The Experts below are selected from a list of 1791 Experts worldwide ranked by ideXlab platform
Olivier J Manzoni - One of the best experts on this subject based on the ideXlab platform.
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Muscarinic M1 Receptor modulation of synaptic plasticity in nucleus accumbens of wild type and fragile x mice
ACS Chemical Neuroscience, 2018Co-Authors: Daniela Neuhofer, Olivier Lassalle, Olivier J ManzoniAbstract:We investigated how metabotropic acetylcholine Receptors control excitatory synaptic plasticity in the mouse nucleus accumbens core. Pharmacological and genetic approaches revealed that M1 mAChRs (Muscarinic acetylcholine Receptors) trigger multiple and interacting forms of synaptic plasticity. As previously described in the dorsal striatum, moderate pharmacological activation of M1 mAChR potentiated postsynaptic NMDARs. The M1-potentiation of NMDAR masked a previously unknown coincident TRPV1-mediated long-term depression (LTD). In addition, strong pharmacological activation of M1 mAChR induced canonical retrograde LTD, mediated by presynaptic CB1R. In the fmr1-/y mouse model of Fragile X, we found that CB1R but not TRPV1 M1-LTD was impaired. Finally, pharmacological blockade of the degradation of anandamide and 2-arachidonylglycerol, the two principal endocannabinoids restored fmr1-/y LTD to wild-type levels. These findings shed new light on the complex influence of acetylcholine on excitatory synapses ...
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Muscarinic M1 Receptor modulation of synaptic plasticity in nucleus accumbens of wild type and fragile x mice
bioRxiv, 2018Co-Authors: Daniela Neuhofer, Olivier Lassalle, Olivier J ManzoniAbstract:We investigated how metabotropic Acetylcholine Receptors control excitatory synaptic plasticity in the mouse nucleus accumbens core. Pharmacological and genetic approaches revealed that M1 mAChRs trigger multiple and interacting forms of synaptic plasticity. As previously described in the dorsal striatum, moderate pharmacological activation of M1 mAChR potentiated postsynaptic NMDARs. The M1-potentiation of NMDAR masked a previously unknown coincident TRPV1-mediated long-term depression (LTD). In addition, strong pharmacological activation of M1 mAChR induced canonical retrograde LTD, mediated by presynaptic CB1R. In the fmr1-/y mouse model of Fragile X, we found that CB1R but not TRPV1 M1-LTD was impaired. Finally, pharmacological blockade of the degradation of anandamide and 2-arachidonylglycerol, the two principal eCBs restored fmr1-/y LTD to wild type levels. These findings shed new lights on the complex influence of Acetylcholine on excitatory synapses in the nucleus accumbens core and identify new substrates of the synaptic deficits of Fragile X.
Elizabeth Scarr - One of the best experts on this subject based on the ideXlab platform.
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Low levels of Muscarinic M1 Receptor-positive neurons in cortical layers III and V in Brodmann areas 9 and 17 from individuals with schizophrenia.
Journal of Psychiatry & Neuroscience, 2018Co-Authors: Elizabeth Scarr, Shaun Hopper, Tim D. Aumann, Gursharan Chana, Ian Everall, Brian DeanAbstract:BACKGROUND: Results of neuroimaging and postmortem studies suggest that people with schizophrenia may have lower levels of Muscarinic M1 Receptors (CHRM1) in the cortex, but not in the hippocampus or thalamus. Here, we use a novel immunohistochemical approach to better understand the likely cause of these low Receptor levels. METHODS: We determined the distribution and number of CHRM1-positive (CHRM1+) neurons in the cortex, medial dorsal nucleus of the thalamus and regions of the hippocampus from controls (n = 12, 12 and 5, respectively) and people with schizophrenia (n = 24, 24 and 13, respectively). RESULTS: Compared with controls, levels of CHRM1+ neurons in people with schizophrenia were lower on pyramidal cells in layer III of Brodmann areas 9 (-44%) and 17 (-45%), and in layer V in Brodmann areas 9 (-45%) and 17 (-62%). We found no significant differences in the number of CHRM1+ neurons in the medial dorsal nucleus of the thalamus or in the hippocampus. LIMITATIONS: Although diagnostic cohort sizes were typical for this type of study, they were relatively small. As well, people with schizophrenia were treated with antipsychotic drugs before death. CONCLUSION: The loss of CHRM1+ pyramidal cells in the cortex of people with schizophrenia may underpin derangements in the cholinergic regulation of GABAergic activity in cortical layer III and in cortical/subcortical communication via pyramidal cells in layer V.
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43.2 Muscarinic M1 ReceptorS: INVOLVEMENT IN THE PATHOPHYSIOLOGY AND TREATMENT OF SCHIZOPHRENIA.
Schizophrenia Bulletin, 2018Co-Authors: Brian Dean, Shaun Hopper, Elizabeth ScarrAbstract:AbstractBackgroundEvidence from postmortem CNS studies and a neuroimaging study suggest that, compared to controls, there are low levels of Muscarinic Receptors in a number of CNS regions from subjects with schizophrenia. Current data suggests the Muscarinic M1 Receptor is lower in the cortex of subjects with schizophrenia but other Muscarinic Receptors may be decreased in sub-cortical regions such as the striatum and hippocampus. In addition, it has been reported that ~25% of subjects with schizophrenia can be divided into a distinct sub-group because they have a marked decrease in cortical Muscarinic M1 Receptors (Muscarinic Receptor deficit schizophrenia (MRDS)). These findings have become of clinical significance because proof of principal data shows that treating subjects with schizophrenia with drugs that activate the Muscarinic M1 Receptor is effective in lessening the symptoms associated with the disorder.MethodsPublished and unpublished data will be reviewed to challenge the hypothesis that drugs that activate the Muscarinic M1 Receptor will be useful in treating schizophrenia.ResultsA proof of clinical trial has shown that treating subjects with treatment resistant schizophrenia with the Muscarinic M1 and 4 Receptor agonist, xanomeline, improves positive and negative symptoms as well as cognitive deficits. Moreover, it has more recently been reported that giving xanomeline on a transdermal patch with a peripheral Muscarinic Receptor antagonist can lessen the unwanted side effects of the drug to that of placebo. Relevant to these data is the finding that there is a sub-group of subjects with MRDS as the absence of cortical Muscarinic M1 Receptors in these Receptors may make these subjects resistant to treatment with Muscarinic M1 Receptor agonists. However, novel studies using postmortem CNS from subjects with MRDS and non-MRDS has shown that whilst subjects with MRDS will likely be resistant to Muscarinic M1 Receptor orthosteric agonists (oxotremorine-M) they will, at least partially, respond to Muscarinic M1 Receptor allosteric agonists (AC-42) or positive allosteric modulators (BQCA).DiscussionMuscarinic Receptor agonism appears to be a promising new treatment for schizophrenia. However, some subjects with MRDS may only respond to activation of the allosteric site on the Muscarinic M1 Receptor. Evidence from a neuroimaging study suggests subjects with MRDS can be identified whilst living. Hence, establishing the Muscarinic Receptor status of subjects involved in trials of Muscarinic M1 Receptor agonists may help in explaining varying levels of treatment responsiveness in subjects with schizophrenia. These conclusions, being directed by data from studies using postmortem CNS, reflect the need for drug discovery and delivery to be based on a growing understanding of the pathophysiology(ies) of schizophrenia.
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Changed gene expression in subjects with schizophrenia and low cortical Muscarinic M1 Receptors predicts disrupted upstream pathways interacting with that Receptor
Molecular Psychiatry, 2016Co-Authors: Elizabeth Scarr, Madhara Udawela, Elizabeth A. Thomas, Brian DeanAbstract:We tested the hypothesis that, compared with subjects with no history of psychiatric illness (controls), changes in gene expression in the dorsolateral prefrontal cortex from two subgroups of subjects with schizophrenia, one with a marked deficit in Muscarinic M1 Receptors (Muscarinic Receptor-deficit schizophrenia (MRDS)), would identify different biochemical pathways that would be affected by their aetiologies. Hence, we measured levels of cortical (Brodmann area 9) mRNA in 15 MRDS subjects, 15 subjects with schizophrenia but without a deficit in Muscarinic M1 Receptors (non-MRDS) and 15 controls using Affymetrix Exon 1.0 ST arrays. Levels of mRNA for 65 genes were significantly different in the cortex of subjects with MRDS and predicted changes in pathways involved in cellular movement and cell-to-cell signalling. Levels of mRNA for 45 genes were significantly different in non-MRDS and predicted changes in pathways involved in cellular growth and proliferation as well as cellular function and maintenance. Changes in gene expression also predicted effects on pathways involved in amino acid metabolism, molecular transport and small-molecule biochemistry in both MRDS and non-MRDS. Overall, our data argue a prominent role for glial function in MRDS and neurodevelopment in non-MRDS. Finally, the interactions of gene with altered levels of mRNA in the cortex of subjects with MRDS suggest many of their affects will be upstream of the Muscarinic M1 Receptor. Our study gives new insight into the molecular pathways affected in the cortex of subjects with MRDS and supports the notion that studying subgroups within the syndrome of schizophrenia is worthwhile.
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The distribution of Muscarinic M1 Receptors in the human hippocampus.
Journal of Chemical Neuroanatomy, 2016Co-Authors: Elizabeth Scarr, Tim D. Aumann, Gursharan Chana, Ian Everall, Brian DeanAbstract:The Muscarinic M1 Receptor plays a significant role in cognition, probably by modulating information processing in key regions such as the hippocampus. To understand how the Muscarinic M1 Receptor achieves these functions in the hippocampus, it is critical to know the distribution of the Receptor within this complex brain region. To date, there are limited data on the distribution of Muscarinic M1 Receptors in the human hippocampus which may also be confounded because some anti-Muscarinic Receptor antibodies have been shown to lack specificity. Initially, using Western blotting and immunohistochemistry, we showed the anti-Muscarinic M1 Receptor antibody to be used in our study bound to a single 62kDa protein that was absent in mice lacking the Muscarinic M1 Receptor gene. Then, using immunohistochemistry, we determined the distribution of Muscarinic M1 Receptors in human hippocampus from 10 subjects with no discernible history of a neurological or psychiatric disorder. Our data shows the Muscarinic M1 Receptor to be predominantly on pyramidal cells in the hippocampus. Muscarinic M1 Receptor positive cells were most apparent in the deep polymorphic layer of the dentate gyrus, the pyramidal cell layer of cornu ammonis region 3, the cellular layers of the subiculum, layer II of the presubiculum and layer III and V of the parahippocampal gyrus. Positive cells were less numerous and less intensely stained in the pyramidal layer of cornu ammonis region 2 and were sparse in the molecular layer of the dentate gyrus as well as cornu ammonis region 1. Although immunoreactivity was present in the granular layer of the dentate gyrus, it was difficult to identity individual immunopositive cells, possibly due to the density of cells. This distribution of the Muscarinic M1 Receptors in human hippocampus, and its localisation on glutamatergic cells, would suggest the Receptor has a significant role in modulating excitatory hippocampal neurotransmission.
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COMT genotype is associated with differential expression of Muscarinic M1 Receptors in human cortex
American Journal of Medical Genetics, 2016Co-Authors: Brian Dean, Elizabeth ScarrAbstract:Catechol-O-methyltransferase (COMT) genotype has been associated with varying levels of cognitive functioning and an altered risk of schizophrenia. COMT regulates the breakdown of catecholamines, particularly dopamine, which is thought critical in maintaining cognitive function and the aetiology of schizophrenia. This hypothesis gained support from reports that the VAL allele at rs4680 was associated with poorer performance on cognitive tests and a slightly increased risk of schizophrenia. More recently, genotype at rs4818, part of a hapblock with rs4680, has been shown to impact on cognitive ability more than genotype at rs4680 but, as yet, not the risk for schizophrenia. Here, we determined if COMT genotype at rs4680 or rs4818, as well as rs165519 and rs737865, two synonymous single nucleotide polymorphisms (SNPs) with no known functional consequences, were associated with an altered risk of schizophrenia and if genotype at the four COMT SNPs was related to expression of the cortical Muscarinic M1 Receptor (CHRM1) because the expression of the cortical CHRM1 has been reported to be lower in schizophrenia and is important in maintaining cognitive functioning in humans. We report that the variation in gene sequence at the four COMT SNPs studied was not associated with an altered the risk of schizophrenia but genotype at rs4680 and rs4818, but not rs165519 and rs737865, were associated with varying levels of cortical CHRM1 expression in the human dorsolateral prefrontal cortex (DLPFC). These data are the first to suggest that levels of CHRM1 in the human DLPFC are, in part, determined by COMT gene sequence. © 2016 Wiley Periodicals, Inc.
Scott D. Kuduk - One of the best experts on this subject based on the ideXlab platform.
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The Muscarinic M1 Receptor positive allosteric modulator PQCA improves cognitive measures in rat, cynomolgus macaque, and rhesus macaque
Psychopharmacology, 2013Co-Authors: Jason M. Uslaner, Donnie Eddins, Vanita Puri, Christopher E. Cannon, Jane Sutcliffe, Chan Sing Chew, Michelle Pearson, Jeffrey A. Vivian, Ronald K. Chang, Scott D. KudukAbstract:Rationale The current standards of care for Alzheimer’s disease, acetylcholinesterase inhibitors, have limited efficacy due to a host of mechanism-related side effects arising from indiscriminate activation of Muscarinic and nicotinic Receptors. The M1 Muscarinic Receptor is predominantly expressed in the brain in regions involved in cognition, and therefore selective activation of the M1 Receptor would be expected to boost cognitive performance with reduced risk of peripheral side effects. Objectives Here we investigated whether the selective M1 Muscarinic Receptor positive allosteric modulator, PQCA, improves cognitive performance and cerebral blood flow. Results PQCA attenuated a scopolamine-induced deficit in novel object recognition in rat, self-ordered spatial search in cynomolgus macaque, and the object retrieval detour task in rhesus macaque. Beneficial effects in each of these assays and species were observed at similar plasma drug concentrations. Furthermore, at similar drug concentrations that were effective in the behavioral studies, PQCA increased blood flow in the frontal cortex of mice, providing a translational biomarker that could be used to guide dose selection for clinical studies. Conclusions These findings provide a framework for appropriately testing an M1 selective compound in patients with Alzheimer’s disease.
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the Muscarinic M1 Receptor positive allosteric modulator pqca improves cognitive measures in rat cynomolgus macaque and rhesus macaque
Psychopharmacology, 2013Co-Authors: Jason M. Uslaner, Donnie Eddins, Vanita Puri, Christopher E. Cannon, Jane Sutcliffe, Chan Sing Chew, Michelle Pearson, Jeffrey A. Vivian, Ronald K. Chang, Scott D. KudukAbstract:Rationale The current standards of care for Alzheimer’s disease, acetylcholinesterase inhibitors, have limited efficacy due to a host of mechanism-related side effects arising from indiscriminate activation of Muscarinic and nicotinic Receptors. The M1 Muscarinic Receptor is predominantly expressed in the brain in regions involved in cognition, and therefore selective activation of the M1 Receptor would be expected to boost cognitive performance with reduced risk of peripheral side effects.
Brian Dean - One of the best experts on this subject based on the ideXlab platform.
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Widespread Changes in Positive Allosteric Modulation of the Muscarinic M1 Receptor in Some Participants With Schizophrenia.
The International Journal of Neuropsychopharmacology, 2019Co-Authors: Shaun Hopper, Geoffrey Pavey, Andrea Gogos, Brian DeanAbstract:BACKGROUND: Preclinical and some human data suggest allosteric modulation of the Muscarinic M1 Receptor (CHRM1) is a promising approach for the treatment of schizophrenia. However, it is suggested there is a subgroup of participants with schizophrenia who have profound loss of cortical CHRM1 (MRDS). This raises the possibility that some participants with schizophrenia may not respond optimally to CHRM1 allosteric modulation. Here we describe a novel methodology to measure positive allosteric modulation of CHRM1 in human CNS and the measurement of that response in the cortex, hippocampus, and striatum from participants with MRDS, non-MRDS and controls. METHODS: The cortex (Brodmann's area 6), hippocampus, and striatum from 40 participants with schizophrenia (20 MRDS and 20 non-MRDS) and 20 controls were used to measure benzyl quinolone carboxylic acid-mediated shift in acetylcholine displacement of [3H]N-methylscopolamine using a novel in situ radioligand binding with autoradiography methodology. RESULTS: Compared with controls, participants with schizophrenia had lower levels of specific [3H]N-methylscopolamine binding in all CNS regions, whilst benzyl quinolone carboxylic acid-modulated binding was less in the striatum, Brodmann's area 6, dentate gyrus, and subiculum. When divided by subgroup, only in MRDS was there lower specific [3H]N-methylscopolamine binding and less benzyl quinolone carboxylic acid-modulated binding in all cortical and subcortical regions studied. CONCLUSIONS: In a subgroup of participants with schizophrenia, there is a widespread decreased responsiveness to a positive allosteric modulator at the CHRM1. This finding may have ramifications it positive allosteric modulators of the CHRM1 are used in clinical trials to treat schizophrenia as some participants may not have an optimal response.
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Low levels of Muscarinic M1 Receptor-positive neurons in cortical layers III and V in Brodmann areas 9 and 17 from individuals with schizophrenia.
Journal of Psychiatry & Neuroscience, 2018Co-Authors: Elizabeth Scarr, Shaun Hopper, Tim D. Aumann, Gursharan Chana, Ian Everall, Brian DeanAbstract:BACKGROUND: Results of neuroimaging and postmortem studies suggest that people with schizophrenia may have lower levels of Muscarinic M1 Receptors (CHRM1) in the cortex, but not in the hippocampus or thalamus. Here, we use a novel immunohistochemical approach to better understand the likely cause of these low Receptor levels. METHODS: We determined the distribution and number of CHRM1-positive (CHRM1+) neurons in the cortex, medial dorsal nucleus of the thalamus and regions of the hippocampus from controls (n = 12, 12 and 5, respectively) and people with schizophrenia (n = 24, 24 and 13, respectively). RESULTS: Compared with controls, levels of CHRM1+ neurons in people with schizophrenia were lower on pyramidal cells in layer III of Brodmann areas 9 (-44%) and 17 (-45%), and in layer V in Brodmann areas 9 (-45%) and 17 (-62%). We found no significant differences in the number of CHRM1+ neurons in the medial dorsal nucleus of the thalamus or in the hippocampus. LIMITATIONS: Although diagnostic cohort sizes were typical for this type of study, they were relatively small. As well, people with schizophrenia were treated with antipsychotic drugs before death. CONCLUSION: The loss of CHRM1+ pyramidal cells in the cortex of people with schizophrenia may underpin derangements in the cholinergic regulation of GABAergic activity in cortical layer III and in cortical/subcortical communication via pyramidal cells in layer V.
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43.2 Muscarinic M1 ReceptorS: INVOLVEMENT IN THE PATHOPHYSIOLOGY AND TREATMENT OF SCHIZOPHRENIA.
Schizophrenia Bulletin, 2018Co-Authors: Brian Dean, Shaun Hopper, Elizabeth ScarrAbstract:AbstractBackgroundEvidence from postmortem CNS studies and a neuroimaging study suggest that, compared to controls, there are low levels of Muscarinic Receptors in a number of CNS regions from subjects with schizophrenia. Current data suggests the Muscarinic M1 Receptor is lower in the cortex of subjects with schizophrenia but other Muscarinic Receptors may be decreased in sub-cortical regions such as the striatum and hippocampus. In addition, it has been reported that ~25% of subjects with schizophrenia can be divided into a distinct sub-group because they have a marked decrease in cortical Muscarinic M1 Receptors (Muscarinic Receptor deficit schizophrenia (MRDS)). These findings have become of clinical significance because proof of principal data shows that treating subjects with schizophrenia with drugs that activate the Muscarinic M1 Receptor is effective in lessening the symptoms associated with the disorder.MethodsPublished and unpublished data will be reviewed to challenge the hypothesis that drugs that activate the Muscarinic M1 Receptor will be useful in treating schizophrenia.ResultsA proof of clinical trial has shown that treating subjects with treatment resistant schizophrenia with the Muscarinic M1 and 4 Receptor agonist, xanomeline, improves positive and negative symptoms as well as cognitive deficits. Moreover, it has more recently been reported that giving xanomeline on a transdermal patch with a peripheral Muscarinic Receptor antagonist can lessen the unwanted side effects of the drug to that of placebo. Relevant to these data is the finding that there is a sub-group of subjects with MRDS as the absence of cortical Muscarinic M1 Receptors in these Receptors may make these subjects resistant to treatment with Muscarinic M1 Receptor agonists. However, novel studies using postmortem CNS from subjects with MRDS and non-MRDS has shown that whilst subjects with MRDS will likely be resistant to Muscarinic M1 Receptor orthosteric agonists (oxotremorine-M) they will, at least partially, respond to Muscarinic M1 Receptor allosteric agonists (AC-42) or positive allosteric modulators (BQCA).DiscussionMuscarinic Receptor agonism appears to be a promising new treatment for schizophrenia. However, some subjects with MRDS may only respond to activation of the allosteric site on the Muscarinic M1 Receptor. Evidence from a neuroimaging study suggests subjects with MRDS can be identified whilst living. Hence, establishing the Muscarinic Receptor status of subjects involved in trials of Muscarinic M1 Receptor agonists may help in explaining varying levels of treatment responsiveness in subjects with schizophrenia. These conclusions, being directed by data from studies using postmortem CNS, reflect the need for drug discovery and delivery to be based on a growing understanding of the pathophysiology(ies) of schizophrenia.
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Changed gene expression in subjects with schizophrenia and low cortical Muscarinic M1 Receptors predicts disrupted upstream pathways interacting with that Receptor
Molecular Psychiatry, 2016Co-Authors: Elizabeth Scarr, Madhara Udawela, Elizabeth A. Thomas, Brian DeanAbstract:We tested the hypothesis that, compared with subjects with no history of psychiatric illness (controls), changes in gene expression in the dorsolateral prefrontal cortex from two subgroups of subjects with schizophrenia, one with a marked deficit in Muscarinic M1 Receptors (Muscarinic Receptor-deficit schizophrenia (MRDS)), would identify different biochemical pathways that would be affected by their aetiologies. Hence, we measured levels of cortical (Brodmann area 9) mRNA in 15 MRDS subjects, 15 subjects with schizophrenia but without a deficit in Muscarinic M1 Receptors (non-MRDS) and 15 controls using Affymetrix Exon 1.0 ST arrays. Levels of mRNA for 65 genes were significantly different in the cortex of subjects with MRDS and predicted changes in pathways involved in cellular movement and cell-to-cell signalling. Levels of mRNA for 45 genes were significantly different in non-MRDS and predicted changes in pathways involved in cellular growth and proliferation as well as cellular function and maintenance. Changes in gene expression also predicted effects on pathways involved in amino acid metabolism, molecular transport and small-molecule biochemistry in both MRDS and non-MRDS. Overall, our data argue a prominent role for glial function in MRDS and neurodevelopment in non-MRDS. Finally, the interactions of gene with altered levels of mRNA in the cortex of subjects with MRDS suggest many of their affects will be upstream of the Muscarinic M1 Receptor. Our study gives new insight into the molecular pathways affected in the cortex of subjects with MRDS and supports the notion that studying subgroups within the syndrome of schizophrenia is worthwhile.
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The distribution of Muscarinic M1 Receptors in the human hippocampus.
Journal of Chemical Neuroanatomy, 2016Co-Authors: Elizabeth Scarr, Tim D. Aumann, Gursharan Chana, Ian Everall, Brian DeanAbstract:The Muscarinic M1 Receptor plays a significant role in cognition, probably by modulating information processing in key regions such as the hippocampus. To understand how the Muscarinic M1 Receptor achieves these functions in the hippocampus, it is critical to know the distribution of the Receptor within this complex brain region. To date, there are limited data on the distribution of Muscarinic M1 Receptors in the human hippocampus which may also be confounded because some anti-Muscarinic Receptor antibodies have been shown to lack specificity. Initially, using Western blotting and immunohistochemistry, we showed the anti-Muscarinic M1 Receptor antibody to be used in our study bound to a single 62kDa protein that was absent in mice lacking the Muscarinic M1 Receptor gene. Then, using immunohistochemistry, we determined the distribution of Muscarinic M1 Receptors in human hippocampus from 10 subjects with no discernible history of a neurological or psychiatric disorder. Our data shows the Muscarinic M1 Receptor to be predominantly on pyramidal cells in the hippocampus. Muscarinic M1 Receptor positive cells were most apparent in the deep polymorphic layer of the dentate gyrus, the pyramidal cell layer of cornu ammonis region 3, the cellular layers of the subiculum, layer II of the presubiculum and layer III and V of the parahippocampal gyrus. Positive cells were less numerous and less intensely stained in the pyramidal layer of cornu ammonis region 2 and were sparse in the molecular layer of the dentate gyrus as well as cornu ammonis region 1. Although immunoreactivity was present in the granular layer of the dentate gyrus, it was difficult to identity individual immunopositive cells, possibly due to the density of cells. This distribution of the Muscarinic M1 Receptors in human hippocampus, and its localisation on glutamatergic cells, would suggest the Receptor has a significant role in modulating excitatory hippocampal neurotransmission.
Jason M. Uslaner - One of the best experts on this subject based on the ideXlab platform.
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The Muscarinic M1 Receptor positive allosteric modulator PQCA improves cognitive measures in rat, cynomolgus macaque, and rhesus macaque
Psychopharmacology, 2013Co-Authors: Jason M. Uslaner, Donnie Eddins, Vanita Puri, Christopher E. Cannon, Jane Sutcliffe, Chan Sing Chew, Michelle Pearson, Jeffrey A. Vivian, Ronald K. Chang, Scott D. KudukAbstract:Rationale The current standards of care for Alzheimer’s disease, acetylcholinesterase inhibitors, have limited efficacy due to a host of mechanism-related side effects arising from indiscriminate activation of Muscarinic and nicotinic Receptors. The M1 Muscarinic Receptor is predominantly expressed in the brain in regions involved in cognition, and therefore selective activation of the M1 Receptor would be expected to boost cognitive performance with reduced risk of peripheral side effects. Objectives Here we investigated whether the selective M1 Muscarinic Receptor positive allosteric modulator, PQCA, improves cognitive performance and cerebral blood flow. Results PQCA attenuated a scopolamine-induced deficit in novel object recognition in rat, self-ordered spatial search in cynomolgus macaque, and the object retrieval detour task in rhesus macaque. Beneficial effects in each of these assays and species were observed at similar plasma drug concentrations. Furthermore, at similar drug concentrations that were effective in the behavioral studies, PQCA increased blood flow in the frontal cortex of mice, providing a translational biomarker that could be used to guide dose selection for clinical studies. Conclusions These findings provide a framework for appropriately testing an M1 selective compound in patients with Alzheimer’s disease.
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the Muscarinic M1 Receptor positive allosteric modulator pqca improves cognitive measures in rat cynomolgus macaque and rhesus macaque
Psychopharmacology, 2013Co-Authors: Jason M. Uslaner, Donnie Eddins, Vanita Puri, Christopher E. Cannon, Jane Sutcliffe, Chan Sing Chew, Michelle Pearson, Jeffrey A. Vivian, Ronald K. Chang, Scott D. KudukAbstract:Rationale The current standards of care for Alzheimer’s disease, acetylcholinesterase inhibitors, have limited efficacy due to a host of mechanism-related side effects arising from indiscriminate activation of Muscarinic and nicotinic Receptors. The M1 Muscarinic Receptor is predominantly expressed in the brain in regions involved in cognition, and therefore selective activation of the M1 Receptor would be expected to boost cognitive performance with reduced risk of peripheral side effects.
