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Prefrontal Inhibitory Signaling in the Control of Social Behaviors
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
The above discussed findings from human clinical studies suggest that impaired cortical inhibition is a key regulator in the pathogenesis of psychiatric disorders with shared social deficits. In line with those clinical findings, impaired inhibition in the cerebral cortex, the mPFC in particular, is routinely found in mouse models carrying genetic modifications known to cause autism in humans. For instance, mice with heterozygous loss-of-function mutations in the SCN1A gene (Scn1a+/−) have reduced Na+ currents and impaired action potential firing in GABAergic neurons and decreased inhibitory transmission in hippocampal CA1 and prefrontal cortex (Han et al. 2012). Similarly, the frequency of spontaneous GABAergic neurotransmission is significantly reduced in the hippocampus of BTBR mice, a model of idiopathic autism (Han et al. 2014). Also, in vitro patch-clamp recordings revealed decreased neuronal excitability in mPFC PV INs of neuroligin 3 R451C knockin mice (Cao et al. 2018), and major reductions in prefrontal synaptic inhibition in neuroligin-2 conditional knockout mice (Liang et al. 2015). In addition, compared to wild-type mice, the neural activity of mPFC PV INs was directly measured using fiber photometry and was found diminished in contactin-associated protein-like 2 (CNTNAP2) knockout mice during social interaction (Selimbeyoglu et al. 2017).
Gastrointestinal Stromal Tumors: From Molecular Pathogenesis to Therapy
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Joaquina Baranda, Stafinur Atay, Andrew K. Godwin
Two additional studies have attempted to further characterize pediatric GISTs using expression profiling [88, 90]. In 2005 Prakash and colleagues performed gene expression analysis on seven gastric samples: five from two pediatric WT patients and two from different young adult patients (1 mutant, 1 WT) and compared these to 10 gastric adult GISTs (9 mutant, 1 WT). Although the sample sizes were small, the authors reported that all of the pediatric and young adult samples, with the exception of one pediatric sample, clustered together and were distinct from the adult GISTs, suggesting major molecular differences between these two GIST subsets. 385 genes were determined to be differentially expressed (> 2-fold change) between the two groups. Genes upregulated in the pediatric and young adult group included neuroligin 4 (NLGN4), ankyrin 3 (ANK3), frizzled 2 (FZD2), insulin-like growth factor receptor type 1 (IGF1R) and phosphorylase kinase alpha 1 (PHKA1). Genes that were significantly downregulated included dermatopontin (DPT), PDGFRA, RAS-family member, RAB38, and G-protein-coupled receptor 88 (GPR88). These results point to a possible genotype/phenotype correlation, since the pediatric/young adult group consisted of mostly WT tumors while the adult group consisted of mutant tumors.
The effect of vitamin B12 on synaptic plasticity of hippocampus in Alzheimer’s disease model rats
Published in International Journal of Neuroscience, 2023
Jahanshahi Mehrdad, Elyasi Leila, Nikmahzar Emsehgol
Another important finding of our study was the effect of vitamin B12 on cell–adhesion molecules. The cell–adhesion molecules, localized at synapses, are vital for synapse specification and integrity [27]. They also show signaling properties by interacting with their partners, organizing the neurotransmission machinery on either directions of the synapses [28]. Neurexins are important cell–adhesion molecules in synapses of the nervous system [29] and PSD–95 is the main protein of postsynaptic density that mediates NMDA receptors clustering within synapses. Both, neurexins and PSD–95, can regulate the balance between excitatory and inhibitory synapses [30]. Therefore, we measured PSD–95, neurexin1, and neuroligin for assessment of the synaptic integrity of hippocampus in the experimental groups and the results showed that concentrations of PSD–95 and neurexin1 proteins were reduced in hippocampus. Abnormalities in the amounts of synaptic proteins in scopolamine–induced AD in the rats, observed in the present study, are possibly because of the progress in the pathological conditions associated with AD and vitamin B12 could attenuate these effects, possibly by prevention of the synaptic degradation leading to neuronal death, as vitamin B12 is a determinant factor linked to neurogenesis [31]. Yet, the precise mechanisms and neurogenesis induced by vitamin B12, the potential functional associations between the neuroprotection of vitamin B12 and interactions between synaptic proteins, and the right signaling routes of vitamin B12 in CNS are unknown.
Synaptic remodeling, lessons from C. elegans
Published in Journal of Neurogenetics, 2020
Andrea Cuentas-Condori, David M. Miller, 3rd
Recent studies have confirmed that dendritic spines in C. elegans DD and VD GABAergic motor neurons display key hallmarks of mammalian spines as they (1) are structurally defined by a dynamic actin cytoskeleton, (2) localize postsynaptic proteins in apposition to excitatory presynaptic terminals (Figure 7(B,C)), (3) localize ER and ribosomes, (4) display Ca++ transients evoked by presynaptic activity and, (5) respond to activity-dependent signals that modulate spine density (Cuentas-Condori et al., 2019; Philbrook et al., 2018). Interestingly, postsynaptic spine formation and maintenance requires the trans-synaptic adhesion protein Neurexin/NRX-1, which functions in presynaptic cholinergic motor neurons. Surprisingly, this Neurexin/NRX-1-dependent effect does not require the canonical trans-synaptic interacting partner, the membrane protein neuroligin/NLG-1 and thus likely interacts with an alternative component that is currently unknown (Philbrook et al., 2018). The dramatic emergence of dendritic spines in remodeling DD neurons offers a unique opportunity to exploit the power of C. elegans genetics and live cell imaging to define evolutionarily ancient but shared mechanisms that drive spine morphogenesis.
Further understanding of glioma mechanisms of pathogenesis: implications for therapeutic development
Published in Expert Review of Anticancer Therapy, 2020
Michael Ruff, Sani Kizilbash, Jan Buckner
A recently described mechanism of a direct neuronal activity to a glioma mitogen link implicates neuronal activity-dependent cleavage on a synaptic-adhesion molecule, neuroligin-3 (NLGN3), which binds to glioma cells similarly as it does for the native oligodendrocyte or oligodendrocyte progenitor cell and stimulates the PIK3-mTOR pathway [56]. NLGN3 sends the glioma cell a mitogenic signal that predominantly facilitates an oligodendrocyte progenitor-cell gene-expression profile pattern. Additionally, NLGN3 offers positive feedback, which results in glioma-cell surface expression of NLGN3, which can then be cleaved. NLGN3 is cleaved from neurons and oligodendrocyte-progenitor cells via ADAM10 sheddase, which can be inhibited by ADAM inhibitors such as INCB3619. ADAM10 sheddase inhibitors prevent the release of neuroligin-3 into the tumor microenvironment and block glioma growth in xenograft models [56]. The association of ADAM10 with glioblastoma-cell migration and invasion has previously been demonstrated. Notably, the up-regulation of ADAM10 sheddase has been demonstrated in more invasive glioblastoma cell lines and in human specimens [57]. The ADAM10-expression levels have correlated with tumor progression as well as the grade of malignancy. Inhibitors of the ADAM family of enzymes have been used in lymphoma and breast cancer [58]. There is very important a direct neuronal activity to glioma link. Clinical trials are to be underway in the very near future with agents targeting ADAM10 in human glioma. Currently, the ADAM10 inhibitor INCB7839 is currently being explored for use in glioma [56].