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

Cholinergic efferent networks located from the medial septal nucleus to the hippocampus play a pivotal role in learning and memory outcomes by generating regular theta rhythms that enhance information retention. Hippocampal cholinergic neurostimulating peptide (HCNP), derived from the N-terminus of HCNP precursor protein (HCNP-pp), promotes the synthesis of acetylcholine in the medial septal nuclei. HCNP-pp deletion significantly reduced theta power in CA1 possibly due to lower levels of choline acetyltransferase-positive axons in CA1 stratum oriens, suggesting cholinergic disruptions in the septo-hippocampal system. This review also explores HCNP as a potent cholinergic regulator in the septo-hippocampal network while also examining the limitations of our understanding of the neurostimulating peptide. Copyright:

Introduction

Theta rhythm, a significant rhythmic type within the hippocampal local field potential, possesses a vital role in memory processing.[1] This theta oscillation is generated by cholinergic projections, which stems from the medial septal nucleus to the CA1-CA stratum oriens of hippocampal functional areas and is crucial for maintaining normal theta rhythmic patterns.[2345] With the internal pacemaker, information is better retained and encoded in episodic memory.[67]

Molecular changes within the medial septal nuclei may affect cholinergic projections, affecting normal theta rhythms and functional memory processes. One notable molecule is the hippocampal cholinergic neurostimulating peptide (HCNP), which is cleaved from a 186 amino acid, 21 kD, long precursor protein (HCNP-pp) along the N-terminus.[8] HCNP was seen to promote acetylcholine production by increasing choline acetyltransferase (ChAT) expression level within the medial septal nuclei,[9] which may affect the cholinergic septo-hippocampal system, correlating to healthy episodic memory retention.

Hippocampal Cholinergic Neurostimulating Peptide-pp Genetic Models

HCNP-pp, also referred to as Raf kinase inhibitory protein or phosphatidylethanolamine-binding protein 1, is an ATP-binding, multifunctional protein with inhibitory abilities on Erk signaling pathways.[1011] HCNP may be synthesized from HCNP-pp cleavage by the thiol protease group.[8] Studies have demonstrated that HCNP-pp transgenic mice exhibit behavioral depressive-like phenotype[12] and electrophysiological higher amplitude of hippocampal field excitatory postsynaptic potentials that is regulated through M1 receptor activation.[3] In addition, these mice may inhibit the regulation of Aß oligomer-induced glutamatergic neuronal activity in the hippocampus through the muscarinic M1 receptor.[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.[1415] 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.

Hippocampal Cholinergic Neurostimulating Peptide

HCNP in 14-day-old postnatal hippocampi[9] was initially isolated and later exhibited nerve- and fibroblast-like abilities, which enhanced cell growth.[1617] 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. Specifically, theta rhythms were observed at reduced power in CA1 regions of mice with inadequate HCNP-pp expressions. These same mice also exhibited lowered hippocampal cholinergic projection,[118] proposing a correlation between HCNP-pp/HCNP with cholinergic projection and theta rhythm. On the other hand, overexpressing HCNP was seen to increase ChAT and promote cholinergic effects, enhancing hippocampal activity under unsaturated conditions of the glutamatergic pathway.[4] However, the same effect was not present in saturated conditions.

Due to its likely involvement in synaptic density maintenance,[38192021] HCNP is a potent cholinergic modulator in the septo-hippocampal system that may improve learning and memory outcomes. HCNP may also support neuronal growth and survival, acting as a neurotrophic-like factor.[8] However, we have not yet caught any evidence that HCNP functions in behavioral cognitive phenotype.

Cholinergic Activity

Hippocampal cholinergic systems play a crucial role in the formation of memory. Recent studies have proposed an additional link between cholinergic effects and anxiety and depression.[122223] Upregulation and overexpression of HCNP-pp caused by CMKII promoter resulted in depressive symptoms,[12] demonstrating potential adverse effects of HCNP-pp alterations. However, inhibiting or removing HCNP-pp alone does not express significant cognitive dysfunctions or depression. In addition, knockout model mice of acetylcholine receptors, such as M1 receptor or alpha 7 nicotinic receptor, do not hinder memory or learning functions,[2425] suggesting a combination of cholinergic dysfunctions may arise to produce cognitive and behavioral deficits. In other words, reducing acetylcholine alone would not induce dysfunctions in the hippocampus, and removal of HCNP should be followed up with additional cholinergic-correlated dysfunctions to exhibit hippocampal deficits.

Studies have also suggested that sufficient ChAT activity may result in normal behaviors due to other present cholinergic regulators,[262728293031] masking HCNP cognitive behavioral deficits in behavioral tests. However, discrepancies arose when observing tropomyosin receptor kinase A (TrkA), a major cholinergic regulator receptor, in relation to cognitive deficits. Specifically, some studies demonstrated no significant changes in behavior when removing TrkA in specific areas with low levels of cholinergic terminals while similar studies exhibited significant cognitive abnormalities;[3233] this discrepancy was likely due to the difference in gene deletion and animal usage within the studies.[323334]

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. As another potential, incomplete suppression of glutamatergic activity in the hippocampus may be necessary to investigate HCNP or HCNP-pp on hippocampal cognitive behavior.[4] Because other hippocampal molecules, such as vinpocetine, recover behavioral and memory outcomes through enhanced cholinergic neurotransmission, HCNP may also improve cognitive functions by targeting cholinergic activity,[35] which are also exhibited by stem cell administrations.[36] Further investigations are necessary to examine the functions of HCNP due to acetylcholine releases. Alzheimer’s disease could be used to examine behavioral phenotypes under glutamatergic neuronal conditions.[4]

Conclusion

HCNP and cholinergic projections are potent targets for recovering learning and memory deficits. There is a likely relationship between cholinergic activity and HCNP-pp; removing HCNP-pp in mice models resulted in decreased choline acetyltransferase-positive axons in the CA1 stratum oriens, which lowered theta oscillations. Lowered hippocampal cholinergic activity in HCNP-pp KO mice models provide evidence of cholinergic functional enhancement abilities of HCNP and demonstrate HCNP-dependent alterations to hippocampal networks, suggesting HCNP to be a cholinergic regulator in the septo-hippocampal system. Although the effects of HCNP on theta rhythms and behavioral outcomes are evident, the function of HCNP is yet to be determined; it is unclear whether the HCNP is dependent on acetylcholine release acceleration or direct trophic effects. Furthermore, observable behavioral changes through hippocampal dysfunction were undetected in cognitive and depressive tests. Future investigations should experiment direct reduction of acetylcholine activity in the hippocampus or number of cholinergic neuronal cells in the medial septal nucleus in addition to testing phenotypic hippocampal dysfunction through suitable behavioral tests possibly under glutamatergic neuronal conditions, such as Alzheimer’s disease.

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