ArticleHippocampus2017
Effects of M1 and M4 activation on excitatory synaptic transmission in CA1.
Article in Hippocampus, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
28 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Cholinergic system in schizophrenia: A systematic review and meta-analysis.Molecular psychiatry · 2025Pooled it
- Effectiveness of KarXT (xanomeline-trospium) for cognitive impairment in schizophrenia: post hoc analyses from a randomised, double-blind, placebo-controlled phase 2 study.Translational psychiatry · 2022Trial
- Towards Mechanism-Informed Treatments for Mental Health.Journal of neurochemistry · 2026Review
- The mechanism of action and clinical efficacy of xanomeline-trospium in schizophrenia: A comprehensive review.Therapeutic advances in psychopharmacology · 2026Review
- Targeting muscarinic receptors for treating schizophrenia.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Review
- Modeling presynaptic inhibition by the amyloid precursor protein demonstrates one potential mechanism for preventing runaway synaptic modification in Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- From theory to therapy: unlocking the potential of muscarinic receptor activation in schizophrenia with the dual M1/M4 muscarinic receptor agonist xanomeline and trospium chloride and insights from clinical trials.The international journal of neuropsychopharmacology · 2025Review
- Network proteomics of the Lewy body dementia brain reveals presynaptic signatures distinct from Alzheimer's disease.Molecular neurodegeneration · 2024Article
- Current Findings and Potential Mechanisms of KarXT (Xanomeline-Trospium) in Schizophrenia Treatment.Clinical drug investigation · 2024Review
- Multiple cholinergic receptor subtypes coordinate dual modulation of acetylcholine on anterior and posterior paraventricular thalamic neurons.Journal of neurochemistry · 2024Article
- Septohippocampal cholinergic system at the intersection of stress and cognition: Current trends and translational implications.The European journal of neuroscience · 2024Review
- Network Proteomics of the Lewy Body Dementia Brain Reveals Presynaptic Signatures Distinct from Alzheimer's Disease.bioRxiv : the preprint server for biology · 2024Article
- Cholinergic Activation of Corticofugal Circuits in the Adult Mouse Prefrontal Cortex.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Muscarinic Modulation of Network Excitability and Short-Term Dynamics in the Dorsal and Ventral Hippocampus.microPublication biology · 2024Article
- Biphasic Cholinergic Modulation of Reverberatory Activity in Neuronal Networks.Neuroscience bulletin · 2023Article
- Xanomeline restores endogenous nicotinic acetylcholine receptor signaling in mouse prefrontal cortex.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2023Article
- Modulation of Muscarinic Signalling in the Central Nervous System by Steroid Hormones and Neurosteroids.International journal of molecular sciences · 2022Review
- Acetylcholine prioritises direct synaptic inputs from entorhinal cortex to CA1 by differential modulation of feedforward inhibitory circuits.Nature communications · 2021Article
- Presynaptic Inhibitory Effects of Acetylcholine in the Hippocampus: A 40-Year Evolution of a Serendipitous Finding.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2021Article
- Targeting muscarinic receptors to treat schizophrenia.Behavioural brain research · 2021Review
Corrections and comments
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Authors and funding
4 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hippocampal networks are particularly susceptible to dysfunction in many neurodegenerative diseases and neuropsychiatric disorders including Alzheimer's disease, Lewy body dementia, and schizophrenia. CA1, a major output region of the hippocampus, receives glutamatergic input from both hippocampal CA3 and entorhinal cortex, via the Schaffer collateral (SC) and temporoammonic (TA) pathways, respectively. SC and TA inputs to CA1 are thought to be differentially involved in the retrieval of previously stored memories versus the encoding of novel information, and switching between these two crucial hippocampal functions is thought to critically depend on acetylcholine (ACh) acting at muscarinic receptors. In this study, we aimed to determine the roles of specific subtypes of muscarinic receptors in mediating the neuromodulatory effects of ACh on glutamatergic synaptic transmission in the SC and TA pathways of CA1. Using selective pharmacological activation of M1 or M4 receptors along with extracellular and intracellular electrophysiology recordings from adult rat hippocampal slices, we demonstrate that activation of M1 receptors increases spontaneous spike rates of neuronal ensembles in CA1 and increases the intrinsic excitability of pyramidal neurons and interneurons. Selective activation of M4 receptors inhibits glutamate release in the SC pathway, while leaving synaptic transmission in the TA pathway comparatively intact. These results suggest specific mechanisms by which M1 and M4 activation may normalize CA1 circuit activity following disruptions of signaling that accompany neurodegenerative dementias or neuropsychiatric disorders. These findings are of particular interest in light of clinical findings that xanomeline, an M1/M4 preferring agonist, was able to improve cognitive and behavioral symptoms in patients with Alzheimer's disease or schizophrenia.
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Registered trials
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