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At least 19 recordsLinked to original sources
PubMed2000

Nicotinic receptor function: new perspectives from knockout mice.

Knockout mice, in which one or more genes of interest are silenced, provide unique opportunities to analyse diverse aspects of gene function in vivo. In particular, the contribution of the encoded protein(s) in complex behaviours can be assessed. Since the first targeted disruption in 1995 of the gene encoding the beta2-subunit of the nicotinic acetylcholine receptor (nAChR), all but a few of the mammalian nAChR subunits have been disrupted (i.e. alpha7, alpha4, alpha3, alpha9, beta4 and beta3). Recent advances brought by genetically modified mice to our understanding of the endogenous composition and role of nAChRs in the nervous system, and of the diverse pharmacological actions of nicotine regarding learning, analgesia, reinforcement, development and aging in the brain will be discussed.

Animals↗
PubMed2002

A single dose of methamphetamine rescues the blunted dopamine D(1)-receptor activity in the neocortex of D(2)- and D(3)-receptor knockout mice.

Knockout mice deficient for dopamine D(2) and D(3) receptors exhibit blunted c-fos responses to D(1)-agonist stimulation. A single dose of methamphetamine (METH), however, leads to a long-term reversal of these blunted c-fos responses in both mutants, and the same effect is obtained with a single administration of a full D(1)-agonist. Consistent with the predominant c-fos expression in the neocortex induced by METH itself, METH pretreatment leads to the largest D(1)-agonist-stimulated c-fos responses in the neocortex of these mutants. For example, a pronounced blunting of neocortical c-fos responses is detected in the prefrontal cortex, a region in which D(1) receptors play a critical role in working memory. METH pretreated mutants, however, exhibit robust c-fos responses in this region that are indistinguishable from wild type. Recent studies indicate that different mechanisms operate in brains of D(2) and D(3) mutants to lead to decreased D(1)-receptor activity. For example, drug-naive D(2), but not D(3), mutants show significantly decreased G protein activation in response to D(1)-agonist stimulation, and METH pretreatment also rescues this abnormal molecular phenotype. Moreover, although the protein phosphatases (PP) 1/2A and 2B play a critical role in modulating G protein activation in wild type, their effect is either diminished (PP1/2A) or abolished (2B) in D(2) mutants. Interestingly however, METH pretreatment does not rescue the activities of these phosphatases in the mutants, suggesting that the long-term effects of a single dose of METH are mediated via effector systems that act downstream of G protein activation.

Animals↗
PubMed2000

Angiotensin II type 1 receptor blockade prevents cardiac remodeling in bradykinin B(2) receptor knockout mice.

Knockout mice (B(2)(-/-)) lacking the bradykinin (BK) B(2) receptor gene develop mild hypertension, cardiac hypertrophy, and myocardial damage. We hypothesized that these effects are due to the hypertrophying and damaging actions of angiotensin II (Ang II) in the absence of the balancing protection of BK. To verify this hypothesis, B(2)(-/-) or wild-type mice (B(2)(+/+)) were administered a nonpeptide antagonist of Ang II type 1 (AT(1)) receptors (A81988) from conception through 180 days of age. Untreated B(2)(+/+) and B(2)(-/-) served as controls. Blood pressure (BP) and heart rate were monitored with the use of tail-cuff plethysmography at regular intervals. Ventricular weights, diameters, wall thickness, chamber volume, and myocardial fibrosis were measured at 40 and 180 days. No differences were observed in BP, heart rate, and cardiac weight and dimensions between treated and untreated B(2)(+/+). The BP of AT(1) antagonist-treated B(2)(-/-) was reduced until 70 days; then, it increased to the levels found in untreated B(2)(-/-). AT(1) receptor blockade resulted in a reduction in left ventricular mass, chamber volume, and wall thickness and abrogated myocardial fibrosis in B(2)(-/-). These results indicate that Ang II is the major factor responsible for ventricular remodeling and myocardial damage in mice with disruption of BK B(2) receptor signaling. The interaction of Ang II and BK appears to be essential for the development of a normal heart.

Angiotensin II↗
PubMed2006

Variable in vivo embryoprotective role for ataxia-telangiectasia-mutated against constitutive and phenytoin-enhanced oxidative stress in atm knockout mice.

Knockout mice lacking the ataxia-telangiectasia-mutated (Atm) protein exhibit impaired detection and repair of DNA damage and increased embryopathies from ionizing radiation in vivo, and vehicle or phenytoin in embryo culture. Here we determined if Atm-deficient mice are more susceptible in vivo to phenytoin embryopathies. Wild-type (+/+) or heterozygous (+/-) Atm knockout dams were mated with +/- males, pregnant dams were treated with phenytoin (65 mg/kg ip) or its vehicle, and resorptions and fetuses were genotyped and characterized. This strain proved resistant to phenytoin-initiated cleft palates but not to other spontaneous and phenytoin-enhanced embryopathies. With vehicle-treated +/- dams, fetal body weight was lower in homozygous Atm-null (-/-) fetuses compared to +/- and +/+ littermates (p < 0.05). Phenytoin enhanced this Atm-dependent embryopathic pattern (p < 0.05). It also enhanced DNA oxidation in -/- Atm-deficient embryos compared to its +/- Atm-deficient (p < 0.001) and +/+ Atm-normal (p < 0.001), phenytoin-exposed littermates and to its -/- vehicle controls (p < 0.01). Postpartum lethality was greater in both +/- and -/- Atm-deficient fetuses compared to +/+ littermates, independent of treatment (0.05 < p < 0.1). By maternal genotype, +/- Atm-deficient dams had fewer implantations than +/+ dams, independent of treatment, and phenytoin decreased litter size (p < 0.05). Conversely, phenytoin-exposed +/+ fetuses were more likely than -/- littermates to die in utero (p < 0.05), and in +/+ dams fetal resorptions and postpartum lethality were variably higher and enhanced by phenytoin (p < 0.05). Despite variable actions in vivo, the embryoprotective effects of Atm suggest a role for reactive oxygen species and oxidative DNA damage in some spontaneous and phenytoin-enhanced embryopathies.

Animals↗
PubMed2003

Cardiovascular diseases: new insights from knockout mice.

Knockout (KO) mice models have generated a wealth of new information on the developmental and physiopathological roles of several hormones and their receptors. In these mice, KO of a specific gene can be lethal at embryonic stages or during early adulthood. Furthermore, in conditions of non-lethality, KO mice may compensate for the repression of a particular protein expression. As a result of these two aspects, various phenotypic expressions occur in KO mice models for several peptides and their respective receptors, as well as for the enzymes involved in their processing.

Animals↗
PubMed2003

Investigation of the transcriptional changes underlying functional defects in the mammary glands of prolactin receptor knockout mice.

Knockout (KO) mice have been created that carry null mutations of genes encoding molecules essential for prolactin (PRL) release, PRL, the receptor for prolactin (PRLR), and various members of the receptor's signaling pathway. This allowed an in vivo genetic analysis of the role of PRL in target organ function. In PRLKO and PRLRKO mice, mammary ductal side branching was absent, terminal end bud (TEB)-like structures persisted at the ductal termini well into maturity, and no alveolar buds formed along the ductal tree. Transplants of recombined mammary glands formed from stromal and epithelial elements with and without PRLR showed normal development, while supplementation of progesterone levels in PRLKO animals restored ductal side branching. During pregnancy, PRLR heterozygous animals initially showed normal ductal and alveolar development. However, alveolar development stalled during late pregnancy, preventing successful lactation. This defect could be rescued by the loss of a single allele of the suppressor of cytokine signaling (SOCS) 1 gene. Transplants of recombined glands containing PRLRKO epithelium and wild-type (WT) stroma formed alveolar buds during pregnancy but showed no lobuloalveolar development. Recombinations of WT epithelium and PRLRKO stroma showed normal development, demonstrating that a direct action of the lactogenic hormones is confined to the epithelium, to promote lobuloalveolar development. Transcript profiling of epithelial transplants expressing or not expressing PRLR was used during early pregnancy to investigate the transcriptional response to lactogens underlying this defect. Such profiling has identified a number of genes with well-characterized roles in mammary development, in addition to a number of novel transcripts.

Animals↗
PubMed2002

Mutation theory of aging, assessed in transgenic mice and knockout mice.

A vital question in the mutation theory of aging is whether mutation accumulates with age. If it does, what are the causes and consequences of the accumulation of mutation? The recent development of transgenic mice has made it possible to study mutation in different kinds of tissues and at a molecular level. An application of these mice to the study of age-dependent alteration has revealed that mutation does accumulate in the aging process. Studies have also revealed several important characteristics of mutation associated with aging. (1) The rate of age-dependent increase of mutant frequency varies among different types of tissue. (2) The rate is not in parallel with the cell proliferation rate of the tissue. (3) Some types of mutation are unique to specific tissues, suggesting the presence of a mechanism of mutation relative to tissue type. On the other hand, several kinds of knockout mice defective in DNA repair have been shown to exhibit tissue lesions and shortened life span. These characteristics provide a new view on the relationship between aging and the genome maintenance system. Here we review the current status of research on the correlation between mutation and aging undertaken by the use of transgenic and knockout mice.

Aging↗
PubMed2005

Chloride transport in the kidney: lessons from human disease and knockout mice.

Knockout mouse models and human inherited diseases have provided important new insights into the physiologic role of chloride transport by CLC Cl(-) channels and KCC K-Cl co-transporters. ClC-K/barrtin Cl(-) channels are important for renal salt reabsorption and possibly for acid secretion by intercalated cells. The endosomal ClC-5 protein is crucial for proximal tubular endocytosis. Its disruption in mice and patients with Dent's disease leads to hypercalciuria and kidney stones through a pathologic cascade that may be entirely explained by an impairment of endocytosis. KCC4 is important for recycling Cl(-) for the basolateral anion exchanger in intercalated cells, as is evident from the renal tubular acidosis resulting from its knockout. Finally, both KCC3 and KCC4 are crucial for proximal tubular cell volume regulation.

Animals↗
PubMed2003

Endothelial responses of the aorta from adrenomedullin transgenic mice and knockout mice.

Adrenomedullin (AM) is a potent vascular wall-derived vasorelaxing peptide which induces the release of nitric oxide (NO). To explore the role of endogenous AM in vascular function, we examined the effects of acetylcholine (ACh), AM, and AM receptor antagonists [AM (22-52), and calcitonin gene-related peptide (CGRP) (8-37)] on the isometric tension of aortic rings isolated from AM transgenic (TG) and knockout (KO) mice and wild type littermates (WT). ACh and AM caused a dose-dependent reduction of the isometric tension of aortic rings, but the degree of vasodilatation was smaller in TG than in KO or WT (% delta tension [10(-6) mol/l ACh]: KO -69 +/- 10%, WT -39 +/- 8%, TG -29 +/- 1%, p < 0.01). On the other hand, N(G)-nitro-L-arginine methyl ester, an NO synthase inhibitor, induced greater vasoconstriction in TG (% delta tension 10(-5)mol/l: KO +78 +/- 16%, WT +99 +/- 27%, TG +184 +/- 20%, p < 0.01), whereas E-4021, a cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase inhibitor, caused greater vasodilation in TG mice. Both AM antagonists increased tension in TG to a greater extent than in KO or WT mice (% delta tension [10(-6) mol/l CGRP (8-37)]: KO +24 +/- 5%, WT +51 +/- 6%, TG +75 +/- 7%, p < 0.01). Endothelial denudation of the aorta diminished the vasoconstriction caused by the AM antagonists. In conclusion, the amounts of AM expressed in the aortic endothelium influenced baseline NO release. AM antagonists increased vascular tone in WT as well as in TG, suggesting that endogenous AM plays a physiological role in the regulation of aortic tone.

Acetylcholine↗
PubMed2005

P2X2 knockout mice and P2X2/P2X3 double knockout mice reveal a role for the P2X2 receptor subunit in mediating multiple sensory effects of ATP.

Extracellular ATP plays a role in nociceptive signalling and sensory regulation of visceral function through ionotropic receptors variably composed of P2X2 and P2X3 subunits. P2X2 and P2X3 subunits can form homomultimeric P2X2, homomultimeric P2X3, or heteromultimeric P2X2/3 receptors. However, the relative contribution of these receptor subtypes to afferent functions of ATP in vivo is poorly understood. Here we describe null mutant mice lacking the P2X2 receptor subunit (P2X2-/-) and double mutant mice lacking both P2X2 and P2X3 subunits (P2X2/P2X3(Dbl-/-)), and compare these with previously characterized P2X3-/- mice. In patch-clamp studies, nodose, coeliac and superior cervical ganglia (SCG) neurones from wild-type mice responded to ATP with sustained inward currents, while dorsal root ganglia (DRG) neurones gave predominantly transient currents. Sensory neurones from P2X2-/- mice responded to ATP with only transient inward currents, while sympathetic neurones had barely detectable responses. Neurones from P2X2/P2X3(Dbl-/-) mice had minimal to no response to ATP. These data indicate that P2X receptors on sensory and sympathetic ganglion neurones involve almost exclusively P2X2 and P2X3 subunits. P2X2-/- and P2X2/P2X3(Dbl-/-) mice had reduced pain-related behaviours in response to intraplantar injection of formalin. Significantly, P2X3-/-, P2X2-/-, and P2X2/P2X3(Dbl-/-) mice had reduced urinary bladder reflexes and decreased pelvic afferent nerve activity in response to bladder distension. No deficits in a wide variety of CNS behavioural tests were observed in P2X2-/- mice. Taken together, these data extend our findings for P2X3-/- mice, and reveal an important contribution of heteromeric P2X2/3 receptors to nociceptive responses and mechanosensory transduction within the urinary bladder.

Adenosine Triphosphate↗
PubMedDate not supplied

Adult X-linked immunodeficiency (XID) mice, IGM-/- single knockout and IGM-/- CD8-/- double knockout mice do not clear polyomavirus infection.

The importance of antibodies for elimination of polyomavirus infection and the prevention of virus induced oncogenesis was studied, X-linked immunodeficiency (XID) mice, IgM-/- single knockout and IgMI-/- CD8-/- double knockout mice, all defective in antibody production, and normal control mice were infected with polyomavirus as adults. The mice were followed for presence of polyoma DNA with a polyoma specific polymerase chain reaction (PCR) over 6 weeks post infection (p.i.), a time point at which polyomavirus DNA is no longer detected in normal adult infected mice. As expected, virus DNA was not detected in normal mice 6 weeks p.i. In both IgM-/- single knockout and IgM-/- CD8-/- double knockout mice a disseminated infection was still observed by 6 weeks p.i. and the latter group of mice succumbed around two months p.i. In XID mice, only one third of the mice were still positive for viral DNA 6 weeks p.i. No polyomavirus induced tumors were observed in any of the mice during the 2-4 month observation period.

Animals↗
PubMed1997

Lipid metabolism in tumour-bearing mice: studies with knockout mice for tumour necrosis factor receptor 1 protein.

The implantation of the Lewis lung carcinoma (a fast-growing mouse tumour that induces cachexia) to both wild-type and gene-deficient mice for the tumour necrosis factor (TNF) receptor type I protein (Tnfr1(0)/Tnfr1(0)), resulted in a considerable loss of carcass (26%) and white (77%) and brown adipose (37%) tissue weights in the wild-type mice, while it induced much less marked effects in the gene-deficient mice. Tumour burden also inflicted an important decrease in total lipoprotein lipase (LPL) activity in epididymal white adipose tissue (50%) in the wild-type mice while no changes were observed in the knockout mice. In addition, all tumour-bearing animals were clearly hypertriglyceridaemic (80% increase in circulating triacylglycerols in wild-type and 36% in knockout mice). It is concluded that although TNF seems to be to some extent responsible for adipose waste, LPL changes and hyperlipaemia (via receptor I), the role of other cytokines (alone or in combination with TNF) in promoting changes in lipid metabolism during cancer cachexia cannot be discarded.

Adipose Tissue↗
PubMed2002

Blood pressure of endothelin-3 null (-/-) knockout mice and endothelin A receptor null (-/-) knockout mice under anaesthesia.

Blood pressure (BP) and heart rate (HR) in endothelin-3 (ET-3) null (-/-) knockout mice and ET(A) receptor (-/-) mice were measured using the servo null pressure measuring technique under halothane anaesthesia. In infant ET-3 (-/-) mice (2-3 weeks old), mean BP and HR were 55+/-2 mmHg and 436+/-30 beats/min respectively. These values were not different from those in age-matched wild-type mice (53+/-3 mmHg and 430+/-18 beats/min respectively). Baroreflex sensitivity, which was calculated as the slope of the relationship between systolic BP and RR interval on an ECG, was also similar in ET-3 (-/-) mice (0.84+/-0.20 ms/mmHg) and wild-type mice (1.07+/-0.38 ms/mmHg). ET(A) receptor (-/-) mice were obtained by caesarean section on the expected day of delivery and tracheotomized, so that they would live for more than 24 h. Mean BP and HR in ET(A) receptor (-/-) mice were 15+/-1 mmHg and 333+/-6 beats/min respectively. These values were not different from those in age-matched, similarly treated wild-type mice (16+/-3 mmHg and 308+/-10 beats/min respectively). Baroreflex sensitivity in the newborn ET(A) receptor (-/-) mice (0.45+/-0.15 ms/mmHg) and wild-type mice (0.31+/-0.06 ms/mmHg) were very low compared with the values in infant wild-type mice, but not different between the mutant mice and their littermates. Moreover, HR in awake ET(A) receptor (-/-) mice (396+/-13 beats/min) was not different from that in wild-type mice (409+/-13 beats/min). These results show that the ET(A) receptor and ET-3 are not involved in cardiovascular regulation, at least during the very early life of the mice. A possible involvement of the ET(A) receptor in BP regulation, if any, seems to occur at later times and/or in some pathological settings.

Animals↗
PubMed1997

Mildly impaired water maze performance in male Fmr1 knockout mice.

Fmr1 knockout mice constitute a putative model of fragile X syndrome, the most common form of heritable mental disability in humans. We have compared the performance of transgenic mice with an Fmr1 knockout with that of normal littermates in hidden- and visible-platform water maze learning, and showed that knockouts exhibit subnormal spatial learning abilities and marginal motor performance deficits. During 12 training trials of the hidden-platform task, escape latency and path length decreased significantly in knockouts and control littermates, and no effect of genotype was found. During four ensuing reversal trials, however, significant differences were found between knockouts and control littermates both in escape latency and path length. During the visible-platform condition, the reversal trials also revealed a difference between knockouts and normal littermates in escape latency, but not in path length. Possibly due to marginal motor incapacity, knockouts swam significantly slower than controls during these latter trials. During both probe trials of the hidden-platform task, knockouts as well as normal littermates spent more time in the target quadrant than in the other quadrants, and percent of time spent in the target quadrant was the same in both groups; swimming velocity was not significantly different between knockouts and normal littermates during these trials. Entries in the target area during the probe trials did show a significant effect of genotype on number of entries. The present results largely confirm and extend our previous findings. Impaired spatial abilities in Fmr1 knockouts might have been due to relatively low response flexibility or high memory interference in Fmr1 knockouts. It remains unclear, however, which brain region or neurochemical system might be involved in these disabilities. We conclude that Fmr1 knockout mice might be a valid model of fragile X mental retardation.

Animals↗
PubMed2002

Production and characterization of Reg knockout mice: reduced proliferation of pancreatic beta-cells in Reg knockout mice.

Reg (regenerating gene) was isolated as a gene specifically expressed in regenerating islets. We have demonstrated in vitro and in vivo that the exogenous addition of rat and human Reg gene products, Reg/REG proteins, induced beta-cell replication via the Reg receptor and thereby ameliorated experimental diabetes. In the present study, we produced Reg knockout mice by homologous recombination. The Reg gene disruption resulted in a null mutation. Knockout mice developed normally. Islets from the Reg knockout mice appeared morphologically indistinguishable from those of normal controls. However, [(3)H]thymidine incorporation in isolated islets from Reg knockout mice was decreased. When hyperplastic islets were induced by the injection of goldthioglucose, the average islet size in Reg knockout mice was significantly smaller than that of control Reg(+/+) mice. We then produced transgenic mice carrying the Reg gene under the control of the rat insulin II promoter (Ins-Reg) to express Reg in beta-cells. Isolated islets from the Ins-Reg transgenic mice showed increased [(3)H]thymidine incorporation. By intercrossing, we produced NOD mice carrying the Ins-Reg transgene and found that development of diabetes in the resultant Ins-Reg transgenic NOD mice was significantly retarded, coinciding with an increase in the pancreatic beta-cell mass. These results indicate that Reg plays an important role in beta-cell growth/regeneration.

Animals↗
PubMed2000

Spatial learning, contextual fear conditioning and conditioned emotional response in Fmr1 knockout mice.

Fmr1 knockout mice are an animal model for fragile X syndrome, the most common form of heritable mental retardation in humans. Fmr1 knockout mice exhibit macro-orchidism and cognitive and behavioural deficits reminiscent of the human phenotype. In the present study additional behavioural and cognitive testing was performed. Knockouts and control littermates were subjected to a spatial learning test using a plus-shaped water maze. Animals had to learn the position of a hidden escape platform during training trials. The position of this platform was changed during subsequent reversal trials. Previously reported deficits in reversal learning were replicated, but we also observed significant differences during the acquisition trials. A plus-shaped water maze experiment with daily changing platform positions failed to provide clear evidence for a working memory impairment, putatively underlying the spatial learning deficits. Two different test settings were used to examine the reported deficit of Fmr1 knockout mice in fear conditioning. Conditioned fear responses were observed in a contextual fear test, and the ability to acquire an emotional response was tested by means of response suppression in a conditioned emotional response procedure. Neither protocol revealed significant differences between controls and knockouts.

Acoustic Stimulation↗
PubMed1999

Calbindin-D(28k) controls [Ca(2+)](i) and insulin release. Evidence obtained from calbindin-d(28k) knockout mice and beta cell lines.

The role of the calcium-binding protein, calbindin-D(28k) in potassium/depolarization-stimulated increases in the cytosolic free Ca(2+) concentration ([Ca(2+)](i)) and insulin release was investigated in pancreatic islets from calbindin-D(28k) nullmutant mice (knockouts; KO) or wild type mice and beta cell lines stably transfected and overexpressing calbindin. Using single islets from KO mice and stimulation with 45 mM KCl, the peak of [Ca(2+)](i) was 3.5-fold greater in islets from KO mice compared with wild type islets (p < 0.01) and [Ca(2+)](i) remained higher during the plateau phase. In addition to the increase in [Ca(2+)](i) in response to KCl there was also a significant increase in insulin release in islets isolated from KO mice. Evidence for modulation by calbindin of [Ca(2+)](i) and insulin release was also noted using beta cell lines. Rat calbindin was stably expressed in betaTC-3 and betaHC-13 cells. In response to depolarizing concentrations of K(+), insulin release was decreased by 45-47% in calbindin expressing betaTC cells and was decreased by 70-80% in calbindin expressing betaHC cells compared with insulin release from vector transfected betaTC or betaHC cells (p < 0.01). In addition, the K(+)-stimulated intracellular calcium peak was markedly inhibited in calbindin expressing betaHC cells compared with vector transfected cells (225 nM versus 1,100 nM, respectively). Buffering of the depolarization-induced rise in [Ca(2+)](i) was also observed in calbindin expressing betaTC cells. In summary, our findings, using both isolated islets from calbindin-D(28k) KO mice and beta cell lines, establish a role for calbindin in the modulation of depolarization-stimulated insulin release and suggest that calbindin can control the rate of insulin release via regulation of [Ca(2+)](i).

1-Methyl-3-isobutylxanthine↗
PubMed2005

Opsin activation of transduction in the rods of dark-reared Rpe65 knockout mice.

Rpe65 knockout mice (Rpe65-/-) are unable to synthesize the visual pigment chromophore 11-cis retinal; however, if these animals are reared in complete darkness, the rod photoreceptors accumulate a small amount of 9-cis retinal and its corresponding visual pigment isorhodopsin. Suction-electrode recording of single rods from dark-reared Rpe65-/- mice showed that the rods were about 400 times less sensitive than wild-type control rods and that the maximum responses were much smaller in amplitude. Spectral sensitivity measurements indicated that Rpe65-/- rod responses were generated by isorhodopsin rather than rhodopsin. Sensitivity and pigment concentration were compared in the same mice by measuring light responses from rods of one eye and pigment concentration from the retina of the other eye. Retinas had 11-35% of the normal pigment level, but the rods were of the order of 20-30 times less sensitive than could be accounted for by the loss in quantum catch. This extra desensitization must be caused by opsin-dependent activation of the visual cascade, which leads to a state equivalent to light adaptation in the dark-adapted rod. By comparing the sensitivity of dark-reared Rpe65-/- rods to that produced in normal rods by background light, we estimate that Rpe65-/- opsin is of the order of 2.5x10(-5) as efficient in activating transduction as photoactivated rhodopsin (Rh*) in WT mice. Dark-reared Rpe65-/- rods are less desensitized than rods from cyclic light-reared Rpe65-/- mice, have about 50% more photocurrent and degenerate at a slower rate. Retinas sectioned after 9 months in darkness show a larger number of photoreceptor nuclei in dark-reared animals than in cyclic light-reared animals, though both have fewer nuclei than in cyclic light-reared wild-type retinas. Both also have shorter outer segments and a lower free-Ca2+ concentration. These experiments provide the first quantitative measurement of opsin activation in physiologically responding mammalian rods.

Animals↗