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PubMed: 24511233

Title
Activation of M1 and M4 muscarinic receptors as potential treatments for Alzheimer's disease and schizophrenia.
Journal
Neuropsychiatric disease and treatment
Volume
10
Issue
None
Pages
183-91
Date
2014-01-01
Authors
Conn PJ | Rook JM | Choi DL | Foster DJ

Evidence 322886ac47
JSON

Interestingly, these M1-deficient mice display increased amphetamine-induced hyperlocomotion and dopamine neurotransmission,47 indicating that M1 modulation may have antipsychotic potential.

p(HGNC:CHRM1) decreases bp(GO:"dopamine secretion, neurotransmission") View Subject | View Object

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p(HGNC:CHRM1) decreases act(a(CHEBI:amphetamine)) View Subject | View Object

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Evidence e4ae5f37db
JSON

Finally, studies in mice exhibiting AD-like Abeta plaque pathologies found that deletion of M1 increased amyloidogenic processes, suggesting that M1 may play a role in regulating AD disease progression.51

p(MGI:Chrm1) decreases act(a(CHEBI:"amyloid-beta")) View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

Evidence 63bb31578d
JSON

M1, M3, and M5 all signal primarily via the Galphaq G-protein and induce Ca2+ mobilization and inositol trisphosphate (IP3) production, while M2 and M4 signal via the Galphai G-protein to inhibit cyclic adenosine monophosphate (cAMP) production.

complex(p(HGNC:CHRM1), p(HGNC:GNAQ)) increases bp(GO:"calcium ion transport") View Subject | View Object

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complex(p(HGNC:CHRM1), p(HGNC:GNAQ)) increases a(MESH:"Inositol 1,4,5-Trisphosphate") View Subject | View Object

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complex(p(HGNC:CHRM2), p(HGNC:GNAI1)) decreases a(CHEBI:"3',5'-cyclic AMP") View Subject | View Object

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complex(p(HGNC:CHRM3), p(HGNC:GNAQ)) increases bp(GO:"calcium ion transport") View Subject | View Object

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complex(p(HGNC:CHRM3), p(HGNC:GNAQ)) increases a(MESH:"Inositol 1,4,5-Trisphosphate") View Subject | View Object

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complex(p(HGNC:CHRM4), p(HGNC:GNAI1)) decreases a(CHEBI:"3',5'-cyclic AMP") View Subject | View Object

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complex(p(HGNC:CHRM5), p(HGNC:GNAQ)) increases bp(GO:"calcium ion transport") View Subject | View Object

Appears in Networks:

complex(p(HGNC:CHRM5), p(HGNC:GNAQ)) increases a(MESH:"Inositol 1,4,5-Trisphosphate") View Subject | View Object

Appears in Networks:

Evidence 5d467e5f1d
JSON

The current primary treatments for AD symptoms are acetylcholinesterase inhibitors (AChEIs) such as donepezil, tacrine, galantamine, and rivastigmine, which potentiate cholinergic signaling.18,19 These treatments not only provide improvements in cognitive symptoms associated with AD,20,21 but also show efficacy in treating the psychiatric symptoms.

a(CHEBI:"EC 3.1.1.7 (acetylcholinesterase) inhibitor") increases bp(GO:"synaptic transmission, cholinergic") View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

a(CHEBI:"EC 3.1.1.7 (acetylcholinesterase) inhibitor") increases bp(GO:cognition) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:"EC 3.1.1.7 (acetylcholinesterase) inhibitor") increases path(MESH:"Mental Processes") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 0dd3021dab
JSON

Unfortunately, cardiovascular and gastrointestinal side effects are often observed with these treatments, effects thought to be mediated by peripherally located ACh receptors. Despite this, AChEIs remain modestly beneficial for treating AD and other forms of dementia.

a(CHEBI:"EC 3.1.1.7 (acetylcholinesterase) inhibitor") association a(MESH:"Cardiovascular System") View Subject | View Object

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a(CHEBI:"EC 3.1.1.7 (acetylcholinesterase) inhibitor") association a(MESH:"Gastrointestinal Tract") View Subject | View Object

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a(MESH:"Cardiovascular System") association a(CHEBI:"EC 3.1.1.7 (acetylcholinesterase) inhibitor") View Subject | View Object

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a(MESH:"Gastrointestinal Tract") association a(CHEBI:"EC 3.1.1.7 (acetylcholinesterase) inhibitor") View Subject | View Object

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Evidence 21b681bfee
JSON

Current treatments include both typical (eg, haloperidol and chlorpromazine) and atypical (eg, risperidone and clozapine) antipsychotics, which act on the dopaminergic system and D2 dopamine receptors in particular. These treatments show partial efficacy in reducing psychotic or positive symptoms;30 however, they demonstrate little to no efficacy in addressing negative symptoms and cognitive impairments, which can prevent patients from participating fully and productively in society

a(CHEBI:"antipsychotic agent") regulates p(HGNC:DRD2) View Subject | View Object

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a(CHEBI:"antipsychotic agent") causesNoChange bp(GO:cognition) View Subject | View Object

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Evidence 0f25eabe0d
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Acetylcholine (ACh) is a neurotransmitter that modulates neuronal function in several areas of the CNS associated with AD and/or SZ pathology, including the striatum, cortex, hippocampus, and prefrontal cortex.5 ACh mediates its actions via two families of receptors, termed the muscarinic ACh receptors (mAChRs) and the nicotinic ACh receptors (nAChRs).

a(CHEBI:acetylcholine) regulates act(a(MESH:Neurons)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Corpus Striatum
MeSH
Hippocampus
MeSH
Prefrontal Cortex

p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic") regulates act(a(CHEBI:acetylcholine)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Corpus Striatum
MeSH
Hippocampus
MeSH
Prefrontal Cortex

p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") regulates act(a(CHEBI:acetylcholine)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Corpus Striatum
MeSH
Hippocampus
MeSH
Prefrontal Cortex

Evidence ce1948c9ef
JSON

Two novel M4-selective compounds, VU10010 and LY2033298, represented a breakthrough when they were described in 2008.84,85 VU10010 is a potent M4-selective PAM that increases affinity/efficacy of ACh to promote M4 mAChR activation.

act(a(CHEBI:acetylcholine)) increases act(p(HGNC:CHRM1)) View Subject | View Object

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a(HBP:VU10010) increases act(a(CHEBI:acetylcholine)) View Subject | View Object

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Evidence 2a7f5c7931
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Both VU0152100 and VU0152099 effectively reversed amphetamine-induced hyperlocomotion, demonstrating antipsychotic-like activity in preclinical models.

act(a(CHEBI:amphetamine)) increases bp(GO:locomotion) View Subject | View Object

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a(HBP:VU0152099) decreases act(a(CHEBI:amphetamine)) View Subject | View Object

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Evidence a2741855af
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Conversely, the nonselective mAChR agonist BuTAC ([5R-(exo)]-6-[4-butylthio-1,2,5-thiadiazol-3-yl]-1-azabicyclo-[3.2.1]-octane) shows an antipsychotic profile when tested in numerous preclinical animal models. Administration of BuTAC reduces apomorphine-induced climbing and apomorphine-induced disruptions of prepulse inhibition78,79 and reduces conditioned avoidance responding in wild-type, but not M4 KO mice.

act(a(CHEBI:apomorphine)) decreases bp(GO:"prepulse inhibition") View Subject | View Object

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a(MESH:"6-(4-butylthio-1,2,5-thiadiazol-3-yl)-1-azabicyclo(3.2.1)octane") decreases act(a(CHEBI:apomorphine)) View Subject | View Object

Appears in Networks:

a(MESH:"6-(4-butylthio-1,2,5-thiadiazol-3-yl)-1-azabicyclo(3.2.1)octane") decreases path(MESH:"Avoidance Learning") View Subject | View Object

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p(HGNC:CHRM4) association path(MESH:"Avoidance Learning") View Subject | View Object

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path(MESH:"Avoidance Learning") association p(HGNC:CHRM4) View Subject | View Object

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Evidence 717d544617
JSON

LY2033298, a structurally distinct M4-selective PAM, was similarly efficacious in several preclinical models of psychosis, including conditioned avoidance responding and apomorphine-impaired prepulse inhibition

act(a(CHEBI:apomorphine)) decreases bp(GO:"prepulse inhibition") View Subject | View Object

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a(MESH:"3-amino-5-chloro-6-methoxy-4-methyl-thieno(2,3-b)pyridine-2-carboxylic acid cyclopropylamide") decreases act(a(CHEBI:amphetamine)) View Subject | View Object

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Evidence 562ade3462
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Moreover, additional pre-clinical studies with TBPB demonstrated efficacy in reducing antipsychotic-like behaviors and in reversing scopolamine-impaired acquisition of contextual fear.59 Studies in cell lines also demonstrated that TBPB promoted a non-amyloidogenic pathway and decreased Abeta production, indicating that M1 modulation may have efficacy in the treatment of both symptomatic and pathologic features of AD

act(a(CHEBI:scopolamine)) decreases bp(GO:"behavioral fear response") View Subject | View Object

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a(MESH:"1-(1'-(2-methylbenzyl)-1,4'-bipiperidin-4-yl)-1H-benzo(d)imidazol-2-(3H)-one") decreases act(a(CHEBI:scopolamine)) View Subject | View Object

Appears in Networks:

a(MESH:"1-(1'-(2-methylbenzyl)-1,4'-bipiperidin-4-yl)-1H-benzo(d)imidazol-2-(3H)-one") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

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Evidence 7f1c007755
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Of these, the M1/M4 -preferring agonist xanomeline was the only one to progress to a phase III clinical trial, where it was assessed for efficacy in ameliorating cognitive deficits observed in AD patients. While xanomeline showed a trend toward improving cognitive function in these patients, this effect did not reach statistical significance. However, this agonist did produce surprisingly robust and dose-dependent reductions in hallucinations, delusions, vocal outbursts, and other behavioral disturbances in these patients

a(CHEBI:xanomeline) increases bp(GO:cognition) View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

a(CHEBI:xanomeline) decreases path(MESH:Hallucinations) View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

a(CHEBI:xanomeline) decreases path(MESH:Delusions) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 28217637f2
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This study reported that xanomeline treatment produced robust improvements in both the positive and the negative symptoms of patients with SZ

a(CHEBI:xanomeline) decreases path(MESH:Schizophrenia) View Subject | View Object

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Evidence da7d06c221
JSON

In addition, xanomeline produced statistically significant improvements in verbal learning and short-term memory, indicating efficacy in treating cognitive symptoms.40 Unfortunately, gastrointestinal side effects were observed, and dose limitations have removed it from consideration for long-term clinical use.

a(CHEBI:xanomeline) increases bp(GO:learning) View Subject | View Object

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a(CHEBI:xanomeline) increases path(MESH:"Memory, Short-Term") View Subject | View Object

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a(CHEBI:xanomeline) association a(MESH:"Gastrointestinal Tract") View Subject | View Object

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a(MESH:"Gastrointestinal Tract") association a(CHEBI:xanomeline) View Subject | View Object

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Evidence 855f566d3f
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The hallmarks of AD pathology are the accumulation of amyloid-beta (Abeta) peptide aggregates (neuritic plaques) and hyperphosphorylated tau protein (neurofibrillary tangles).

a(HBP:"amyloid-beta aggregates") association path(MESH:"Plaque, Amyloid") View Subject | View Object

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path(MESH:"Neurofibrillary Tangles") biomarkerFor path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Plaque, Amyloid") association a(HBP:"amyloid-beta aggregates") View Subject | View Object

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path(MESH:"Plaque, Amyloid") biomarkerFor path(MESH:"Alzheimer Disease") View Subject | View Object

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Evidence 48952cdc4b
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Recent drug discovery efforts in our group have yielded novel M1-selective PAMs VU0405652 (ML169) and VU0456940, both of which potentiate M1-mediated non-amyloidogenic amyloid precursor protein (APPsalpha) processing, suggesting disease-modifying potential in AD

a(HBP:VU0456940) increases act(p(HGNC:CHRM1)) View Subject | View Object

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a(MESH:"VU 0405652") increases act(p(HGNC:CHRM1)) View Subject | View Object

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act(p(HGNC:CHRM1)) increases deg(a(HBP:"sAPP-alpha")) View Subject | View Object

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Evidence 911341cded
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In brain slices, VU10010 selectively potentiated mAChR-mediated reductions in glutamatergic, but not GABAergic, signaling in hippocampal neurons, indicating a key role for M4 in regulating hippocampal function, and possibly in modulating cognition.

a(HBP:VU10010) increases act(p(HGNC:CHRM4)) View Subject | View Object

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Annotations
MeSH
Hippocampus

act(p(HGNC:CHRM4)) decreases bp(GO:"synaptic transmission, glutamatergic") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

Evidence 351a3e209f
JSON

Another early allosteric agonist, TBPB (1-(1’-(2-methylbenzyl) -1,4’-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-1), also exhibited impressive selectivity for M1 mAChRs and potentiated NMDA receptor currents in CA1 hippocampal cells.

a(MESH:"1-(1'-(2-methylbenzyl)-1,4'-bipiperidin-4-yl)-1H-benzo(d)imidazol-2-(3H)-one") increases act(p(HGNC:CHRM1)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
CA1 Region, Hippocampal

act(p(HGNC:CHRM1)) increases act(p(HGNCGENEFAMILY:"Glutamate ionotropic receptor NMDA type subunits")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
CA1 Region, Hippocampal

Evidence aba98c2055
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Subsequent optimization produced two analogs of AC-42 (AC-260584 and 77-LH-28-1), which maintained M1 selectivity and possessed properties suitable for use in animal models. Both AC-260584 and 77-LH-28-1 displayed antipsychotic and cognition-enhancing efficacy in pre-clinical models

a(MESH:"1-(3-(4-butyl-1-piperidinyl)propyl)-3,4-dihydro-2(1H)-quinolinone") increases act(p(HGNC:CHRM1)) View Subject | View Object

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a(MESH:"4-(3-(4-butylpiperidin-1-yl)propyl)-7-fluoro-4H-benzo(1,4)oxazin-3-one") increases act(p(HGNC:CHRM1)) View Subject | View Object

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act(p(HGNC:CHRM1)) increases bp(GO:cognition) View Subject | View Object

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Evidence 2ec8705d94
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The first subtype-selective M1 PAM to be characterized was benzyl quinolone carboxylic acid (BQCA);68 BQCA exhibited high selectivity with no activity at mAChR subtypes M2–M5 and induced up to a 129-fold leftward shift in ACh potency at the M1 mAChR

a(MESH:"1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid") increases act(p(HGNC:CHRM1)) View Subject | View Object

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act(p(HGNC:CHRM1)) increases a(CHEBI:acetylcholine) View Subject | View Object

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Evidence f4cead2185
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In brain slice electrophysiology studies, BQCA enhanced excitatory postsynaptic currents in medial prefrontal cortical neurons,69 an area critical for higher cognitive, learning, and memory functions.70 In pre-clinical animal studies, BQCA reversed scopolamine-impaired contextual fear conditioning and rescued medial prefrontal cortex-dependent discrimination reversal learning deficits in a transgenic mouse model of AD.

a(MESH:"1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid") increases bp(GO:"excitatory postsynaptic potential") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Prefrontal Cortex

a(MESH:"1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid") decreases act(a(CHEBI:scopolamine)) View Subject | View Object

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a(MESH:"1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid") increases bp(GO:"behavioral fear response") View Subject | View Object

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a(MESH:"1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid") increases bp(GO:learning) View Subject | View Object

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a(MESH:"Prefrontal Cortex") association bp(GO:cognition) View Subject | View Object

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MeSH
Prefrontal Cortex

a(MESH:"Prefrontal Cortex") association bp(GO:learning) View Subject | View Object

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Annotations
MeSH
Prefrontal Cortex

a(MESH:"Prefrontal Cortex") association bp(GO:memory) View Subject | View Object

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MeSH
Prefrontal Cortex

bp(GO:cognition) association a(MESH:"Prefrontal Cortex") View Subject | View Object

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MeSH
Prefrontal Cortex

bp(GO:learning) association a(MESH:"Prefrontal Cortex") View Subject | View Object

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MeSH
Prefrontal Cortex

bp(GO:memory) association a(MESH:"Prefrontal Cortex") View Subject | View Object

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Annotations
MeSH
Prefrontal Cortex

Evidence 58b61377f8
JSON

Additionally, recent studies demonstrated that BQCA was effective in reversing memory deficits in Y-maze object recognition and spontaneous alternation tasks in rats.71,72

a(MESH:"1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid") increases bp(GO:memory) View Subject | View Object

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Evidence 19d177fa16
JSON

The popular amyloid cascade hypothesis posits that the gradual build-up of Abeta plaques leads to neuronal inflammation, dysfunction, and, eventually, cell death. The two brain regions most critically affected by this degeneration are the cortex and hippocampus, both of which are involved in cognition, learning, and memory.

a(MESH:"Cerebral Cortex") association bp(GO:cognition) View Subject | View Object

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Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

a(MESH:"Cerebral Cortex") association bp(GO:learning) View Subject | View Object

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Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

a(MESH:"Cerebral Cortex") association bp(GO:memory) View Subject | View Object

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MeSH
Cerebral Cortex
MeSH
Hippocampus

a(MESH:Hippocampus) association bp(GO:cognition) View Subject | View Object

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Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

a(MESH:Hippocampus) association bp(GO:learning) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

a(MESH:Hippocampus) association bp(GO:memory) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

bp(GO:cognition) association a(MESH:Hippocampus) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

bp(GO:cognition) association a(MESH:"Cerebral Cortex") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

bp(GO:learning) association a(MESH:Hippocampus) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

bp(GO:learning) association a(MESH:"Cerebral Cortex") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

bp(GO:memory) association a(MESH:Hippocampus) View Subject | View Object

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Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

bp(GO:memory) association a(MESH:"Cerebral Cortex") View Subject | View Object

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Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

path(MESH:"Plaque, Amyloid") increases bp(HBP:neuroinflammation) View Subject | View Object

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Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

path(MESH:"Plaque, Amyloid") increases bp(GO:"cell death") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

Evidence 32f6966bbe
JSON

M1 mAChRs have been demonstrated to potentiate NMDA-receptor signaling in the hippocampus and cortex,48,49 brain areas intimately associated with learning and memory. In addition, M1 KO mice displayed reduced hippocampal long-term potentiation, a mechanism heavily implicated in learning and memory. Behaviorally, M1 KO animals display deficits in several medial prefrontal cortex-dependent cognitive tasks, including non-matching-to- sample, win-shift radial arm maze, and social discrimination tasks.

a(MESH:"Cerebral Cortex") association bp(GO:learning) View Subject | View Object

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MeSH
Cerebral Cortex
MeSH
Hippocampus

a(MESH:"Cerebral Cortex") association bp(GO:memory) View Subject | View Object

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Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

a(MESH:Hippocampus) association bp(GO:learning) View Subject | View Object

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Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

a(MESH:Hippocampus) association bp(GO:memory) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

bp(GO:"long-term synaptic potentiation") association bp(GO:learning) View Subject | View Object

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Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

bp(GO:"long-term synaptic potentiation") association bp(GO:memory) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

bp(GO:learning) association a(MESH:Hippocampus) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

bp(GO:learning) association a(MESH:"Cerebral Cortex") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

bp(GO:memory) association a(MESH:"Cerebral Cortex") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

bp(GO:learning) association bp(GO:"long-term synaptic potentiation") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

bp(GO:memory) association a(MESH:Hippocampus) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

bp(GO:memory) association bp(GO:"long-term synaptic potentiation") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

p(HGNC:CHRM1) increases act(p(HGNCGENEFAMILY:"Glutamate ionotropic receptor NMDA type subunits")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

p(HGNC:CHRM1) increases bp(GO:"long-term synaptic potentiation") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

Evidence 4dd1ff3ed6
JSON

The M4 receptor is highly expressed in the striatum, hippocampus, and neocortex,45,46 suggesting that this mAChR subtype is ideally located to modulate dopaminergic signaling. In support of this hypothesis, M4 KO mice exhibit a hyperdopaminergic phenotype that is resistant to mAChR agonist-induced attenuation of dopamine levels.

a(MESH:"Corpus Striatum") association p(HGNC:CHRM4) View Subject | View Object

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a(MESH:Hippocampus) association p(HGNC:CHRM4) View Subject | View Object

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a(MESH:Neocortex) association p(HGNC:CHRM4) View Subject | View Object

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p(HGNC:CHRM4) association a(MESH:Hippocampus) View Subject | View Object

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p(HGNC:CHRM4) association a(MESH:"Corpus Striatum") View Subject | View Object

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p(HGNC:CHRM4) association a(MESH:Neocortex) View Subject | View Object

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p(HGNC:CHRM4) regulates bp(GO:"synaptic transmission, dopaminergic") View Subject | View Object

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Evidence d62bc8596f
JSON

In addition, administration of nonselective muscarinic antagonists can produce or exacerbate cognitive deficits in animals,15 as well as in AD patients and both young and old control subjects,16,17 suggesting that mAChRs can directly modulate cognition.

a(MESH:"Muscarinic Antagonists") decreases bp(GO:cognition) View Subject | View Object

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MeSH
Alzheimer Disease

p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic") regulates bp(GO:cognition) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 2fc80855c3
JSON

Furthermore, administration of nonselective muscarinic antagonists can induce cognitive deficits and psychosis in humans,16,37 indicating that mAChR activation may provide pro-cognitive and antipsychotic efficacy.

a(MESH:"Muscarinic Antagonists") increases path(MESH:"Cognitive Dysfunction") View Subject | View Object

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a(MESH:"Muscarinic Antagonists") association path(MESH:"Mental Processes") View Subject | View Object

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path(MESH:"Mental Processes") association a(MESH:"Muscarinic Antagonists") View Subject | View Object

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Evidence 4410d63222
JSON

More recently, the M1-selective allosteric agonist VU0357017 was discovered, which displayed improved potency via binding to a novel allosteric site on the M1 mAChR. VU0357017 significantly blocked scopolamine-impaired contextual fear conditioning and enhanced spatial and contextual fear learning

a(MESH:VU0357017) increases complex(a(MESH:VU0357017), p(HGNC:CHRM1)) View Subject | View Object

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a(MESH:VU0357017) decreases act(a(CHEBI:scopolamine)) View Subject | View Object

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a(MESH:VU0357017) increases bp(GO:"behavioral fear response") View Subject | View Object

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complex(a(MESH:VU0357017), p(HGNC:CHRM1)) increases act(p(HGNC:CHRM1)) View Subject | View Object

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Evidence 2c6d3e180f
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Accumulating evidence suggests that the three clusters of SZ symptoms cannot be ascribed solely to alterations in monoaminergic signaling as dysregulation of glutamatergic, gamma-aminobutyric acid (GABA)-ergic, and cholinergic systems have also been reported

bp(GO:"gamma-aminobutyric acid signaling pathway") association path(MESH:Schizophrenia) View Subject | View Object

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bp(GO:"synaptic transmission, cholinergic") association path(MESH:Schizophrenia) View Subject | View Object

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bp(GO:"synaptic transmission, glutamatergic") association path(MESH:Schizophrenia) View Subject | View Object

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path(MESH:Schizophrenia) association bp(GO:"synaptic transmission, cholinergic") View Subject | View Object

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path(MESH:Schizophrenia) association bp(GO:"synaptic transmission, glutamatergic") View Subject | View Object

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path(MESH:Schizophrenia) association bp(GO:"gamma-aminobutyric acid signaling pathway") View Subject | View Object

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Evidence 6f52e281f0
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1 Several lines of evidence suggest that impaired cholinergic signaling plays a key role in mediating both the cognitive and the behavioral impairments observed in AD patients.12 The basal forebrain cholinergic system is disproportionately affected in AD patients, with a robust loss of cholinergic neurons, including those innervating the hippocampus and cortex.

bp(GO:"synaptic transmission, cholinergic") association bp(GO:cognition) View Subject | View Object

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bp(GO:"synaptic transmission, cholinergic") association bp(GO:behavior) View Subject | View Object

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bp(GO:behavior) association bp(GO:"synaptic transmission, cholinergic") View Subject | View Object

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bp(GO:cognition) association bp(GO:"synaptic transmission, cholinergic") View Subject | View Object

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path(MESH:"Alzheimer Disease") decreases bp(GO:"synaptic transmission, cholinergic") View Subject | View Object

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path(MESH:"Alzheimer Disease") decreases a(MESH:"Cholinergic Neurons") View Subject | View Object

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Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

Evidence f735600fdc
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Psychosis is the hallmark symptom of SZ and manifests as hallucinations, disordered thought/speech, and delusions. While these psychotic symptoms are commonly associated with SZ, it has become well documented that these patients also experience cognitive and behavioral disturbances that are not adequately addressed by currently prescribed typical and atypical psychotics.

bp(GO:behavior) association path(MESH:Schizophrenia) View Subject | View Object

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bp(GO:cognition) association path(MESH:Schizophrenia) View Subject | View Object

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path(MESH:Delusions) association path(MESH:Schizophrenia) View Subject | View Object

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path(MESH:Hallucinations) association path(MESH:Schizophrenia) View Subject | View Object

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path(MESH:Schizophrenia) association path(MESH:Hallucinations) View Subject | View Object

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path(MESH:Schizophrenia) association path(MESH:Delusions) View Subject | View Object

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path(MESH:Schizophrenia) association bp(GO:cognition) View Subject | View Object

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path(MESH:Schizophrenia) association bp(GO:behavior) View Subject | View Object

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Evidence 8247ef7b2a
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Conversely, the most commonly associated symptoms of AD are cognitive in nature and include deficits in learning and memory. However, 50%–80% of AD patients display psychotic and behavioral disturbances that are correlated with poor social and functional outcomes

bp(GO:cognition) association path(MESH:"Alzheimer Disease") View Subject | View Object

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bp(GO:learning) association path(MESH:"Alzheimer Disease") View Subject | View Object

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bp(GO:memory) association path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Alzheimer Disease") association path(MESH:"Psychotic Disorders") View Subject | View Object

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path(MESH:"Alzheimer Disease") association bp(GO:cognition) View Subject | View Object

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path(MESH:"Alzheimer Disease") association bp(GO:learning) View Subject | View Object

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path(MESH:"Alzheimer Disease") association bp(GO:memory) View Subject | View Object

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path(MESH:"Psychotic Disorders") association path(MESH:"Alzheimer Disease") View Subject | View Object

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Evidence afc8bd3e5f
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The M1 mAChR subtype is the most predominantly expressed mAChR subtype in the CNS and is expressed in several brain regions implicated in the regulation of cognitive processes, including the striatum, prefrontal cortex, and hippocampus.

bp(GO:cognition) association p(HGNC:CHRM1) View Subject | View Object

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MeSH
Corpus Striatum
MeSH
Hippocampus
MeSH
Prefrontal Cortex

p(HGNC:CHRM1) association bp(GO:cognition) View Subject | View Object

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Corpus Striatum
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Hippocampus
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Prefrontal Cortex

Evidence 7495e9b51e
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N-methyl-D-aspartate (NMDA) receptors play a critical role in regulating synaptic plasticity, and disrupted NMDA-receptor neurotransmission is thought to underlie the cognitive deficits observed in numerous psychiatric diseases.

bp(GO:cognition) association p(HGNCGENEFAMILY:"Glutamate ionotropic receptor NMDA type subunits") View Subject | View Object

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p(HGNCGENEFAMILY:"Glutamate ionotropic receptor NMDA type subunits") regulates bp(MESH:"Neuronal Plasticity") View Subject | View Object

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p(HGNCGENEFAMILY:"Glutamate ionotropic receptor NMDA type subunits") association bp(GO:cognition) View Subject | View Object

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Evidence 377fecf04d
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Age is the primary risk factor for AD, and the disease usually manifests in individuals after the age of 60 years. Due to an aging population, the prevalence of AD is predicted to rise to 66 million people by the year 2030.

bp(MESH:Aging) association path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Alzheimer Disease") association bp(MESH:Aging) View Subject | View Object

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Evidence 1854d8faa5
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A recent clinical study utilizing the M1-selective allosteric agonist GSK1034702 demonstrated pro-cognitive efficacy in a nicotine abstinence model of episodic memory impairment in smokers, 67 providing exciting evidence that M1-selective activation can provide pro-cognitive benefits in humans

complex(a(MESH:"GSK 1034702"), p(HGNC:CHRM1)) increases bp(GO:cognition) View Subject | View Object

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Evidence c4d42d5e10
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Schizophrenia (SZ) and Alzheimer’s disease (AD) are two devastating disorders of the central nervous system (CNS) that present clinically with cognitive impairments and psychotic symptoms

path(MESH:"Alzheimer Disease") association path(MESH:"Psychotic Disorders") View Subject | View Object

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MeSH
Central Nervous System

path(MESH:"Alzheimer Disease") association path(MESH:"Cognitive Dysfunction") View Subject | View Object

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MeSH
Central Nervous System

path(MESH:"Cognitive Dysfunction") association path(MESH:"Alzheimer Disease") View Subject | View Object

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Central Nervous System

path(MESH:"Cognitive Dysfunction") association path(MESH:Schizophrenia) View Subject | View Object

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Central Nervous System

path(MESH:"Psychotic Disorders") association path(MESH:"Alzheimer Disease") View Subject | View Object

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Central Nervous System

path(MESH:"Psychotic Disorders") association path(MESH:Schizophrenia) View Subject | View Object

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Central Nervous System

path(MESH:Schizophrenia) association path(MESH:"Psychotic Disorders") View Subject | View Object

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MeSH
Central Nervous System

path(MESH:Schizophrenia) association path(MESH:"Cognitive Dysfunction") View Subject | View Object

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MeSH
Central Nervous System

Evidence a3509a42de
JSON

AD is the most commonly diagnosed form of dementia and currently affects approximately 35 million individuals worldwide.7 AD is a progressive neurodegenerative disease that is characterized by a host of cognitive deficits, including impairments in learning and memory. In addition to the well-documented cognitive impairments, AD patients also display behavioral disturbances, including anxiety, depression, and psychosis

path(MESH:"Alzheimer Disease") association path(MESH:"Psychotic Disorders") View Subject | View Object

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path(MESH:"Alzheimer Disease") association path(MESH:"Cognitive Dysfunction") View Subject | View Object

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path(MESH:"Alzheimer Disease") decreases bp(GO:cognition) View Subject | View Object

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path(MESH:"Alzheimer Disease") decreases bp(GO:learning) View Subject | View Object

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path(MESH:"Alzheimer Disease") association path(MESH:Dementia) View Subject | View Object

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path(MESH:"Alzheimer Disease") increases path(MESH:Depression) View Subject | View Object

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path(MESH:"Alzheimer Disease") increases path(MESH:Anxiety) View Subject | View Object

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path(MESH:"Cognitive Dysfunction") association path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Psychotic Disorders") association path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:Dementia) association path(MESH:"Alzheimer Disease") View Subject | View Object

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Evidence b907b5e5df
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Another commonality between AD and SZ is the apparent involvement of dysregulated cholinergic signaling in the brain.

path(MESH:"Alzheimer Disease") decreases bp(GO:"synaptic transmission, cholinergic") View Subject | View Object

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path(MESH:Schizophrenia) decreases bp(GO:"synaptic transmission, cholinergic") View Subject | View Object

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Evidence de964fb676
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The hallmark psychotic symptoms of SZ are the positive cluster and include auditory hallucinations, delusional beliefs, and disorganized thoughts and speech. SZ patients also exhibit negative symptoms, including anhedonia, dysfunctional social interactions, and poverty of thoughts and speech, as well as cognitive disturbances affecting several behavioral domains, including working memory, attention, and executive function

path(MESH:"Executive Function") association path(MESH:Schizophrenia) View Subject | View Object

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path(MESH:"Memory, Short-Term") association path(MESH:Schizophrenia) View Subject | View Object

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path(MESH:"Social Isolation") biomarkerFor path(MESH:Schizophrenia) View Subject | View Object

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path(MESH:Anhedonia) biomarkerFor path(MESH:Schizophrenia) View Subject | View Object

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path(MESH:Attention) association path(MESH:Schizophrenia) View Subject | View Object

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path(MESH:Delusions) biomarkerFor path(MESH:Schizophrenia) View Subject | View Object

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path(MESH:Hallucinations) biomarkerFor path(MESH:Schizophrenia) View Subject | View Object

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path(MESH:Schizophrenia) association path(MESH:"Memory, Short-Term") View Subject | View Object

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path(MESH:Schizophrenia) association path(MESH:Attention) View Subject | View Object

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path(MESH:Schizophrenia) association path(MESH:"Executive Function") View Subject | View Object

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About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.