Small Molecular Therapeutics Promoting Neuronal Plasticity, Hippocampal Learning, and Memory

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: 31 October 2025 | Viewed by 3379

Special Issue Editor

1. Simmaron Research Inc., 948 Incline Way, Incline Village, NV 89451, USA
2. Research and Development Laboratory, Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA
Interests: microglia; astroglia; neural stem cells; neuroinflammatory; neurodegenerative diseases; mitochondrial metabolism; misfolding of α-synuclein; neuronal plasticity

Special Issue Information

Dear Colleagues,

A synaptic transmission is an event by which a neuron relays information to the next neuron through the synapse. Typically, synaptic vesicles containing ions, metabolites, and neurotransmitters are released via pre-synaptic neurons and are then absorbed by post-synaptic neurons. While receiving these signaling vesicles, a post-synaptic neuron orchestrates a series of modifications on its dendrites to facilitate this neurotransmission. Some of these modifications include stretching the length of basal dendrites, the formation of new dendritic branches, the synthesis and maturation of dendritic spines, and the augmentation of metabotropic calcium flow. Collectively, these events are known as morphological plasticity. The preservation of morphological plasticity in a healthy brain is critical in the execution of cognitive tasks including learning and memory. However, the role of morphological plasticity has not been properly studied in the context of Alzheimer’s disease and dementia. Overwhelming evidence suggests that an AD brain might be associated with compromised neuronal plasticity. If this is the case, how can it be improved or restored? This Special Issue will be dedicated to the molecular alterations of morphological plasticity in the neurons of AD brains. It will also focus on the potential benefits and drawbacks of small molecular therapeutics on the preservation, restoration, and upregulation of morphological plasticity.

Dr. Avik Roy
Guest Editor

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Keywords

  • synaptic transmission
  • dendritic spines
  • metabotropic calcium influx
  • dendritic morphogenesis
  • small molecular therapeutics promoting neuronal plasticity

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Published Papers (2 papers)

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Research

9 pages, 2110 KiB  
Communication
Shorter Infantile Amnesia in Females: Important Implications for the Next Generation
by Yuheng Yang, Yuya Sakimoto, Makoto Goshima and Dai Mitsushima
Cells 2025, 14(5), 354; https://doi.org/10.3390/cells14050354 - 28 Feb 2025
Viewed by 483
Abstract
The sex-specific development of hippocampal learning in juveniles remains unclear. Using an inhibitory avoidance task, we assessed contextual learning in both sexes of juvenile rats. While sex hormone levels and activating effects are low in juveniles, females showed superior performance to males, suggesting [...] Read more.
The sex-specific development of hippocampal learning in juveniles remains unclear. Using an inhibitory avoidance task, we assessed contextual learning in both sexes of juvenile rats. While sex hormone levels and activating effects are low in juveniles, females showed superior performance to males, suggesting that females have a shorter period of infantile amnesia than males. It was already known that when infants are cared for by mothers with high parenting behavior, they are likely to become high parenting mothers themselves. In addition, neonatal testosterone is known to masculinize the brain, causing behavioral, neural, and hormonal sex differences. Here, we reviewed the purposeful significance of sex-specific development for learning, along with the interaction of developmental changes in the hormonal environment. Full article
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29 pages, 10636 KiB  
Article
JRM-28, a Novel HDAC2 Inhibitor, Upregulates Plasticity-Associated Proteins in Hippocampal Neurons and Enhances Morphological Plasticity via Activation of CREB: Implications for Alzheimer’s Disease
by A. F. M. Towheedur Rahman, Sarojini Bulbule, Jawad Bin Belayet, Anna Benko, Carl Gunnar Gottschalk, David N. Frick, Leggy A. Arnold, M. Mahmun Hossain and Avik Roy
Cells 2024, 13(23), 1964; https://doi.org/10.3390/cells13231964 - 27 Nov 2024
Viewed by 2385
Abstract
Enhancement of neuronal plasticity by small-molecule therapeutics protects cognitive skills and also ameliorates progressive neurodegenerative pathologies like Alzheimer’s disease (AD) and dementia. One such compound, a novel histone deacetylase 2 (HDAC2) inhibitor named JRM-28, was shown here to enhance dendritic strength, augment spine [...] Read more.
Enhancement of neuronal plasticity by small-molecule therapeutics protects cognitive skills and also ameliorates progressive neurodegenerative pathologies like Alzheimer’s disease (AD) and dementia. One such compound, a novel histone deacetylase 2 (HDAC2) inhibitor named JRM-28, was shown here to enhance dendritic strength, augment spine density, and upregulate post-synaptic neurotransmission in hippocampal neurons. The molecular basis for this effect correlates with JRM-28-induced upregulation of the transcription of cAMP response element-binding protein(CREB), induction of its transcriptional activity, and subsequent stimulation of expressions of CREB-dependent plasticity-associated genes, such as those encoding N-methyl-D-aspartate (NMDA) receptor subunit NR2A and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR1. Specifically, JRM-28 stimulated the NMDA- and AMPA-receptor-sensitive ionotropic calcium influx in hippocampal neurons. Interestingly, JRM-28 did not induce NMDA- and AMPA-sensitive calcium influx in hippocampal neurons once the expression of CREB was knocked down by creb siRNA, suggesting the critical role of CREB in JRM-28-mediated upregulation of synaptic plasticity. Finally, JRM-28 upregulated CREB mRNA, CREB-dependent plasticity-associated markers, and ionotropic calcium influx in iPSC-derived AD human neurons, indicating its therapeutic implications in the amelioration of AD pathologies. Full article
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