 function and synaptic transmission.
Neurobiology of aging 05/2009; 32(3):486-96. · 5.94 Impact Factor
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ABSTRACT: The senescence-accelerated mouse (SAM) is a murine model of aging that was developed from the AKR/J strain. We examined whether there are behavioral differences among SAM prone 6 (SAMP6; an established model of senile osteoporosis), SAM resistant 1 (SAMR1), and AKR/J, using a modified SmithKline/Harwell/Imperial College/Royal Hospital/Phenotype Assessment (SHIRPA) procedure and pharmacological tests. The modified SHIRPA, which is suitable for rapid and comprehensive phenotyping of transgenic and gene-targeted mice, revealed increased rearing, spontaneous activity, locomotor activity, tail elevation, head bobbing, and tail rattling behaviors of SAMP6 compared with SAMR1 and AKR/J. These phenotypes are consistent with alteration of the dopamine system in SAMP6. Adopting a pharmacological approach to examine dopamine signaling, we evaluated the locomotor activity of the mice after intraperitoneal administration of apomorphine, a subtype non-selective dopamine receptor agonist. Apomorphine at 1mg/kg significantly increased the locomotor activity of SAMP6, but not SAMR1 or AKR/J. At 3mg/kg, apomorphine significantly increased the locomotor activities of all three strains, but the increase in SAMP6 was still significantly greater than that in SAMR1 or AKR/J. These results indicate increased sensitivity of the dopamine receptor signaling pathway in SAMP6. Thus, alteration of dopamine receptor signal transduction appears to be one of the underlying mechanisms of the increased locomotor activity of SAMP6. The combination of modified SHIRPA and examination of drug threshold dose differences between strains appears to be an effective approach to extend the applicability of existing mouse models.
Neuroscience Letters 05/2009; 458(2):53-6. · 2.11 Impact Factor
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ABSTRACT: Rolling mouse Nagoya (tg(rol)) is a spontaneously occurring P/Q-type voltage-gated Ca2+ channel (VGCC) mutant mouse. A P/Q-type VGCC with the tg(rol) mutation has lower voltage sensitivity of activation, and mice with a homozygous genotype (tg(rol)/tg(rol)) but not with a heterozygous genotype (tg(rol)/+) show impaired motor coordination of the hind limbs. To investigate the roles of P/Q-type VGCC in pain sensing mechanisms, behavioral responses of adult tg(rol) mice to thermal, mechanical and chemical nociceptive stimuli were examined by the plantar, tail-flick, von Frey and formalin tests. The latency of the withdrawal response to thermal stimuli in the plantar or tail-flick tests was significantly longer in tg(rol)/tg(rol) mice than in tg(rol)/+ and wild-type (+/+) mice, and in tg(rol)/+ mice than in +/+ mice. The withdrawal response to mechanical stimuli in the von Frey test was lower in tg(rol)/tg(rol) mice than in +/+ mice. Although the licking time during the first 5 min after the formalin injection was similar among all of the three genotypes, that during 5-60 min was significantly shorter in tg(rol)/tg(rol) mice than in tg(rol)/+ and +/+ mice, and in tg(rol)/+ mice than in +/+ mice. Artificial inflammation induced by injection of complete Freund's adjuvant (CFA) into a hind paw significantly enhanced the withdrawal response recorded in the plantar and von Frey tests regardless of the mouse genotype. The CFA-enhanced response in the tg(rol)/tg(rol) mice was similar to the response in +/+ mice without the CFA injection. These results suggest that tg(rol) mutant mice show hypoalgesic responses caused by a lower sensitivity to nociceptive thermal, mechanical and chemical stimuli. It is concluded that the P/Q-type VGCC has a pro-nociceptive role and that the tg(rol) mutant mouse may be a useful tool to investigate the role of the P/Q-type VGCC in pain sensing mechanisms.
Neuroscience 03/2009; 160(1):165-73. · 3.38 Impact Factor
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ABSTRACT: Rolling Nagoya mice carrying Ca(v)2.1alpha1 gene mutation show ataxia, whereas heterozygous mice show no apparently abnormal behavior. It has been reported that Ca(v)2.1 regulates neurotransmitter release and that Ca(2+) influx through Ca(v)2.1 decreases with aging. Age-related decline in cognitive function could be at least partly attributable to decreases in Ca(v)2.1-related neurotransmission. In this study to examine age-related cognitive alterations in heterozygous mice, we used Y-maze and delayed spatial win-shift eight-arm radial-maze tests, and 2- and 22-month-old mice. Although there was no difference between 2-month-old heterozygous and wild-type mice, 22-month-old heterozygous mice showed decreased memory formation versus 2-month-old heterozygous mice in both tests. Expression analysis in forebrain showed that total Ca(v)2.1alpha1 mRNA, including wild-type and mutant-type Ca(v)2.1alpha1 mRNA, in 2-month-old heterozygous mice was expressed at a level similar to that in 22-month-old heterozygous mice. However, wild-type Ca(v)2.1alpha1 mRNA was expressed at a lower level in 22-month-old mice than in 2-month-old mice, and mutant-type Ca(v)2.1alpha1 mRNA was expressed at a higher level in 22-month-old versus 2-month-old mice. Our results suggest that aged heterozygous mice show deficits in spatial learning due to Ca(v)2.1 channel dysfunction and that heterozygous mice may be a useful model for examining mechanisms underlying age-related cognitive dysfunction.
Experimental gerontology 01/2009; 44(4):274-9. · 3.34 Impact Factor
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ABSTRACT: The motor function of senescence-accelerated mouse prone 6 (SAMP6) was evaluated with a battery of behavioral tests: locomotor activity test, traction test, wire hanging test, and rotating rod test. SAMP6 exhibited increased locomotor activity compared with senescence-accelerated mouse resistant 1 (SAMR1). There was no difference between SAMP6 and SAMR1 in the traction and wire hanging tests. In the rotating rod test, shorter retention times at each day in the accelerating version of the test were observed in SAMP6 compared with SAMR1, indicating a motor coordination deficit of SAMP6. To understand the mechanism involved, we focused on the dopamine system. Measurement of dopamine and its metabolites with HPLC revealed that the concentrations of dopamine in nucleus accumbens (NAcs) and cerebellum and of one or more dopamine metabolites in all tissues assayed were significantly higher in SAMP6 compared with SAMR1. Increases of dopamine transporter and dopamine receptor 1 (D1) in striatum, of dopamine receptor 3 (D3) in NAc, and of D1 and D3 in cerebellum in SAMP6 were observed. These results indicate that increased dopamine concentration in NAc and increased expression of D1 in striatum are possible cause(s) of the increased locomotor activity of SAMP6, and that increased D3 expression in cerebellum contributes to the motor coordination deficit of SAMP6.
Physiology & Behavior 12/2008; 96(3):464-9. · 2.87 Impact Factor
