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Molecular Mechanisms of Brain Wiring

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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 December 2023) | Viewed by 5370

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Special Issue Editor

Dr. Alessandra Sclip

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Guest Editor

Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305, USA
Interests: brain wiring; synaptic adhesion molecules; synaptic physiology; neuron–astrocyte communication

Special Issue Information

Dear Colleagues,

Neurons in the brain wire in precise and stereotyped ways to form complex circuits that control behavioral outcomes. Although recent technological advances have allowed mapping of the anatomical, physiological, and functional properties of individual neurons, the molecular mechanisms underlying wiring specificity are largely unknown. Deciphering the mechanism regulating brain wiring is not only important for basic neuroscience but is also relevant for translational medicine as many neurodevelopmental disorders have been associated to changes in neuronal connectivity or synaptic function.

The objective of this Special Issue is to assemble current knowledge on the genetic programs regulating the wiring of neural circuitry and shaping synaptic properties.

This Special Issue may include original research articles focusing on the study of the mechanisms instructing synapse formation and specification during neurodevelopment and adulthood or providing insight on neuronal connectivity in physiology and disease. Papers describing novel methods in assessing synaptic changes as well as review paper discussing challenges and conceptual advances in the field are also welcome.

Dr. Alessandra Sclip
Guest Editor

Manuscript Submission Information

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Keywords

molecular anatomy of synapses
synaptic transmission
synaptic adhesion molecules
neuronal networks
circuit assembly
molecular mechanisms

Published Papers (5 papers)

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Research

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11 pages, 2625 KiB

Open AccessArticle

Correlation of Presynaptic and Postsynaptic Proteins with Pathology in Alzheimer’s Disease

by Geidy E. Serrano, Jessica Walker, Courtney Nelson, Michael Glass, Richard Arce, Anthony Intorcia, Madison P. Cline, Natalie Nabaty, Amanda Acuña, Ashton Huppert Steed, Lucia I. Sue, Christine Belden, Parichita Choudhury, Eric Reiman, Alireza Atri and Thomas G. Beach

Int. J. Mol. Sci. 2024, 25(6), 3130; https://doi.org/10.3390/ijms25063130 - 8 Mar 2024

Viewed by 736

Abstract

Synaptic transmission is essential for nervous system function and the loss of synapses is a known major contributor to dementia. Alzheimer’s disease dementia (ADD) is characterized by synaptic loss in the mesial temporal lobe and cerebral neocortex, both of which are brain areas associated with memory and cognition. The association of synaptic loss and ADD was established in the late 1980s, and it has been estimated that 30–50% of neocortical synaptic protein is lost in ADD, but there has not yet been a quantitative profiling of different synaptic proteins in different brain regions in ADD from the same individuals. Very recently, positron emission tomography (PET) imaging of synapses is being developed, accelerating the focus on the role of synaptic loss in ADD and other conditions. In this study, we quantified the densities of two synaptic proteins, the presynaptic protein Synaptosome Associated Protein 25 (SNAP25) and the postsynaptic protein postsynaptic density protein 95 (PSD95) in the human brain, using enzyme-linked immunosorbent assays (ELISA). Protein was extracted from the cingulate gyrus, hippocampus, frontal, primary visual, and entorhinal cortex from cognitively unimpaired controls, subjects with mild cognitive impairment (MCI), and subjects with dementia that have different levels of Alzheimer’s pathology. SNAP25 is significantly reduced in ADD when compared to controls in the frontal cortex, visual cortex, and cingulate, while the hippocampus showed a smaller, non-significant reduction, and entorhinal cortex concentrations were not different. In contrast, all brain areas showed lower PSD95 concentrations in ADD when compared to controls without dementia, although in the hippocampus, this failed to reach significance. Interestingly, cognitively unimpaired cases with high levels of AD pathology had higher levels of both synaptic proteins in all brain regions. SNAP25 and PSD95 concentrations significantly correlated with densities of neurofibrillary tangles, amyloid plaques, and Mini Mental State Examination (MMSE) scores. Our results suggest that synaptic transmission is affected by ADD in multiple brain regions. The differences were less marked in the entorhinal cortex and the hippocampus, most likely due to a ceiling effect imposed by the very early development of neurofibrillary tangles in older people in these brain regions. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Brain Wiring)

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18 pages, 8573 KiB

Open AccessArticle

Olanzapine Effects on Parvalbumin/GAD67 Cell Numbers in Layers/Subregions of Dorsal Hippocampus of Chronically Socially Isolated Rats

by Andrijana Stanisavljević Ilić, Snežana Đorđević, Dragoš Inta, Stefan Borgwardt and Dragana Filipović

Int. J. Mol. Sci. 2023, 24(24), 17181; https://doi.org/10.3390/ijms242417181 - 6 Dec 2023

Viewed by 865

Abstract

Depression is linked to changes in GABAergic inhibitory neurons, especially parvalbumin (PV) interneurons, which are susceptible to redox dysregulation. Olanzapine (Olz) is an atypical antipsychotic whose mode of action remains unclear. We determined the effect of Olz on PV-positive (+) and glutamate decarboxylase 67 (GAD67) + cell numbers in the layers of dorsal hippocampus (dHIPP) cornu ammonis (CA1–CA3) and dentate gyrus (DG) subregions in rats exposed to chronic social isolation (CSIS), which is an animal model of depression. Antioxidative enzymes and proinflammatory cytokine levels were also examined. CSIS decreased the PV+ cell numbers in the Stratum Oriens (SO) and Stratum Pyramidale (SP) of dCA1 and dDG. It increased interleukin-6 (IL-6), suppressor of cytokine signaling 3 (SOCS3), and copper–zinc superoxide dismutase (CuZnSOD) levels, and it decreased catalase (CAT) protein levels. Olz in CSIS increased the number of GAD67+ cells in the SO and SP layers of dCA1 with no effect on PV+ cells. It reduced the PV+ and GAD67+ cell numbers in the Stratum Radiatum of dCA3 in CSIS. Olz antagonizes the CSIS-induced increase in CuZnSOD, CAT and SOCS3 protein levels with no effect on IL-6. Data suggest that the protective Olz effects in CSIS may be mediated by altering the number of PV+ and GAD67+ cells in dHIPP subregional layers. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Brain Wiring)

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18 pages, 1431 KiB

Open AccessArticle

Molecular Mechanisms for Changing Brain Connectivity in Mice and Humans

by Pascale Voelker, Aldis P. Weible, Cristopher M. Niell, Mary K. Rothbart and Michael I. Posner

Int. J. Mol. Sci. 2023, 24(21), 15840; https://doi.org/10.3390/ijms242115840 - 31 Oct 2023

Viewed by 656

Abstract

The goal of this study was to examine commonalities in the molecular basis of learning in mice and humans. In previous work we have demonstrated that the anterior cingulate cortex (ACC) and hippocampus (HC) are involved in learning a two-choice visuospatial discrimination task. Here, we began by looking for candidate genes upregulated in mouse ACC and HC with learning. We then determined which of these were also upregulated in mouse blood. Finally, we used RT-PCR to compare candidate gene expression in mouse blood with that from humans following one of two forms of learning: a working memory task (network training) or meditation (a generalized training shown to change many networks). Two genes were upregulated in mice following learning: caspase recruitment domain-containing protein 6 (Card6) and inosine monophosphate dehydrogenase 2 (Impdh2). The Impdh2 gene product catalyzes the first committed step of guanine nucleotide synthesis and is tightly linked to cell proliferation. The Card6 gene product positively modulates signal transduction. In humans, Card6 was significantly upregulated, and Impdh2 trended toward upregulation with training. These genes have been shown to regulate pathways that influence nuclear factor kappa B (NF-κB), a factor previously found to be related to enhanced synaptic function and learning. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Brain Wiring)

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22 pages, 4974 KiB

Open AccessArticle

Activation of 5-HT1A Receptors Normalizes the Overexpression of Presynaptic 5-HT1A Receptors and Alleviates Diabetic Neuropathic Pain

by Neha Munawar, Milad S. Bitar and Willias Masocha

Int. J. Mol. Sci. 2023, 24(18), 14334; https://doi.org/10.3390/ijms241814334 - 20 Sep 2023

Cited by 2 | Viewed by 1167

Abstract

Neuropathic pain is a well-documented phenomenon in experimental and clinical diabetes; however, current treatment is unsatisfactory. Serotoninergic-containing neurons are key components of the descending autoinhibitory pathway, and a decrease in their activity may contribute at least in part to diabetic neuropathic pain (DNP). A streptozotocin (STZ)-treated rat was used as a model for type 1 diabetes mellitus (T1DM). Pain transmission was evaluated using well-established nociceptive-based techniques, including the Hargreaves apparatus, cold plate and dynamic plantar aesthesiometer. Using qRT-PCR, Western blotting, immunohistochemistry, and HPLC-based techniques, we also measured in the central nervous system and peripheral nervous system of diabetic animals the expression and localization of 5-HT1A receptors (5-HT1AR), levels of key enzymes involved in the synthesis and degradation of tryptophan and 5-HT, including tryptophan hydroxylase-2 (Tph-2), tryptophan 2,3-dioxygenase (Tdo), indoleamine 2,3-dioxygenase 1 (Ido1) and Ido2. Moreover, spinal concentrations of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA, a metabolite of 5-HT) and quinolinic acid (QA, a metabolite of tryptophan) were also quantified. Diabetic rats developed thermal hyperalgesia and cold/mechanical allodynia, and these behavioral abnormalities appear to be associated with the upregulation in the levels of expression of critical molecules related to the serotoninergic nervous system, including presynaptic 5-HT1AR and the enzymes Tph-2, Tdo, Ido1 and Ido2. Interestingly, the level of postsynaptic 5-HT1AR remains unaltered in STZ-induced T1DM. Chronic treatment of diabetic animals with 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT), a selective 5-HT1AR agonist, downregulated the upregulation of neuronal presynaptic 5-HT1AR, increased spinal release of 5-HT (↑ 5-HIAA/5-HT) and reduced the concentration of QA, decreased mRNA expression of Tdo, Ido1 and Ido2, arrested neuronal degeneration and ameliorated pain-related behavior as exemplified by thermal hyperalgesia and cold/mechanical allodynia. These data show that 8-OH-DPAT alleviates DNP and other components of the serotoninergic system, including the ratio of 5-HIAA/5-HT and 5-HT1AR, and could be a useful therapeutic agent for managing DNP. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Brain Wiring)

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Review

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16 pages, 1389 KiB

Open AccessReview

Astrocytes as Neuroimmunocytes in Alzheimer’s Disease: A Biochemical Tool in the Neuron–Glia Crosstalk along the Pathogenetic Pathways

by Stefano Stanca, Martina Rossetti and Paolo Bongioanni

Int. J. Mol. Sci. 2023, 24(18), 13880; https://doi.org/10.3390/ijms241813880 - 9 Sep 2023

Cited by 1 | Viewed by 1295

Abstract

This work aimed at assessing Alzheimer’s disease (AD) pathogenesis through the investigation of the astrocytic role to transduce the load of amyloid-beta (Aβ) into neuronal death. The backbone of this review is focused on the deepening of the molecular pathways eliciting the activation of astrocytes crucial phenomena in the understanding of AD as an autoimmune pathology. The complex relations among astrocytes, Aβ and tau, together with the role played by the tripartite synapsis are discussed. A review of studies published from 1979 to 2023 on Scopus, PubMed and Google Scholar databases was conducted. The selected papers focused not only on the morphological and metabolic characteristics of astrocytes, but also on the latest notions about their multifunctional involvement in AD pathogenesis. Astrocytes participate in crucial pathways, including pruning and sprouting, by which the AD neurodegeneration evolves from an aggregopathy to neuroinflammation, loss of synapses and neuronal death. A1 astrocytes stimulate the production of pro-inflammatory molecules which have been correlated with the progression of AD cognitive impairment. Further research is needed to “hold back” the A1 polarization and, thus, to slow the worsening of the disease. AD clinical expression is the result of dysfunctional neuronal interactions, but this is only the end of a process involving a plurality of protagonists. One of these is the astrocyte, whose importance this work intends to put under the spotlight in the AD scenario, reflecting the multifaceted nature of this disease in the functional versatility of this glial population. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Brain Wiring)

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