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New Insights into Neuronal Pathways Regulating Brain Development and Higher Functions

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 5005

Special Issue Editor

Prof. Dr. Kozo Kaibuchi

E-Mail Website
Guest Editor
Division of Cell Biology, International Center for Brain Science, Fujita Health University, Toyoake, Japan
Interests: neurotransmitters; learning and memory; emotion; receptors; G proteins; phosphorylation; signal transduction; gene expression; synapses; mathematical modeling

Special Issue Information

Dear Colleagues,

It is well known that brain development and higher functions such as learning, memory and emotion are regulated by neurotransmitters such as glutamate, dopamine and acetylcholine, and neurotrophic factors including BDNF and NT-3. The elucidation of the intracellular signaling mechanisms of these extracellular signals is very important not only for understanding the regulatory mechanisms of brain development and higher functions, but also for uncovering the etiology and pathophysiology of psychiatric and neurological disorders and developing therapeutic strategies.

However, since the brain is composed of heterogeneous cell populations and the intracellular signals differ among cell types, the systematic analysis of intracellular signals at the whole-brain level has been extremely difficult. In recent years, with the development of advanced technologies such as tissue optical clearing technology and light-sheet microscopy, it has become possible to observe fluorescent proteins such as GFP proteins at the whole-brain level in rodents and non-human primates. In addition, with advances in optogenetics, single-cell omics, viral vectors, gene editing and mathematical modeling, the foundations are now in place to promote studies of signal transduction in multiple brain regions.

This Special Issue is focused on neuronal pathways, and invites original papers and review articles on physiological and pathological aspects related to the regulation of brain development and functions.

Prof. Dr. Kozo Kaibuchi
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neurotransmitters
  • learning and memory
  • emotion
  • receptors
  • G proteins
  • phosphorylation
  • signal transduction
  • gene expression
  • synapses
  • mathematical modeling

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Published Papers (2 papers)

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Research

13 pages, 915 KiB  
Communication
The Evaluation of Rac1 Signaling as a Potential Therapeutic Target of Alzheimer’s Disease
by Huanhuan Wang, Yukie Yamahashi, Marcel Riedl, Mutsuki Amano and Kozo Kaibuchi
Int. J. Mol. Sci. 2023, 24(15), 11880; https://doi.org/10.3390/ijms241511880 - 25 Jul 2023
Cited by 4 | Viewed by 1628
Abstract
The Small GTPase Rac1 is critical for various fundamental cellular processes, including cognitive functions. The cyclical activation and inactivation of Rac1, mediated by Rac guanine nucleotide exchange factors (RacGEFs) and Rac GTPase-activating proteins (RacGAPs), respectively, are essential for activating intracellular signaling pathways and [...] Read more.
The Small GTPase Rac1 is critical for various fundamental cellular processes, including cognitive functions. The cyclical activation and inactivation of Rac1, mediated by Rac guanine nucleotide exchange factors (RacGEFs) and Rac GTPase-activating proteins (RacGAPs), respectively, are essential for activating intracellular signaling pathways and controlling cellular processes. We have recently shown that the Alzheimer’s disease (AD) therapeutic drug donepezil activates the Rac1-PAK pathway in the nucleus accumbens (NAc) for enhanced aversive learning. Also, PAK activation itself in the NAc enhances aversive learning. As aversive learning allows short-term preliminary AD drug screening, here we tested whether sustained Rac1 activation by RacGAP inhibition can be used as an AD therapeutic strategy for improving AD-learning deficits based on aversive learning. We found that the RacGAP domain of breakpoint cluster region protein (Bcr) (Bcr-GAP) efficiently inhibited Rac1 activity in a membrane ruffling assay. We also found that, in striatal/accumbal primary neurons, Bcr knockdown by microRNA mimic-expressing adeno-associated virus (AAV-miRNA mimic) activated Rac1-PAK signaling, while Bcr-GAP-expressing AAV inactivated it. Furthermore, conditional knockdown of Bcr in the NAc of wild-type adult mice enhanced aversive learning, while Bcr-GAP expression in the NAc inhibited it. The findings indicate that Rac1 activation by RacGAP inhibition enhances aversive learning, implying the AD therapeutic potential of Rac1 signaling. Full article
(This article belongs to the Special Issue New Insights into Neuronal Pathways Regulating Brain Development and Higher Functions)
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19 pages, 2681 KiB  
Article
Rho-Kinase/ROCK Phosphorylates PSD-93 Downstream of NMDARs to Orchestrate Synaptic Plasticity
by Emran Hossen, Yasuhiro Funahashi, Md. Omar Faruk, Rijwan Uddin Ahammad, Mutsuki Amano, Kiyofumi Yamada and Kozo Kaibuchi
Int. J. Mol. Sci. 2023, 24(1), 404; https://doi.org/10.3390/ijms24010404 - 26 Dec 2022
Cited by 8 | Viewed by 2832
Abstract
The N-methyl-D-aspartate receptor (NMDAR)-mediated structural plasticity of dendritic spines plays an important role in synaptic transmission in the brain during learning and memory formation. The Rho family of small GTPase RhoA and its downstream effector Rho-kinase/ROCK are considered as one of the major [...] Read more.
The N-methyl-D-aspartate receptor (NMDAR)-mediated structural plasticity of dendritic spines plays an important role in synaptic transmission in the brain during learning and memory formation. The Rho family of small GTPase RhoA and its downstream effector Rho-kinase/ROCK are considered as one of the major regulators of synaptic plasticity and dendritic spine formation, including long-term potentiation (LTP). However, the mechanism by which Rho-kinase regulates synaptic plasticity is not yet fully understood. Here, we found that Rho-kinase directly phosphorylated discs large MAGUK scaffold protein 2 (DLG2/PSD-93), a major postsynaptic scaffold protein that connects postsynaptic proteins with NMDARs; an ionotropic glutamate receptor, which plays a critical role in synaptic plasticity. Stimulation of striatal slices with an NMDAR agonist induced Rho-kinase-mediated phosphorylation of PSD-93 at Thr612. We also identified PSD-93-interacting proteins, including DLG4 (PSD-95), NMDARs, synaptic Ras GTPase-activating protein 1 (SynGAP1), ADAM metallopeptidase domain 22 (ADAM22), and leucine-rich glioma-inactivated 1 (LGI1), by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Among them, Rho-kinase increased the binding of PSD-93 to PSD-95 and NMDARs. Furthermore, we found that chemical-LTP induced by glycine, which activates NMDARs, increased PSD-93 phosphorylation at Thr612, spine size, and PSD-93 colocalization with PSD-95, while these events were blocked by pretreatment with a Rho-kinase inhibitor. These results indicate that Rho-kinase phosphorylates PSD-93 downstream of NMDARs, and suggest that Rho-kinase mediated phosphorylation of PSD-93 increases the association with PSD-95 and NMDARs to regulate structural synaptic plasticity. Full article
(This article belongs to the Special Issue New Insights into Neuronal Pathways Regulating Brain Development and Higher Functions)
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