Max Cynader

Max Cynader
University of British Columbia - Vancouver | UBC · Centre For Brain Health

About

242
Publications
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14,259
Citations
Citations since 2016
2 Research Items
2143 Citations
20162017201820192020202120220100200300
20162017201820192020202120220100200300
20162017201820192020202120220100200300
20162017201820192020202120220100200300

Publications

Publications (242)
Article
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Background: Prenatal alcohol exposure is the leading preventable cause of behavioral and cognitive deficits, which may affect between 2 and 5 % of children in North America. While the underlying mechanisms of alcohol's effects on development remain relatively unknown, emerging evidence implicates epigenetic mechanisms in mediating the range of sym...
Article
Background: Significant protease activations have been reported after traumatic brain injury (TBI). These proteases are responsible for cleavage of transmembrane proteins in neurons, glial, and endothelial cells and this results in the release of their extracellular domains (ectodomains). Methods: Two TBI models were employed here, representing...
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TDP-43 (TAR DNA binding protein 43) is a heterogeneous nuclear ribonucleoprotein (hnRNP) that has been found to play an important role in neurodegenerative diseases. TDP-43's involvement in nuclear factor-kappaB pathways has been reported in both neurons and microglial cells. The NF-κB pathway targets hundreds of genes, many of which are involved i...
Article
Synaptic competition is widely believed to be central to the formation and function of neuronal networks, yet the underlying mechanisms are poorly described. To investigate synaptic competition in vitro, we have developed a novel two input pathway competition model using a 3-compartment microfluidic device. Axons from cultured rat cortical neurons...
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The presence of an extra whole or part of chromosome 21 in people with Down syndrome (DS) is associated with multiple neurological changes, including pathological aging that often meets the criteria for Alzheimer's Disease (AD). In addition, trisomies have been shown to disrupt normal epigenetic marks across the genome, perhaps in response to chang...
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TAR DNA-binding protein 43 (TDP-43) is a protein that is involved in the pathology of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). In patients with these neurodegenerative diseases, TDP-43 does not remain in its normal nuclear location, but instead forms insoluble aggregates in both the nucleus and cytoplasm of...
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Progranulin (PGRN) haploinsufficiency accounts for up to 10% of frontotemporal lobe dementia. PGRN has also been implicated in neuroinflammation in acute and chronic neurological disorders. Here we report that both protein and mRNA levels of cortical and hippocampal PGRN are significantly enhanced following pilocarpine-induced status epilepticus. W...
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Secretory trafficking through the Golgi complex is critical for neuronal development, function, and stress response. Altered secretion is associated with the pathogenesis of various neurological diseases. We found that c-Jun amino-terminal kinase 3 (JNK3) inhibited secretory trafficking by promoting the depletion of phosphatidylinositol 4-phosphate...
Article
Loss-of-function mutations in the progranulin (GRN) gene are a common cause of autosomal dominant frontotemporal lobar degeneration, a fatal and progressive neurodegenerative disorder common in people less than 65 years of age. In the brain, progranulin is expressed in multiple regions at varying levels, and has been hypothesized to play a neuropro...
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In this paper, the auditory motion aftereffect (aMAE) was studied, using real moving sound as both the adapting and the test stimulus. The sound was generated by a loudspeaker mounted on a robot arm that was able to move quietly in three-dimensional space. A total of 7 subjects with normal hearing were tested in three experiments. The results from...
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The NMDAR plays a unique and vital role in subcellular signaling. Calcium influx initiates signaling cascades important for both synaptic plasticity and survival; however, overactivation of the receptor leads to toxicity and cell death. This dichotomy is partially explained by the subcellular location of the receptor. NMDARs located at the synapse...
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The study of experience-dependent ocular dominance (OD) plasticity has greatly contributed to the understanding of visual development. During the critical period, preventing input from one eye results in a significant impairment of vision, and loss of cortical responsivity via the deprived eye. Residual ocular dominance plasticity has recently been...
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The c-jun N-terminal kinase (JNK) proteins are encoded by three genes (Jnk1-3), giving rise to 10 isoforms in the mammalian brain. The differential roles of JNK isoforms in neuronal cell death and development have been noticed in several pathological and physiological contexts. However, the mechanisms underlying the regulation of different JNK isof...
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Although the palmitoyl acyltransferase (PAT) zinc-finger DHHC containing 17 (zD17) has been implicated in genetic neurological disorders by regulating protein palmitoylation, the role of zD17 in acute brain injury remains unknown. Here, we report that zD17 contributes to acute ischemic brain injury via a mechanism independent of its PAT activity. W...
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Frontotemporal dementia (FTD) has been linked to mutations in the progranulin gene (GRN) that lead to progranulin (PGRN) haploinsufficiency. Thus far, our understanding of the effects of PGRN depletion in the brain has been derived from investigation of gross pathology, and more detailed analyses of cellular function have been lacking. We report th...
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To investigate the morphologic and molecular consequences of 30- and 90-minute central retinal artery ligation (CRAL)-induced retinal ischemia, followed by 3 and 12 hours of reperfusion, and to identify potential targets for therapy. Retinal ischemia was induced for 30 and 90 minutes by ligating the rat central retinal artery, and corresponding eff...
Article
Null mutations in the progranulin gene (PGRN) have been identified as a major cause of frontotemporal dementia with ubiquitinated inclusions. In this disorder, ubiquitinated, aggregated protein inclusions of a normally nuclear-located RNA processing protein called TAR DNA binding protein (TDP-43) accumulate in the neuronal cytoplasm (FTLD-TDP). To...
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Excitotoxic neuronal damage caused by overactivation of N-methyl-D-aspartate glutamate receptors (NMDARs) is thought to be a principal cause of neuronal loss after stroke and brain trauma. Here we report that activation of sterol regulatory element binding protein-1 (SREBP-1) transcription factor in affected neurons is an essential step in NMDAR-me...
Article
Purpose. To investigate the pattern of dopamine-ß-hydroxylase (DBH)-containing fibers in human and monkey eyes. Methods. DBH-containing fibers were detected by immuno-histochemistry. The primary antibody used recognized DBH, the key enzyme in the conversion of dopamine to noradrenaline. Results. In the anterior segment, DBH immunoreaction product w...
Article
The AMPA receptor (AMPAR) subunits GluR1 and GluR2 show different properties in central neurons and affect AMPAR trafficking via distinct mechanisms. This subunit-specificity is partly achieved by recruiting unique protein modifications on different subunits. Here, we show that palmitoylation of GluR1 and GluR2 subunits also displays subunit-specif...
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We report the first demonstration that Krüpple-like factor 4 (KLF4) mRNA is dramatically and rapidly upregulated by NMDA application in primary cortical neuron cultures. We also report that NMDA induced significant and transient upregulation of KLF4 protein expression, in both cortical neuron cultures and native brain slices. The increase of KLF4 m...
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Bilirubin, an abundant bile pigment in mammalian serum, was once considered a toxic waste product and has more recently been recognized as a potent antioxidant of physiological importance. However, its potential biological functions in other fields are not well understood. Herein we show that bilirubin is also a powerful immunomodulatory agent. Bil...
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Anisomycin is both a well-established protein synthesis inhibitor and a potent activator of the p38/JNK MAPK pathway. It has been used to block the late phase of long-term potentiation (LTP) and long-term depression (LTD) in hippocampus. In this study, we have found that anisomycin produces a time-dependent decline in the magnitude of the field EPS...
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Oxidative stress plays an important role in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Bilirubin is regarded today as a potent antioxidant. Recent studies show that the potent antioxidant actions of bilirubin reflect an amplification mechanism whereby biliverdin reductase (BVR) phys...
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Zinc is packaged in, and released from, a subset of glutamatergic synapses in the mammalian telencephalon where it has been shown to act as a potent neuromodulator. In order to establish the functional role for zincergic neurons in visual cortical function and plasticity we have compared the topographic distribution of zincergic terminals in the pr...
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Increasing evidence shows that oxidative stress plays an important role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). In recent years, bilirubin has been demonstrated to be a potent antioxidant in vitro. In this study, we administered bilirubin to rats with acute and chronic EA...
Article
Evidence has shown that excitotoxicity may contribute to the loss of central nervous system axons and oligodendrocytes in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Because dendrites and synapses are vulnerable to excitotoxicity, we examined these structures in acute and chronic models of EAE. Immunostaining for microtu...
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Fas ligand (FasL) is an essential molecule strongly expressed in some immunoprivileged sites, but is expressed at very low levels in normal CNS. In this study, acute experimental autoimmune encephalomyelitis (EAE) was induced in Lewis rats with guinea pig myelin basic protein. Intrathecal infusion of recombinant FasL before EAE onset dose dependent...
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During a critical period in its postnatal development the mammalian visual cortex displays susceptibility to experience-dependent alterations of neuronal response properties. Plasticity represents an integrated set of developmental processes controlled by a transcriptional hierarchy that coordinates the action of many genes. To illuminate the expre...
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Increasing evidence shows that oxidative stress plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of the human disease, multiple sclerosis (MS). Heme oxygenase-1 (HO-1) is a heat shock protein induced by oxidative stress. HO-1 metabolizes heme to the antioxidant bilirubin and carbon mono...
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We have found previously that astrocytes can provide cysteine to neurons. However, cysteine has been reported to be neurotoxic although it plays a pivotal role in regulating intracellular levels of glutathione, the major cellular antioxidant. Here, we show that cysteine toxicity is a result of hydroxyl radicals generated during cysteine autoxidatio...
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Both cholinergic and serotonergic modulatory projections to mammalian striate cortex have been demonstrated to be involved in the regulation of postnatal plasticity, and a striking alteration in the number and intracortical distribution of cholinergic and serotonergic receptors takes place during the critical period for cortical plasticity. As well...
Article
The hybridization patterns of 18,371 high-density-grid-arrayed non-redundant complementary DNA (cDNA) clones were examined using three different sources of cDNA probes. The first set of probes was synthesized from mRNA isolated from visual brain areas MT and V4 of Vervet monkey. The second set of probes was derived from cDNA libraries constructed f...
Article
Full-text available
In this paper, the auditory motion aftereffect (aMAE) was studied, using real moving sound as both the adapting and the test stimulus. The sound was generated by a loudspeaker mounted on a robot arm that was able to move quietly in three-dimensional space. A total of 7 subjects with normal hearing were tested in three experiments. The results from...
Article
Cysteine is the rate-limiting precursor of glutathione synthesis. Evidence suggests that astrocytes can provide cysteine and/or glutathione to neurons. However, it is still unclear how cysteine is released and what the mechanisms of cysteine maintenance by astrocytes entail. In this report, we analyzed cysteine, glutathione, and related compounds i...
Article
It has been known since the 1960s that, if one eye of a young kitten is covered, there is a change in neuronal connections in the visual pathway in the brain for that eye. In a Perspective, Cynader discusses new findings ( Trachtenberg et al. ) showing that alterations in neural connections from the sensory-deprived eye are found first in the lower...
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Recent studies have identified the potential for an important role for serotonin (5-HT) receptors in the developmental plasticity of the kitten visual cortex. 5-HT(2C) receptors are transiently expressed in a patchy fashion in the visual cortex of kittens between 30-80 days of age complementary to patches demarcated by cytochrome oxidase staining....
Article
The fluorescence-conjugated N-methyl-D-aspartate receptor-selective antagonist, BODIPY-conantokin-G, was employed to label N-methyl-D-aspartate receptors in living neurons derived from the visual cortex of embryonic rats. The fluorescent labeling was visualized and analysed using confocal microscopy and digital imaging techniques. BODIPY-conantokin...
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Pairs of stimulus attributes, such as color and orientation, that are normally uncorrelated in the real world are generally perceived independently; that is, the perception of color is usually uninfluenced by orientation and vice versa. Yet this independence can be altered by relatively brief exposure to artificially correlated stimuli, as has been...
Article
In order to study the neurosupportive effects of glial cells, we optimized a glial-neuron non-contact co-culture method. Astrocyte conditioned medium (ACM) and an astrocyte feeder layer were used to promote neuronal attachment and neuronal survival respectively. Neuron-enriched cultures were prepared from cortices of E-18 day rat embryos. Instead o...
Article
Gene therapy in the anterior and posterior segment tissues may have the potential to favorably influence aqueous hydrodynamics and retinal ganglion cell biology, thereby preventing, delaying, or minimizing glaucomatous damage to the optic nerve. We demonstrated the feasibility of using a herpes viral vector (ribonucleotide reductase defective HSV-1...
Article
Axonal loss and degeneration in multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE) have been suggested by brain imaging, pathological and axonal transport studies. Further elucidation of the processes and mechanisms of axonal degeneration in demyelinating diseases is therefore of potential importance in order to alleviate the...
Article
To investigate the pattern of dopamine-beta-hydroxylase (DBH)-containing fibers in human and monkey eyes. DBH-containing fibers were detected by immunohistochemistry. The primary antibody used recognized DBH, the key enzyme in the conversion of dopamine to noradrenaline. In the anterior segment, DBH immunoreaction product was found in the periphera...
Article
Full-text available
Two patterns of appropriately filtered acoustic white noise can be binaurally fused by the human auditory system to extract pitch and location information that is not available to either ear alone. This phenomenon is called dichotic pitch. Here we present a new method for generating more effective and useful dichotic pitch stimuli. These novel stim...
Article
To localize nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) in normal human and monkey eyes. NADPH-d activity in ocular tissue sections was revealed by histochemical staining. NADPH-d staining was found in the anterior and posterior ocular segment of both species. In the anterior segment, reaction product was present in the corneal...
Article
The expression and distribution patterns of transmitter receptors change dramatically during pre- and post-natal development of the visual cortex, but the factors that control these processes are largely unknown. We have tested the hypothesis that input activity from the lateral geniculate nucleus (LGN), one major input source to visual cortex, may...
Article
The neuroprotective effects of the NMDA receptor blocker APV were compared with those of bcl-2 in a glutamate-induced excitotoxic cell death model in cultured rat cortical neurons. Exposure to 100 microM glutamate for 5 h caused approximately 95% of the cultured neurons to die in 24 h. The NMDA-selective antagonist D-(-)-2-amino-5-phosphonopentanoa...
Article
To date, there have been only a few studies of the auditory motion aftereffect (aMAE). All of these studies used simulated moving sound as adapting or test stimuli. In the present study, real moving sound was used as both the adapting and test stimuli. The real moving sound was generated with a loudspeaker mounted on a robot arm which was able to m...
Article
The expression and distribution of alpha 1 receptors in cultured neurons derived from rat visual cortex were studied with confocal microscopy using the fluorescently labeled alpha 1 adrenergic receptor selective antagonist BODIPY FL prazosin. The receptors were found to be clustered on neuronal somata and on proximal dendrites. We found that expres...
Article
We have addressed the role of serotonin-2C (5-HT2C) receptors in the development and maintenance of synaptic plasticity in the kitten visual cortex. In visual cortical slices, taken from 40- to 80-day-old kittens, bath application of serotonin markedly facilitated the induction of both long-term depression (LTD) and long-term potentiation (LTP). Fi...
Article
We have investigated the role of serotonin-2C (5-HT2C) receptors in modulation of ocular dominance plasticity in kitten visual cortex. A small quantity of the 5-HT2C receptor blocker, mesulergine, was infused into the visual cortex of one hemisphere of 5- to 7-week-old kittens using osmotic minipumps, while the control hemisphere received vehicle s...
Article
The purpose of this study was to visualize muscarinic receptors and their distribution on cardiomyocytes and to examine the effects of muscarinic cholinergic receptor (mACh-R) stimulation with carbachol on phosphatidylcholine hydrolysis. Cardiomyocytes were prepared as primary culture from 7-day-old chick embryo hearts. Cardiomyocytes, grown on cov...
Article
Intraocular pressure (IOP), which causes the lamina cribrosa to bulge backward, produces a pressure gradient along the axoplasm of exiting optic nerve axons, and challenges the circulation, interacts with presently unknown physiologic or anatomic factors to harm the optic nerve and causes loss of vision. Present treatment of glaucoma is limited to...
Article
The product of the bcl-2 oncogene has been shown to play an important role in apoptosis and programmed cell death. In this study, a herpes simplex virus type-1 vector was constructed to carry the human bcl-2 gene. The possible role of bcl-2 in protecting neurons from excitoxicity was investigated by using the viral vector to deliver the gene into n...
Article
Nerve growth factor (NGF) has been shown to play important roles in neuronal survival, growth and differentiation. Recently, we have found that intracortical infusion of NGF into adult cat visual cortex can recreate ocular dominance plasticity, suggesting that NGF is also involved in activity-dependent modification of synaptic connectivity in the a...
Article
In primary neuronal cultures derived from the visual cortex of embryonic day 16-18 rats, intracellular free calcium concentration, [Ca2+]i, was increased by bath application of glutamate in a dose-dependent manner. Noradrenaline applied alone had relatively small effects. However, when glutamate concentrations eliciting modest increases in [Ca2+]i...
Article
It has been previously reported that the monoclonal antibody SMI-32 reveals a characteristic pattern of immunostaining which may be used to delineate various cortical modules in the monkey visual system. We wished to examine staining patterns with this antibody at both the lateral geniculate nucleus (LGN) and cortical levels with regard to magno- a...
Article
Purpose. To express a foreign gene in the aqueous outflow pathway of the living cat eye by infection with a herpes virus vector. Methods. Living cats received intracameral injection of 3x105 or 8x107 pfu of ICP6- HSV-1 (capable of replicating only in actively proliferating cells) containing the lac-z reporter gene. Some eyes were pre-treated with P...
Article
Ligand-stimulated phosphoinositide hydrolysis activates a bifurcating second messenger system, releasing inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DG), which activates protein kinase C (PKC). Yet, in developing cat visual cortex and hippocampus, high levels of [3H]PDBu binding (labelling PKC) appear much earlier than do [3H]IP3 labelle...
Article
Defective herpes simplex virus type 1 vectors (HSV amplicons) have been used as vehicles for efficiently delivering foreign genes into non-dividing cells such as neutrons in vitro and in vivo. This system is useful for studying neuronal physiology and may have potential for human gene therapy of neuronal disorders. The preparation of infectious amp...
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Synaptic depression was assessed from intracellular recordings in cortical tissue slices. Evoked postsynaptic potentials exhibited synaptic depression with an exponential or double exponential decrease (time constants: < 1-30 s) in amplitude during repetitive afferent stimulation by short trains of suprathreshold stimuli. Depressed synaptic respons...
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Full-text available
Thromboxane A2 (TxA2) receptors in human eye sections were identified and localised using a potent TxA2 specific agonist, 125-iodinated 5-heptenoic acid 7-[3-[3-hydroxy-4-[4-(iodo-125I) phenoxy]-1-butenyl]-7- oxabicyclo[2.2.1]hept-2-yl]-,[1S-[1a,2a,(Z),3B(1E,3S*),4a]]-C23 H29 IO5 (125I-BOP) in a binding assay. TxA2 receptors were concentrated in se...
Article
It is now well established that environmental signals mediated via neurotransmitters and hormones can induce responses in cells which involve a cascade of receptors, G proteins, and second messengers. These in turn can induce transcription factors which regulate long-term changes in gene expression. It has been proposed that the stimulus-transcript...
Article
Alpha-1 and alpha-2 adrenergic receptors were localized in developing cat visual cortex by using [3H]prazosin and [3H]rauwolscine, respectively as selective ligands. The effects of neuronal input on the development of the two receptor subtypes were also studied in animals with lesions at various sites within the central visual pathways. Binding den...
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Previous studies have indicated that adrenergic receptors show significant changes either in laminar distribution or in number during the critical period of kitten visual cortex development. In order to further investigate the postnatal development of this neurotransmitter system, especially in relation to the critical period, we used a polyclonal...
Article
Direction-selective neurons in cat striate cortex were tested with bar-shaped stimuli, sequentially flashed at spatially displaced positions chosen to elicit maximal direction selectivity. Temporally overlapping flash exposures of prolonged duration (400-1000 ms) were employed at a series of onset asynchronies to explore the nature of temporal tuni...
Article
Neurofilament proteins are major constituents of the neuronal cytoskeleton. When phosphorylated, neurofilament proteins are thought to be involved in slowing down the slower component of axonal transport, thereby increasing neurofilament stability and conferring resistance to proteolysis. In order to investigate the correlation between phosphorylat...
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Full-text available
Activity-dependent modifiability of cortical ocular dominance occurs only during early postnatal life, within the so-called "critical period," but not thereafter in adult visual cortex. To examine the role of neurotrophins in the activity- and age-dependent stimulation-induced modifiability of visual cortex, we tested whether intracortical infusion...
Article
Thymidine kinase-deficient herpes simplex virus type 1 [tk(-) HSV-1] replicates well in dividing cells but not in nondividing cells such as neurons, suggesting a potential use in the treatment of brain tumors. We attempted to examine the efficacy of using tk(-) HSV-1 for treating brain tumors in immunocompetent animals. 9L glioma cells were culture...
Article
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The fluorescently labeled muscarinic M1 receptor-selective antagonist BODIPY FL pirenzepine has been employed to study the activity-dependent distribution and expression of muscarinic M1 ACh receptors (M1AChRs) in cultured neurons derived from rat visual cortex. Displacement experiments showed that like pirenzepine, binding of BODIPY FL pirenzepine...
Article
Full-text available
Muscarinic cholinergic agents are used to lower intraocular pressure in the medical management of glaucoma and subtypes of muscarinic receptors have now been recognised in many tissues including the eye. To localise muscarinic receptors and their M1 and M2 subtypes in the human eye, in vitro ligand binding and autoradiographic techniques with densi...
Article
Receptor autoradiographic methods specific for M3 and M1 muscarinic acetylcholine receptors were used to investigate the development and input-dependent laminar redistribution of these receptor populations during the critical period for kitten visual cortex plasticity. Analysis of the binding curves of [3H]4-diphenylacetyl-N-methyl-piperidine (4-DA...
Article
Receptor autoradiographic methods specific for M3 and M1 muscarinic acetylcholine receptors were used to investigate the development and input-dependent laminar redistribution of these receptor populations during the critical period for kitten visual cortex plasticity. Analysis of the binding curves of (4-DAMP) and [3H]pirenzepine (PZ) indicated th...
Article
We have used the method of subtractive hybridization to isolate cDNA clones of mRNAs expressed in abundance in the visual cortex of 30-day-old kittens but absent or in lower abundance in the adult cat visual cortex. Of 12,000 colonies screened, 200 clones which hybridized to the subtracted probe were isolated and characterized. Northern blots confi...
Article
The localization of tachykinin-immunoreactivity in the cat visual cortex (area 17) was investigated using immunohistochemical methods. Strong laminar specificity was observed, with immunoreactivity highest in layer V, followed by layers I, VI, II and III, and the lowest density in layer IV. Most of the immunoreactive product was localized in neuron...
Article
The effects of postnatal development, aging and the oestrous cycle on muscarinic acetylcholine receptor (mAChR) properties were examined in in vitro living slices of rat neocortex. Using the hydrophilic antagonist ([3H]NMS) to label cell surface mAChRs, an increase in both Bmax and Kd was found during the first postnatal weeks. These values peaked...
Article
Full-text available
Cholinergic agents used to lower intraocular pressure in the medical management of glaucoma act on muscarinic receptors in the eye. Recently, subtypes of muscarinic receptors have been recognized in many tissues including the eye. To localize the M3 muscarinic receptor subtype and m3 messenger RNA (mRNA) in the human eye, we used in vitro ligand bi...