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Biomolecules
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Advances in Brain Development and Disease
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Advances in Brain Development and Disease

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 5546

Special Issue Editors

Dr. Frank Schubert

E-Mail Website
Guest Editor
School of Biological Sciences, University of Portsmouth, Hampshire, UK
Interests: developmental neurobiology; molecular mechanisms of brain development; neurogenesis; paediatric brain tumours; evolution of gene families
Special Issues, Collections and Topics in MDPI journals
Dr. Ricardo J. Rodrigues

E-Mail Website
Guest Editor
CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal
Interests: brain development; neurodegeneration; neuromodulation; purinergic receptors; NMDA receptors; adenosine; ATP; glutamate; neuronal migration; epilepsy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Brain development is achieved through a tightly controlled sequence of events—from neurogenesis, cell migration, differentiation, and neuritogenesis, to synapse formation and stabilization—in order to establish the neuronal network and a functional and healthy brain. Impairment of any of these critical stages of brain development, either by genetic variants or caused by extrinsic factors, can lead to long-term deleterious effects ranging from mild cognitive impairment to severe neurological and psychiatric conditions. Hence, it is essential to fully understand the mechanisms regulating the different processes governing brain development. In the last few decades, our knowledge on how the brain develops, particularly the molecular mechanisms involved or the relevance of the interactions between the different cells and extracellular matrix, has greatly improved. Yet, our current knowledge in this field is still at an “embryonic” stage. Furthermore, it will also be crucial to understand the spatial–temporal relevance of the different regulatory mechanisms and how they are integrated. In this Special Issue, we hope to gather contributions that highlight both the physiological mechanisms underlying brain development, and development-related brain disorders.

You may choose our Joint Special Issue in Neurosci.   

Dr. Frank Schubert
Dr. Ricardo J. Rodrigues 
Guest Editors

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. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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.

Published Papers (4 papers)

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Research

18 pages, 2891 KiB  
Article
Postweaning Development Influences Endogenous VPAC1 Modulation of LTP Induced by Theta-Burst Stimulation: A Link to Maturation of the Hippocampal GABAergic System
by Marta Gil, Ana Caulino-Rocha, Marta Bento, Nádia C. Rodrigues, Armando Silva-Cruz, Joaquim A. Ribeiro and Diana Cunha-Reis
Biomolecules 2024, 14(3), 379; https://doi.org/10.3390/biom14030379 - 20 Mar 2024
Viewed by 788
Abstract
Long-term potentiation (LTP) induced by theta-burst stimulation (TBS) undergoes postweaning developmental changes partially linked to GABAergic circuit maturation. Endogenous vasoactive intestinal peptide (VIP) acting on its VPAC1 receptor strongly influences LTP induced by theta-burst stimulation (TBS), an effect dependent on GABAergic transmission. [...] Read more.
Long-term potentiation (LTP) induced by theta-burst stimulation (TBS) undergoes postweaning developmental changes partially linked to GABAergic circuit maturation. Endogenous vasoactive intestinal peptide (VIP) acting on its VPAC1 receptor strongly influences LTP induced by theta-burst stimulation (TBS), an effect dependent on GABAergic transmission. Although VPAC1 receptor levels are developmentally regulated during embryogenesis, their variation along postweaning development is unknown, as is the VPAC1 modulation of LTP or its relation to hippocampal GABAergic circuit maturation. As such, we investigated how VPAC1 modulation of LTP adjusts from weaning to adulthood along with GABAergic circuit maturation. As described, LTP induced by mild TBS (5 bursts, 4 pulses delivered at 100 Hz) was increasingly greater from weaning to adulthood. The influence of the VPAC1 receptor antagonist PG 97-269 (100 nM) on TBS-induced LTP was much larger in juvenile (3-week-old) than in young adult (6–7-week-old) or adult (12-week-old) rats. This effect was not associated with a developmental decrease in synaptic VPAC1 receptor levels. However, an increase in pre and post-synaptic GABAergic synaptic markers suggests an increase in the number of GABAergic synaptic contacts that is more prominent than the one observed in glutamatergic connections during this period. Conversely, endogenous VPAC2 receptor activation did not significantly influence TBS-induced LTP. VPAC2 receptor levels enhance pronouncedly during postweaning development, but not at synaptic sites. Given the involvement of VIP interneurons in several aspects of hippocampal-dependent learning, neurodevelopmental disorders, and epilepsy, this could provide important insights into the role of VIP modulation of hippocampal synaptic plasticity during normal and altered brain development potentially contributing to epileptogenesis. Full article
(This article belongs to the Special Issue Advances in Brain Development and Disease)
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21 pages, 2309 KiB  
Article
Extra-Synaptic GABAA Receptor Potentiation and Neurosteroid-Induced Learning Deficits Are Inhibited by GR3027, a GABAA Modulating Steroid Antagonist
by Sara K. S. Bengtsson, Jessica Sjöstedt, Evgenya Malinina, Roshni Das, Magnus Doverskog, Maja Johansson, David Haage and Torbjörn Bäckström
Biomolecules 2023, 13(10), 1496; https://doi.org/10.3390/biom13101496 - 09 Oct 2023
Cited by 1 | Viewed by 1125
Abstract
Objectives In Vitro: To study the effects of GR3027 (golexanolone) on neurosteroid-induced GABA-mediated current responses under physiological GABAergic conditions with recombinant human α5β3γ2L and α1β2γ2L GABAA receptors expressed in human embryonic kidney cells, using the response patch clamp technique combined with the [...] Read more.
Objectives In Vitro: To study the effects of GR3027 (golexanolone) on neurosteroid-induced GABA-mediated current responses under physiological GABAergic conditions with recombinant human α5β3γ2L and α1β2γ2L GABAA receptors expressed in human embryonic kidney cells, using the response patch clamp technique combined with the Dynaflow™ application system. With α5β3γ2L receptors, 0.01–3 μM GR3027, in a concentration-dependent manner, reduced the current response induced by 200 nM THDOC + 0.3 µM GABA, as well as the THDOC-induced direct gated effect. GR3027 (1 μM) alone had no effect on the GABA-mediated current response or current in the absence of GABA. With α1β2γ2L receptors, GR3027 alone had no effect on the GABA-mediated current response or did not affect the receptor by itself. Meanwhile, 1–3 µM GR3027 reduced the current response induced by 200 nM THDOC + 30 µM GABA and 3 µM GR3027 that induced by 200 nM THDOC when GABA was not present. Objectives In Vivo: GR3027 reduces allopregnanolone (AP)-induced decreased learning and anesthesia in male Wistar rats. Rats treated i.v. with AP (2.2 mg/kg) or vehicle were given GR3027 in ratios of 1:0.5 to 1:5 dissolved in 10% 2-hydroxypropyl-beta-cyclodextrin. A dose ratio of AP:GR3027 of at least 1:2.5 antagonized the AP-induced decreased learning in the Morris Water Mase (MWM) and 1:7.5 antagonized the loss of righting reflex (LoR). GR3027 treatment did not change other functions in the rat compared to the vehicle group. Conclusions: GR3027 functions in vitro as an inhibitor of GABAA receptors holding α5β3γ2L and α1β2γ2L, in vivo, in the rat, as a dose-dependent inhibitor toward AP’s negative effects on LoR and learning in the MWM. Full article
(This article belongs to the Special Issue Advances in Brain Development and Disease)
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19 pages, 3901 KiB  
Article
Unconventional Source of Neurotoxic Protein Aggregation from Organelle Off-Target Bax∆2 in Alzheimer’s Disease
by Qi Yao, Anne Caroline Mascarenhas dos Santos, Huaiyuan Zhang, Adriana Mañas, Ammarah Hussaini, Ujin Kim, Congtai Xu, Sana Basheer, Shinya Tasaki and Jialing Xiang
Biomolecules 2023, 13(6), 970; https://doi.org/10.3390/biom13060970 - 10 Jun 2023
Viewed by 1519
Abstract
Protein aggregates are a hallmark of Alzheimer’s disease (AD). Extensive studies have focused on β-amyloid plaques and Tau tangles. Here, we illustrate a novel source of protein aggregates in AD neurons from organelle off-target proteins. Bax is a mitochondrial pore-forming pro-death protein. What [...] Read more.
Protein aggregates are a hallmark of Alzheimer’s disease (AD). Extensive studies have focused on β-amyloid plaques and Tau tangles. Here, we illustrate a novel source of protein aggregates in AD neurons from organelle off-target proteins. Bax is a mitochondrial pore-forming pro-death protein. What happens to Bax if it fails to target mitochondria? We previously showed that a mitochondrial target-deficient alternatively spliced variant, Bax∆2, formed large cytosolic protein aggregates and triggered caspase 8-mediated cell death. Bax∆2 protein levels were low in most normal organs and the proteins were quickly degraded in cancer. Here, we found that 85% of AD patients had Bax∆2 required alternative splicing. Increased Bax∆2 proteins were mostly accumulated in neurons of AD-susceptible brain regions. Intracellularly, Bax∆2 aggregates distributed independently of Tau tangles. Interestingly, Bax∆2 aggregates triggered the formation of stress granules (SGs), a large protein-RNA complex involved in AD pathogenesis. Although the functional domains required for aggregation and cell death are the same as in cancer cells, Bax∆2 relied on SGs, not caspase 8, for neuronal cell death. These results imply that the aggregation of organelle off-target proteins, such as Bax∆2, broadens the scope of traditional AD pathogenic proteins that contribute to the neuronal stress responses and AD pathogenesis. Full article
(This article belongs to the Special Issue Advances in Brain Development and Disease)
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16 pages, 4306 KiB  
Article
Histological Analysis of a Mouse Model of the 22q11.2 Microdeletion Syndrome
by Hidenori Tabata, Daisuke Mori, Tohru Matsuki, Kaichi Yoshizaki, Masato Asai, Atsuo Nakayama, Norio Ozaki and Koh-ichi Nagata
Biomolecules 2023, 13(5), 763; https://doi.org/10.3390/biom13050763 - 27 Apr 2023
Viewed by 1598
Abstract
22q11.2 deletion syndrome (22q11.2DS) is associated with a high risk of developing various psychiatric and developmental disorders, including schizophrenia and early-onset Parkinson’s disease. Recently, a mouse model of this disease, Del(3.0Mb)/+, mimicking the 3.0 Mb deletion which is most frequently found in patients [...] Read more.
22q11.2 deletion syndrome (22q11.2DS) is associated with a high risk of developing various psychiatric and developmental disorders, including schizophrenia and early-onset Parkinson’s disease. Recently, a mouse model of this disease, Del(3.0Mb)/+, mimicking the 3.0 Mb deletion which is most frequently found in patients with 22q11.2DS, was generated. The behavior of this mouse model was extensively studied and several abnormalities related to the symptoms of 22q11.2DS were found. However, the histological features of their brains have been little addressed. Here we describe the cytoarchitectures of the brains of Del(3.0Mb)/+ mice. First, we investigated the overall histology of the embryonic and adult cerebral cortices, but they were indistinguishable from the wild type. However, the morphologies of individual neurons were slightly but significantly changed from the wild type counterparts in a region-specific manner. The dendritic branches and/or dendritic spine densities of neurons in the medial prefrontal cortex, nucleus accumbens, and primary somatosensory cortex were reduced. We also observed reduced axon innervation of dopaminergic neurons into the prefrontal cortex. Given these affected neurons function together as the dopamine system to control animal behaviors, the impairment we observed may explain a part of the abnormal behaviors of Del(3.0Mb)/+ mice and the psychiatric symptoms of 22q11.2DS. Full article
(This article belongs to the Special Issue Advances in Brain Development and Disease)
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