Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is generally believed that a smooth execution of a compound movement, or motor coordination, requires learning of component movements as well as experience-based refinement of the motor program as a whole. PKC gamma mutant mice display impaired motor coordination but intact eyeblink conditioning, a form of component movement learning. Cerebellar long-term depression, a putative cellular mechanism for component motor learning, is also unimpaired. Thus, PKC gamma mutant mice are defective in refinement of the motor program. In the accompanying paper, we demonstrate that innervation of multiple climbing fibers onto Purkinje cells persists in adulthood in these mutant mice. We propose that this defective elimination of surplus climbing fibers underlies motor discoordination.
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PMID:Impaired motor coordination correlates with persistent multiple climbing fiber innervation in PKC gamma mutant mice. 854 9

Targeted deletion of metabotropic glutamate receptor-subtype 1 (mGluR1) gene can cause defects in development and function in the cerebellum. We introduced the mGluR1alpha transgene into mGluR1-null mutant [mGluR1 (-/-)] mice with a Purkinje cell (PC)-specific promoter. mGluR1-rescue mice showed normal cerebellar long-term depression and regression of multiple climbing fiber innervation, events significantly impaired in mGluR1 (-/-) mice. The impaired motor coordination was rescued by this transgene, in a dose-dependent manner. We propose that mGluR1 in PCs is a key molecule for normal synapse formation, synaptic plasticity, and motor control in the cerebellum.
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PMID:mGluR1 in cerebellar Purkinje cells essential for long-term depression, synapse elimination, and motor coordination. 1084 66

The effect of Gi protein inactivation was evaluated in an animal model of depression, the mouse forced swimming test. Animals were i.c.v. injected with pertussis toxin (PTX) or with antisense oligodeoxynucleotides directed against the alpha subunit of each Gi-protein subtype (anti-Gi alpha(1), anti-Gi alpha(2), anti-Gi alpha(3), anti-Go alpha(1), anti-Go alpha(2)). The administration of PTX (0.25 micro g per mouse i.c.v.) produced an increase in the mobility time. Similarly, anti-Gi alpha(2) (25 micro g per mouse i.c.v.), anti-Gi alpha(3) (25 micro g per mouse i.c.v.), anti-Go alpha(1) (12.5-25 micro g per mouse i.c.v.) and anti-Go alpha(2) (12.5-25 micro g per mouse i.c.v.) increased the mobility time. The antidepressant-like effect obtained was similar to that produced by amitriptyline and clomipramine. By contrast, pretreatment with anti-Gi alpha(1) (3.12-25 micro g per mouse i.c.v.) never modified the mobility time in comparison with control animals. At the highest effective doses, none of the compounds used impaired motor coordination (rota rod test), nor modified spontaneous motility and inspection activity, (hole board test). These results indicate the involvement of Gi(2), Gi(3), Go(1), and Go(2), but not Gi(1), protein subtypes in the transduction mechanism responsible for the induction of an antidepressant-like effect in the mouse forced swimming test.
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PMID:Inactivation of Gi proteins induces an antidepressant-like effect in the mouse forced-swimming test. 1224 76

The effect of the i.c.v. administration of pertussis toxin (PTX) and antisense oligodeoxynucleotides directed against the alpha subunit of different Gi-proteins (anti-Gi alpha(1), anti-Gi alpha(2), anti-Gi alpha(3), anti-Go alpha(1), anti-Go alpha(2)) on the antidepressant-like effect induced by amitriptyline and clomipramine, was evaluated in the mouse forced swimming test, an animal model of depression. The administration of amitriptyline (15 mg kg(-1) s.c.) and clomipramine (25 mg kg(-1) s.c.) produced an increase in the mobility time that was prevented by PTX (0.25 micro g per mouse i.c.v.), administered 11 days before the mouse forced swimming test. Anti-Gi alpha(1) (12.5 micro g per mouse i.c.v.), anti-Gi alpha(2) (12.5 micro g per mouse i.c.v.), anti-Gi alpha(3) (6.25 micro g per mouse i.c.v.), and anti-Go alpha(1) (6.25 micro g per mouse i.c.v.), administered 24 and 18 h before the training session, prevented the amitriptyline and clomipramine increase of the mobility time. By contrast, pretreatment with anti-Go alpha(2) (1.56-12.5 micro g per mouse i.c.v.) never modified the antidepressant-like effect induced by the two investigated compounds. At the highest effective doses, none of the compounds used impaired motor coordination, as revealed by the rota-rod test, nor modified spontaneous motility and inspection activity, as revealed by the hole-board test. These results suggest the important role played by Gi(1), Gi(2), Gi(3), and Go(1) protein subtypes and the lack of involvement by Go(2) protein subtype in the transduction mechanism responsible for the antidepressant-like effect produced by amitriptyline and clomipramine.
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PMID:Role of Gi proteins in the antidepressant-like effect of amitriptyline and clomipramine. 1237 92

The gamma isotype of protein kinase C (PKC gamma) is a member of the classical PKC (cPKC) subfamily which is activated by Ca(2+) and diacylglycerol in the presence of phosphatidylserine. Physiologically, PKC gamma is activated by a mechanism coupled with receptor-mediated breakdown of inositol phospholipid as other cPKC isotypes such as PKC alpha and PKC beta. PKC gamma is expressed solely in the brain and spinal cord and its localization is restricted to neurons, while PKC alpha and PKC beta are expressed in many tissues in addition to the brain. Within the brain, PKC gamma is the most abundant in the cerebellum, hippocampus and cerebral cortex, where the existence of neuronal plasticity has been demonstrated. Pharmacological and electrophysiological studies have shown that several neuronal functions, including long term potentiation (LTP) and long term depression (LTD), specifically require PKC gamma. Generation of mice deficient in PKC gamma provided more information regarding the physiological functions of this isotype. PKC gamma deficient mice (i) have modified long term potentiation (LTP) in hippocampus, (ii) exhibit mild deficits in spatial and contextual learning (iii) exhibit impaired motor coordination due to persistent multiple innervations of climbing fibers on Purkinje cells, (iv) show attenuation of opioid receptor activation, and (v) show decreased effects of ethanol on type A of gamma-aminobutyric acid (GABA) receptor. Furthermore, a point mutation in the PKC gamma gene may contribute to retinitis pigmentosa and Parkinsonian syndrome. This article reviews the specific functions of this neuron-specific isotype of PKC in neuronal signal transduction.
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PMID:Protein kinase C gamma (PKC gamma): function of neuron specific isotype. 1241 16

A novel ionotropic glutamate receptor subunit delta2 (GluRdelta2), which is specifically expressed in cerebellar Purkinje neurons (PNs), is implicated in the induction of long-term depression. Mutant mice deficient in GluRdelta2 (delta2-/-) have abnormal cerebellar synaptic organization and impaired motor coordination and learning. Previous in vivo extracellular recordings indelta2-/- revealed that PN activity distinct from that in wild-type (WT) mice is attributable to enhanced climbing fiber activity. Here, we report that GABAergic synaptic transmission was enhanced in the molecular layer of the cerebellar cortex in delta2-/-. Optical recordings in cerebellar slice preparations indicated that application of bicuculline, a GABA(A) receptor antagonist, increased the amplitude and area of excitation propagation more in delta2-/- than in WT. Whole-cell patch-clamp recordings from PNs demonstrated that miniature IPSC (mIPSC) amplitude were larger in delta2-/- than in WT. Also, rebound potentiation (RP), a type of long-lasting inhibitory synaptic potentiation inducible by postsynaptic depolarization of PNs in WT, was not induced in slices prepared from delta2-/-. In contrast, RP was induced in cultured PNs prepared from delta2-/-. Pharmacologic activation of climbing fibers in WT in vivo increased mIPSC amplitudes in PNs and prevented RP induction. These results suggest that enhanced climbing fiber activity in delta2-/- potentiates IPSC amplitudes in PNs through RP in vivo, resulting in the prevention of additional RP induction.
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PMID:Enhanced inhibitory synaptic transmission in the cerebellar molecular layer of the GluRdelta2 knock-out mouse. 1557 40

We previously demonstrated that metabotropic glutamate receptor-subtype 1 knockout [mGluR1 (-/-)] mice showed ataxic gait, deficient long-term depression and impaired synapse elimination and these phenotypes were rescued by introduction of an mGluR1 transgene with Purkinje cell-specific promoter (mGluR1-rescue mice). However, roles of mGluR1 in the adult brain remain elusive, mainly due to lack of conventional and reproducible method to block mGluR1 expression at a certain developmental stage. Here, we established a versatile mouse line, mGluR1 conditional knockout (cKO) mice using the tetracycline-controlled gene expression system to understand the roles of mGluR1 in the adult brain. The mGluR1 cKO mice express mGluR1 only in Purkinje cells and show normal motor coordination. Blockade of expression of mGluR1 in the adult mGluR1 cKO mice led to impaired motor coordination, suggesting that mGluR1 is essential for cerebellar function in mice not only during postnatal development but also in adulthood.
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PMID:Metabotropic glutamate receptor subtype-1 is essential for motor coordination in the adult cerebellum. 1727 Mar

Methoxyisopropanol and Methoxyisopropyl Acetate, commonly known as propylene glycol monomethyl ether (PGME) and propylene glycol monomethyl ether acetate (PGMEA), respectively, have fragrance, solvent, and viscosity-decreasing functions in cosmetics, although only Methoxyisopropanol is in current use at concentrations ranging from 4% to 35%. Methoxyisopropanol is easily absorbed into the bloodstream upon inhalation or ingestion. The acetate ester is readily metabolized to Methoxyisopropanol in the body, which is excreted unchanged in the expired breath or in the urine as free or conjugated Methoxyisopropanol, or as the primary metabolite propylene glycol. In acute oral toxicity studies, the LD(50) values of Methoxyisopropanol were 4.6 to 9.2 g/kg in rats, with similar low acute toxicity in other animal species. Inhalation exposures of rats, mice, and rabbits to 3000 ppm Methoxyisopropanol for 6 h per day for 9 days to 13 weeks produced increased relative liver weights, signs of central nervous system (CNS) depression, and in some cases, elevated serum alkaline phosphatase, alanine aminotransferase, or hepatocellular hypertrophy, but the kidneys were unaffected. The no observed adverse effect level (NOAEL) for 13-week inhalation exposures to Methoxyisopropanol was 1000 ppm in rats and rabbits. In a 90-day dermal exposure study using rabbits, 10 ml/kg undiluted Methoxyisopropanol produced narcosis and increased kidney weights and the NOAEL was 7.0 ml/kg. Chronic (2-year) daily inhalation exposures of rats and mice to 3000 ppm Methoxyisopropanol produced signs of liver toxicity (rats and mice) and some evidence of renal toxicity in rats. The only observation at 1000 ppm was dark foci of the liver in male rats. For female rats and male and female mice, the NOAEL of this chronic inhalation study was 1000 ppm Methoxyisopropanol. Methoxyisopropanol and Methoxyisopropyl Acetate were found to be nonirritating to slightly irritating and non-sensitizing in rabbit and guinea pig skin. Repeated applications of undiluted Methoxyisopropanol to the eyes of rabbits produced transient slight to moderate irritation. Pregnant rats exposed to 200 or 600 ppm Methoxyisopropanol by inhalation on gestation days 6 to 17 had no effects on maternal health or normal fetal development. Adult male rats exposed to these concentrations had no effects on the reproductive organs. Pregnant rats and rabbits exposed to 500 to 3000 ppm Methoxyisopropanol by inhalation during gestation had no significant embryotoxic or fetotoxic effects, althougth CNS depression and reduced body weight gain were observed in the 3000 ppm group. In a two-generation inhalation study using rats, continuous inhalation of 3000 ppm Methoxyisopropanol produced CNS depression, prolonged estrous cycles, reduced fertility indices, reduced pup weights and pup survival, and delayed sexual development, with a NOAEL for reproductive and developmental effects of 1000 ppm. In a continuous breeding protocol using mice, 2.0% Methoxyisopropanol in drinking water produced reduced growth, reduced relative epididymis weight, reduced relative prostate weight, and increased liver weight (females only) in offspring, with a NOAEL at a 1% concentration. Exposure of mice or rats to 300 ppm to 3000 ppm Methoxyisopropanol by inhalation produced no signs of carcinogenicity. Methoxyisopropanol was negative for mutagenicity or genetic toxicity in the bacterial reverse mutation assay (<or= 5000 microg/plate), the unscheduled DNA synthesis (UDS) assay (<or= 0.1 M), V79 Chinese hamster lung assay (>100 mM), and in the Siberian hamster embryo assay (concentrations not reported). In other assays, 100 mM Methoxyisopropanol increased sister chromatid exchanges in V79 cells. In human inhalation exposure studies of 1 to 7 h duration, 50 to 75 ppm Methoxyisopropanol vapor had an objectionable odor; 150 ppm was slightly irritating to the eyes and throat; 250 ppm produced eye irritation, lacrimation, blinking, rhinorrhea, and headache; 300 ppm was mildly irritating to the eyes, nose, and throat; 750 ppm was extremely irritating; and 2050 ppm produced extreme discomfort with severe lacrimation, blepharospasm, and painful breathing. None of the concentrations tested impaired motor coordination or performance on neurological tests. The irritating effects subsided within 15 min to 24 h of removal from the inhalation chamber. The National Institute of Occupational Safety and Health (NIOSH) recommended an 8-h time-weighted average for occupational exposure of 100 ppm. A margin of safety of 500 was determined, based on a calculated exposure from the normal use of nail polish remover products (100% absorption) and the NOAEL for reproductive toxicity. The absorption of Methoxyisopropanol through the nail is likely to be low, suggesting this margin of safety is conservative. Because Methoxyisopropanol is volatile, exposure by inhalation is possible, but the odor becomes objectionable at 50 to 75 ppm in air. The Cosmetic Ingredient Review (CIR) Expert Panel concluded that Methoxyisopropanol and Methoxyisopropyl Acetate are safe for use in nail care products in the practices of use and concentration as described in this safety assessment.
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PMID:Final report on the safety assessment of methoxyisopropanol and methoxyisopropyl acetate as used in cosmetics. 1883 Aug 62

Chicken acidic leucine-rich EGF-like domain-containing brain protein (CALEB), also known as chondroitin sulfate proteoglycan (CSPG)5 or neuroglycan C, is a neural chondroitin sulfate-containing and epidermal growth factor (EGF)-domain-containing transmembrane protein that is implicated in synaptic maturation. Here, we studied the role of CALEB within the developing cerebellum. Adult CALEB-deficient mice displayed impaired motor coordination in Rota-Rod experiments. Analysis of the neuronal connectivity of Purkinje cells by patch-clamp recordings demonstrated impairments of presynaptic maturation of inhibitory synapses. GABAergic synapses on Purkinje cells revealed decreased evoked amplitudes, altered paired-pulse facilitation and reduced depression after repetitive stimulation at early postnatal but not at mature stages. Furthermore, the elimination of supernumerary climbing fiber synapses on Purkinje cells was found to occur at earlier developmental stages in the absence of CALEB. For example, at postnatal day 8 in wild-type mice, 54% of Purkinje cells had three or more climbing fiber synapses in contrast to mutants where this number was decreased to less than 25%. The basic properties of the climbing fiber Purkinje cell synapse remained unaffected. Using Sholl analysis of dye-injected Purkinje cells we revealed that the branching pattern of the dendritic tree of Purkinje cells was not impaired in CALEB-deficient mice. The alterations observed by patch-clamp recordings correlated with a specific pattern and timing of expression of CALEB in Purkinje cells, i.e. it is dynamically regulated during development from a high chondroitin sulfate-containing form to a non-chondroitin sulfate-containing form. Thus, our results demonstrated an involvement of CALEB in the presynaptic differentiation of cerebellar GABAergic synapses and revealed a new role for CALEB in synapse elimination in Purkinje cells.
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PMID:Impaired presynaptic function and elimination of synapses at premature stages during postnatal development of the cerebellum in the absence of CALEB (CSPG5/neuroglycan C). 2388 29

Infants born to women with depressive symptoms are at higher risk for insecure attachment and behavioral problems. Thus current medical practice is to continue psychotropic medication of pregnant women with depression despite concerns about its behavioral teratology. There are few animal studies focused on long-term behavioral effects of prenatal antidepressant exposure; in addition, studies have not looked at individual differences in baseline affective state as a source of response variability. In this study, fluoxetine, a selective serotonin reuptake inhibitor (SSRI), was administered to male and female rat pups from postnatal days 2-7 to model exposure to antidepressants in the human third trimester. Four behavioral measures were conducted from the neonatal to adult age periods in Low and High lines selectively bred for their rate of ultrasonic vocalizations after brief maternal separation. Neonatal fluoxetine administration decreased distress calls in both lines, but to a greater extent in High line rats than Low line. Neonatal fluoxetine also impaired motor coordination in neonates. Neonatal fluoxetine administration decreased social behavior in both juvenile and adult subjects. Fluoxetine-related reductions in anxiety behavior were not observed at the two older ages. As expected, High line subjects displayed more anxiety behavior than Low line subjects at all three test ages. These results suggest that there are may be significant behavioral consequences of antidepressant use during late pregnancy on offspring maternal attachment and social behavior, with implications for increased risk of autism spectrum disorders.
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PMID:Effects of neonatal fluoxetine exposure on behavior across development in rats selectively bred for an infantile affective trait. 2550 15


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