ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2023
Xanomeline restores endogenous nicotinic acetylcholine receptor signaling in mouse prefrontal cortex.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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7 citing papers in PubMed, 18 citations in OpenAlex.
- The Role of Astrocytes in the Molecular Pathophysiology of Schizophrenia: Between Neurodevelopment and Neurodegeneration.Biomolecules · 2025Review
- Ginkgo Biloba as a niche theme cognitive enhancer agent, 1420 dokumen of Scopus database. A bibliometric study from 1988 to 2024.F1000Research · 2025Article
- Enhanced prefrontal nicotinic signaling as evidence of active compensation in Alzheimer's disease models.Translational neurodegeneration · 2024Article
- Medial prefrontal cortex acetylcholine signaling mediates the ability to learn an active avoidance response following learned helplessness training.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2024Article
- CHRNA5 links chandelier cells to severity of amyloid pathology in aging and Alzheimer's disease.Translational psychiatry · 2024Article
- Deficits in integrative NMDA receptors caused by Grin1 disruption can be rescued in adulthood.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2023Article
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3 authors at 1 institution in 1 country.
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Abstract
Cholinergic synapses in prefrontal cortex are vital for attention, but this modulatory system undergoes substantial pre- and post-synaptic alterations during adulthood. To examine the integrated impact of these changes, we optophysiologically probe cholinergic synapses ex vivo, revealing a clear decline in neurotransmission in middle adulthood. Pharmacological dissection of synaptic components reveals a selective reduction in postsynaptic nicotinic receptor currents. Other components of cholinergic synapses appear stable, by contrast, including acetylcholine autoinhibition, metabolism, and excitation of postsynaptic muscarinic receptors. Pursuing strategies to strengthen cholinergic neurotransmission, we find that positive allosteric modulation of nicotinic receptors with NS9283 is effective in young adults but wanes with age. To boost nicotinic receptor availability, we harness the second messenger pathways of the preserved excitatory muscarinic receptors with xanomeline. This muscarinic agonist and cognitive-enhancer restores nicotinic signaling in older mice significantly, in a muscarinic- and PKC-dependent manner. The rescued nicotinic component regains youthful sensitivity to allosteric enhancement: treatment with xanomeline and NS9283 restores cholinergic synapses in older mice to the strength, speed, and receptor mechanism of young adults. Our results reveal a new and efficient strategy to rescue age-related nicotinic signaling deficits, demonstrating a novel pathway for xanomeline to restore cognitively-essential endogenous cholinergic neurotransmission.
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