Reduced Cholinergic Activity in the Hippocampus of Hippocampal Cholinergic Neurostimulating Peptide Precursor Protein Knockout Mice

Abstract

The cholinergic efferent network from the medial septal nucleus to the hippocampus has an important role in learning and memory processes. This cholinergic projection can generate theta oscillations in the hippocampus to efficiently encode novel information. Hippocampal cholinergic neurostimulating peptide (HCNP) induces acetylcholine synthesis in medial septal nuclei. HCNP is processed from the N-terminal region of a 186 amino acid, 21 kD HCNP precursor protein called HCNP-pp (also known as Raf kinase inhibitory protein (RKIP) and phosphatidylethanolamine-binding protein 1 (PEBP1)). In this study, we generated HCNP-pp knockout (KO) mice and assessed their cholinergic septo-hippocampal projection, local field potentials in CA1, and behavioral phenotypes. No significant behavioral phenotype was observed in HCNP-pp KO mice. However, theta power in the CA1 of HCNP-pp KO mice was significantly reduced because of fewer cholineacetyltransferase-positive axons in the CA1 stratum oriens. These observations indicated disruption of cholinergic activity in the septo-hippocampal network. Our study demonstrates that HCNP may be a cholinergic regulator in the septo-hippocampal network.

Reduction of acetylcholine in the hippocampus of hippocampal cholinergic neurostimulating peptide precursor protein knockout mice

“…We demonstrated that HCNP-pp KO mice show diminished cholinergic projection to CA1. Additionally, the theta activity in CA1 of the hippocampus was reduced in HCNP-pp KO mice 18 . This electrophysiological data suggest that HCNP and/or HCNP-pp is involved in generation of theta oscillations in the hippocampus, which entrains the theta oscillation of the MSN via enhanced ACh release in the medial septum and the enhanced release of ACh in the CA1 stratum oriens 19 , 20 .…”

The unsolved mystery of hippocampal cholinergic neurostimulating peptide: A potent cholinergic regulator

“…[ 4 ] On the other hand, conditional HCNP-pp knockout mice using Cre-ERT/loxP system by CaMKII-Cre transgenic mice revealed reduced power of theta rhythms in CA1 regions, whereas those mice showed no significant behavioral abnormality in locomotor, anxiety, or cognitive function. [ 13 ] In this model, downregulation of HCNP-pp expressions was possibly limited in cells controlled by CaMKII promoter, a hippocampal excitatory neuronal expression regulator, while HCNP-pp expressions are known to exist in inhibitory neurons, oligodendroglia, and hippocampal pyramidal neurons. [ 14 15 ] Further investigations are needed to provide a plausible explanation for HCNP function, including HCNP-pp downregulation in other kinds of cells by using Cre-transgenic mice driven other promotors.…”

“…HCNP in 14-day-old postnatal hippocampi[ 9 ] was initially isolated and later exhibited nerve- and fibroblast-like abilities, which enhanced cell growth. [ 16 17 ] Cholinergic axon terminals also decreased in stratum oriens of mice with inadequate HCNP-pp levels,[ 13 ] suggesting ChAT regulatory abilities of HCNP in septal cholinergic neuronal cells. Furthermore, HCNP in the hippocampus was found to be correlated to theta activity.…”

“…A recent study on HCNP-pp KO mice failed to evaluate behaviors dependent on septo-hippocampal systems in behavioral tests on locomotion, anxiety, memory, and depression. [ 13 ] However, electrophysiological evaluation demonstrated lower hippocampal cholinergic activity in HCNP-pp KO mice, indicative of hippocampal dysfunction through HCNP reduction. There is a potential that suitable tests were needed to specifically assess septo-hippocampal cholinergic functions even though cholinergic dysfunctions were revealed.…”

Liraglutide inhibits the progression of prediabetes in rats by reducing Raf-1 kinase inhibitor protein

“…The amino terminal of RKIP can be cleaved by sulfhydryl-containing chymotrypsin into a polypeptide of 11 amino acid residues, namely hippocampal cholinergic neurostimulating peptide (HCNP). HCNP can activate choline acetyltransferase in the central nervous system, promote the synthesis of acetylcholine, and then act on the cholinergic neuroreceptor system (10). In vitro experiments have shown that HCNP promotes insulin secretion, but it is not clear whether this effect passes through the cholinergic nervous system.…”