Muscarinic Acetylcholine Receptors-Mediated Activation of PKC Restores the Hippocampal Immediate Early Gene Expression and CREB Phosphorylation in Scopolamine-Induced Amnesic Mice.

Abstract

Amnesia is the inability to store new information and recall old memories. After the postulation of cholinergic hypothesis of geriatric memory dysfunction, the cholinergic signaling became a popular target to understand the underlying molecular mechanism of amnesia and its recovery. Scopolamine is a non-selective cholinergic receptor antagonist and induces amnesia through downregulation of synaptic plasticity genes including immediate early genes (IEGs). Scopolamine-induced amnesic mouse model is widely used to study the memory impairment that mimics the pathophysiology of aging, neurodegenerative, and neuropsychiatric disorders. However, a detailed understanding of cholinergic signaling-mediated regulation of plasticity-related gene expression remains elusive. Therefore, we have investigated the role of muscarinic acetylcholine receptors (mAChRs) and their downstream mediator protein kinase C (PKC) in the regulation of IEGs expression in amnesic mice hippocampus. Pilocarpine, a mAChRs agonist, was used to activate the cholinergic signaling in scopolamine-induced amnesia. Further, a PKC activator bryostatin 1 was used to understand the sole involvement of PKC as a downstream mediator of mAChRs-mediated signaling. Pilocarpine treatment significantly restored the scopolamine-induced impaired recognition memory and downregulated hippocampal IEGs expression and phosphorylation of ERK1/2 (extracellular signal-regulated kinase 1/2) and CREB (cAMP response element-binding protein). On the other hand, the bryostatin 1-mediated activation of PKC in scopolamine-induced amnesia selectively restored the hippocampal IEGs expression, recognition memory, and phosphorylation of ERK1/2 and CREB. Taken together, our findings suggest that mAChRs and their downstream mediator PKC regulate the hippocampal IEGs expression and ERK1/2-mediated CREB phosphorylation in scopolamine-induced amnesic mice.

• Authors: Bhabotosh Barman, Akanksha Kushwaha, Mahendra Kumar Thakur
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 59 Issue 9 Pg. 5722-5733 (Sep 2022) ISSN: 1559-1182 [Electronic] United States
• PMID: 35789976 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Chemical References

• Cholinergic Agents
• Creb1 protein, mouse
• Cyclic AMP Response Element-Binding Protein
• Receptors, Muscarinic
• Pilocarpine
• Scopolamine
• Protein Kinase C

Topics

• Amnesia (genetics)
• Animals
• Cholinergic Agents (pharmacology)
• Cyclic AMP Response Element-Binding Protein
• Genes, Immediate-Early
• Hippocampus (metabolism)
• Memory Disorders
• Mice
• Phosphorylation
• Pilocarpine
• Protein Kinase C (metabolism)
• Receptors, Muscarinic (metabolism)
• Scopolamine (pharmacology)