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Zoological Research May 2024Proper regulation of synapse formation and elimination is critical for establishing mature neuronal circuits and maintaining brain function. Synaptic abnormalities, such...
Proper regulation of synapse formation and elimination is critical for establishing mature neuronal circuits and maintaining brain function. Synaptic abnormalities, such as defects in the density and morphology of postsynaptic dendritic spines, underlie the pathology of various neuropsychiatric disorders. Protocadherin 17 (PCDH17) is associated with major mood disorders, including bipolar disorder and depression. However, the molecular mechanisms by which PCDH17 regulates spine number, morphology, and behavior remain elusive. In this study, we found that PCDH17 functions at postsynaptic sites, restricting the number and size of dendritic spines in excitatory neurons. Selective overexpression of PCDH17 in the ventral hippocampal CA1 results in spine loss and anxiety- and depression-like behaviors in mice. Mechanistically, PCDH17 interacts with actin-relevant proteins and regulates actin filament (F-actin) organization. Specifically, PCDH17 binds to ROCK2, increasing its expression and subsequently enhancing the activity of downstream targets such as LIMK1 and the phosphorylation of cofilin serine-3 (Ser3). Inhibition of ROCK2 activity with belumosudil (KD025) ameliorates the defective F-actin organization and spine structure induced by PCDH17 overexpression, suggesting that ROCK2 mediates the effects of PCDH17 on F-actin content and spine development. Hence, these findings reveal a novel mechanism by which PCDH17 regulates synapse development and behavior, providing pathological insights into the neurobiological basis of mood disorders.
Topics: Animals; Dendritic Spines; Mice; Actin Cytoskeleton; Cadherins; rho-Associated Kinases; Gene Expression Regulation
PubMed: 38747058
DOI: 10.24272/j.issn.2095-8137.2024.055 -
Research Square Apr 2024Bipolar disorder (BD) is characterized by disrupted circadian rhythms and neuronal loss. Lithium is neuroprotective and used to treat BD, but outcomes are variable. Past...
Differential contributions of circadian clock genes to cell survival in bipolar disorder patient derived neuronal progenitor cells distinguishes lithium responders and non-responders.
Bipolar disorder (BD) is characterized by disrupted circadian rhythms and neuronal loss. Lithium is neuroprotective and used to treat BD, but outcomes are variable. Past research identified that circadian rhythms in BD patient neurons are associated with lithium response (Li-R) or non-response (Li-NR). However, the underlying cellular mechanisms remain unknown. To study interactions among circadian clock genes and cell survival, and their role in BD and predicting lithium response, we tested selected genes ( , and ) and small molecule modulators of ROR/REV-ERB nuclear receptors in models of cell survival using mouse neurons and stem-cell derived neuronal progenitor cells (NPC) from BD patients and controls. In apoptosis assays using staurosporine (STS), lithium was neuroprotective. Knockdown of , and modified cell survival across models. In NPCs, reduced expression of and led to more extensive cell death in Li-NR vs. Li-R. Reduced expression caused more extensive cell death in BD vs. control NPCs, without distinguishing Li-R and Li-NR. In IMHN, The REV-ERB agonist GSK4112 had strong effects on circadian rhythm amplitude, and was neuroprotective in mouse neurons and control NPCs, but not in BD NPCs. Expression of cell survival genes following STS and GSK4112 treatments revealed BD-associated, and Li-R associated differences in expression profiles. We conclude that the neuroprotective response to lithium is similar in NPCs from Li-R and Li-NR. However, knockdown of circadian clock genes or stimulation of REV-ERBs reveal distinct contributions to cell death in BD patient NPCs, some of which distinguish Li-R and Li-NR.
PubMed: 38746315
DOI: 10.21203/rs.3.rs-4331810/v1 -
BioRxiv : the Preprint Server For... Apr 2024Many inherited retinal diseases target photoreceptors, which transduce light into a neural signal that is processed by the downstream visual system. As photoreceptors...
UNLABELLED
Many inherited retinal diseases target photoreceptors, which transduce light into a neural signal that is processed by the downstream visual system. As photoreceptors degenerate, physiological and morphological changes to retinal synapses and circuitry reduce sensitivity and increase noise, degrading visual signal fidelity. Here, we pharmacologically targeted the first synapse in the retina in an effort to reduce circuit noise without sacrificing visual sensitivity. We tested a strategy to partially replace the neurotransmitter lost when photoreceptors die with an agonist of receptors that ON bipolars cells use to detect glutamate released from photoreceptors. In mice, which express a photoreceptor mutation that causes retinitis pigmentosa (RP), we found that a low dose of the mGluR6 agonist L-2-amino-4-phosphonobutyric acid (L-AP4) reduced pathological noise induced by photoreceptor degeneration. After making electroretinogram recordings in mice to characterize the developmental time course of visual signal degeneration, we examined effects of L-AP4 on sensitivity and circuit noise by recording light-evoked responses from individual retinal ganglion cells (RGCs). L-AP4 decreased circuit noise evident in RGC recordings without significantly reducing response amplitudes, an effect that persisted over the entire time course of rod photoreceptor degeneration. Subsequent recordings from rod bipolar cells (RBCs) showed that RBCs are more depolarized in retinas, likely contributing to downstream circuit noise and reduced synaptic gain, both of which appear to be ameliorated by hyperpolarizing RBCs with L-AP4. These beneficial effects may reduce pathological circuit remodeling and preserve the efficacy of therapies designed to restore vision.
SIGNIFICANCE STATEMENT
Retinitis Pigmentosa (RP) is an inherited degenerative disease that affects more than two million people worldwide. RP patients first lose peripheral and low-light vision due to the progressive death of their highly sensitive rod photoreceptors. Photoreceptor degeneration induces pathological noise within the retinal circuit, leading to dramatic structural changes that may hamper therapies to restore visual sensitivity. We discovered a pharmacological treatment that reduces pathological activity in a mouse model of RP without diminishing signaling in surviving circuitry. Partially replacing the neurotransmitter lost when photoreceptors die reduced noise in the retinal circuit without eliminating light sensitivity. This approach could limit the impact of the disease on retinal neurons and preserve the efficacy of subsequent restorative therapies.
PubMed: 38746092
DOI: 10.1101/2024.04.30.591881 -
Computers in Biology and Medicine May 2024Carbon nanotube (CNT) fiber electrodes have demonstrated exceptional spatial selectivity and sustained reliability in the context of intrafascicular electrical...
Carbon nanotube (CNT) fiber electrodes have demonstrated exceptional spatial selectivity and sustained reliability in the context of intrafascicular electrical stimulation, as evidenced through rigorous animal experimentation. A significant presence of unmyelinated C fibers, known to induce uncomfortable somatosensory experiences, exists within peripheral nerves. This presence poses a considerable challenge to the excitation of myelinated Aβ fibers, which are crucial for tactile sensation. To achieve nuanced tactile sensory feedback utilizing CNT fiber electrodes, the selective stimulation of Aβ sensory afferents emerges as a critical factor. In confronting this challenge, the present investigation sought to refine and apply a rat sciatic-nerve model leveraging the capabilities of the COMSOL-NEURON framework. This approach enables a systematic evaluation of the influence exerted by stimulation parameters and electrode geometry on the activation dynamics of both myelinated Aβ and unmyelinated C fibers. The findings advocate for the utilization of current pulses featuring a pulse width of 600 μs, alongside the deployment of CNT fibers characterized by a diminutive diameter of 10 μm, with an exclusively exposed cross-sectional area, to facilitate reduced activation current thresholds. Comparative analysis under monopolar and bipolar electrical stimulation conditions revealed proximate activation thresholds, albeit with bipolar stimulation exhibiting superior fiber selectivity relative to its monopolar counterpart. Concerning pulse waveform characteristics, the adoption of an anodic-first biphasic stimulation modality is favored, taking into account the dual criteria of activation threshold and fiber selectivity optimization. Consequently, this investigation furnishes an efficacious stimulation paradigm for the selective activation of touch-related nerve fibers, alongside provisioning a comprehensive theoretical foundation for the realization of natural tactile feedback within the domain of prosthetic hand applications.
PubMed: 38733726
DOI: 10.1016/j.compbiomed.2024.108556 -
International Journal of Molecular... Apr 2024Alterations in intraocular and external pressure critically involve the pathogenesis of glaucoma, traumatic retinal injury (TRI), and other retinal disorders, and... (Review)
Review
Alterations in intraocular and external pressure critically involve the pathogenesis of glaucoma, traumatic retinal injury (TRI), and other retinal disorders, and retinal neurons have been reported to express multiple mechanical-sensitive channels (MSCs) in recent decades. However, the role of MSCs in visual functions and pressure-related retinal conditions has been unclear. This review will focus on the variety and functional significance of the MSCs permeable to K, Na, and Ca, primarily including the big potassium channel (BK); the two-pore domain potassium channels TRAAK and TREK; Piezo; the epithelial sodium channel (ENaC); and the transient receptor potential channels vanilloid TRPV1, TRPV2, and TRPV4 in retinal photoreceptors, bipolar cells, horizontal cells, amacrine cells, and ganglion cells. Most MSCs do not directly mediate visual signals in vertebrate retinas. On the other hand, some studies have shown that MSCs can open in physiological conditions and regulate the activities of retinal neurons. While these data reasonably predict the crossing of visual and mechanical signals, how retinal light pathways deal with endogenous and exogenous mechanical stimulation is uncertain.
Topics: Humans; Animals; Ion Channels; Retinal Neurons; Mechanotransduction, Cellular; Retina
PubMed: 38732096
DOI: 10.3390/ijms25094877 -
Journal of Affective Disorders May 2024This exploratory study investigated cerebrospinal fluid (CSF) synaptic protein biomarkers in bipolar disorder (BD), aiming to highlight the neurobiological basis of the...
BACKGROUND
This exploratory study investigated cerebrospinal fluid (CSF) synaptic protein biomarkers in bipolar disorder (BD), aiming to highlight the neurobiological basis of the disorder. With shared cognitive impairment features between BD and Alzheimer's disease, and considering increased dementia risk in BD patients, the study explores potential connections.
METHODS
Fifty-nine well-characterized patients with BD and thirty-seven healthy control individuals were examined and followed for one year. Synaptic proteins encompassing neuronal pentraxins (NPTX)1, NPTX2, and NPTX-receptor, 14-3-3 protein family epsilon, and zeta/delta, activating protein-2 complex subunit beta, synucleins beta-synuclein and gamma-synuclein, complexin-2, phosphatidylethanolamine-binding protein 1, rab GDP dissociation inhibitor alpha, and syntaxins 1B and 7 were measured in CSF using a microflow liquid chromatography-mass spectrometric multiple reaction monitoring set-up. Biomarker levels were compared between BD and HC and in BD before, during, and after mood episodes.
RESULTS
The synaptic proteins revealed no statistically significant differences between BD and HC, neither at baseline, one-year follow-up, or in terms of changes from baseline to follow-up. Moreover, the CSF synaptic protein levels in patients with BD were unaltered compared to baseline when they stabilized in euthymia following an affective episode and at one-year follow-up.
LIMITATION
It is uncertain what the CSF biomarker concentrations reflect since we yet do not know the mechanisms of release of these proteins, and we are uncertain of what increased or decreased levels reflect.
CONCLUSION
This first-ever investigation of a panel of CSF protein biomarkers of synaptic dysfunction in patients with BD and HC individuals found no statistically significant differences cross-sectionally or longitudinally.
PubMed: 38723679
DOI: 10.1016/j.jad.2024.05.034 -
International Journal of Bipolar... May 2024Red onion husk, a readily available agricultural waste material, contains diverse bioactive compounds with potential health benefits. This study aimed to assess the...
BACKGROUND
Red onion husk, a readily available agricultural waste material, contains diverse bioactive compounds with potential health benefits. This study aimed to assess the safety and therapeutic potential of red onion husk extract in managing manic-like symptoms and associated neurochemical dysfunctions.
METHODS
Acute and repeated oral dose studies were conducted in mice and rats to evaluate the safety profile of the extract. FT-IR analysis identified functional groups in the extract, while GC-MS analysis identified specific bioactive compounds in the flavonoid-rich fraction. A ketamine-induced manic behaviour model in Wistar rats was employed to assess the extract's efficacy in attenuating manic-like symptoms. Behavioural and neurochemical analyses were performed to further investigate the extract's effects.
RESULTS
The extract demonstrated a favourable safety profile in both acute and repeated dose studies. FT-IR analysis revealed a complex mixture of organic compounds, including hydroxyl groups, alkynes/nitriles, aromatic and non-aromatic C = C bonds, amines, and polysaccharides. GC-MS analysis identified 17 bioactive compounds, including five-methyl-2-phenylindolizine, methadone N-oxide, and 3-phenylthiane, S-oxide. Ketamine administration significantly increased oxidative stress markers, TBARS, and suppressed antioxidant enzyme activities (SOD, GPx, CAT) in both the cerebral cortex and hippocampus, alongside elevated acetylcholinesterase (AchE) activity, indicating enhanced neuronal excitability. Pre-treatment with FRF (25 mg/kg) effectively mitigated ketamine-induced oxidative stress, as evidenced by reduced TBARS levels and partially restored SOD and GPx activities. Interestingly, FRF significantly increased CAT activity (p < 0.001), potentially suggesting an additional compensatory mechanism. Notably, FRF pre-treatment also counteracted ketamine-upregulated AchE activity, offering neuroprotection against heightened neuronal excitability.
CONCLUSION
Red onion husk extract exhibits a favourable safety profile and exerts potent antioxidant and neuroprotective effects, possibly through modulating Nrf2 signalling pathways. Its ability to counteract ketamine-induced oxidative stress and neuronal hyperactivity highlights its potential as a complementary therapeutic strategy for managing manic episodes in bipolar disorder. Further research is warranted to elucidate the precise molecular mechanisms underlying FRF's action and explore its clinical efficacy in human studies.
PubMed: 38722415
DOI: 10.1186/s40345-024-00338-7 -
ENeuro May 2024Retinal prosthetics are one of the leading therapeutic strategies to restore lost vision in patients with retinitis pigmentosa and age-related macular degeneration. Much...
Retinal prosthetics are one of the leading therapeutic strategies to restore lost vision in patients with retinitis pigmentosa and age-related macular degeneration. Much work has described patterns of spiking in retinal ganglion cells (RGCs) in response to electrical stimulation, but less work has examined the underlying retinal circuitry that is activated by electrical stimulation to drive these responses. Surprisingly, little is known about the role of inhibition in generating electrical responses or how inhibition might be altered during degeneration. Using whole-cell voltage-clamp recordings during subretinal electrical stimulation in the and wild-type () retina, we found electrically evoked synaptic inputs differed between ON and OFF RGC populations, with ON cells receiving mostly excitation and OFF cells receiving mostly inhibition and very little excitation. We found that the inhibition of OFF bipolar cells limits excitation in OFF RGCs, and a majority of both pre- and postsynaptic inhibition in the OFF pathway arises from glycinergic amacrine cells, and the stimulation of the ON pathway contributes to inhibitory inputs to the RGC. We also show that this presynaptic inhibition in the OFF pathway is greater in the retina, compared with that in the retina.
Topics: Animals; Retinal Ganglion Cells; Electric Stimulation; Retinal Degeneration; Mice, Inbred C57BL; Retinal Bipolar Cells; Patch-Clamp Techniques; Visual Pathways; Neural Inhibition; Female; Male; Retina; Amacrine Cells
PubMed: 38719453
DOI: 10.1523/ENEURO.0110-24.2024 -
Revista Brasileira de Psiquiatria (Sao... 2024Evidence from diffusion tensor imaging (DTI) and postmortem studies has demonstrated white-matter (WM) deficits in bipolar disorder (BD). Changes in peripheral blood...
OBJECTIVES
Evidence from diffusion tensor imaging (DTI) and postmortem studies has demonstrated white-matter (WM) deficits in bipolar disorder (BD). Changes in peripheral blood biomarkers have also been observed; however, studies evaluating the potential relationship between brain alterations and the periphery are scarce. The objective of this systematic review is to investigate the relationship between blood-based biomarkers and WM in BD.
METHODS
PubMed, Embase, and PsycINFO were used to conduct literature searches. Cross-sectional or longitudinal studies reporting original data which investigated both a blood-based biomarker and WM (by neuroimaging) in BD were included.
RESULTS
Of 3,750 studies retrieved, 23 were included. Several classes of biomarkers were found to have a significant relationship with WM in BD. These included cytokines and growth factors (interleukin-8 [IL-8], tumor necrosis factor alpha [TNF-a], and insulin-like growth factor binding protein 3 [IGFBP-3]), innate immune system (natural killer cells [NK]), metabolic markers (lipid hydroperoxidase, cholesterol, triglycerides), the kynurenine (Kyn) pathway (5-hydroxyindoleacetic acid, kynurenic acid [Kyna]), and various gene polymorphisms (serotonin-transporter-linked promoter region).
CONCLUSION
This systematic review revealed that blood-based biomarkers are associated with markers of WM deficits observed in BD. Longitudinal studies investigating the potential clinical utility of these specific biomarkers are encouraged.
Topics: Bipolar Disorder; Humans; Biomarkers; White Matter; Myelin Sheath; Cytokines
PubMed: 38712923
DOI: 10.47626/1516-4446-2023-3267 -
Pharmacological Reviews May 2024Over the last six decades, lithium has been considered the gold standard treatment for the long-term management of bipolar disorder due to its efficacy in preventing... (Review)
Review
Over the last six decades, lithium has been considered the gold standard treatment for the long-term management of bipolar disorder due to its efficacy in preventing both manic and depressive episodes as well as suicidal behaviors. Nevertheless, despite numerous observed effects on various cellular pathways and biologic systems, the precise mechanism through which lithium stabilizes mood remains elusive. Furthermore, there is recent support for the therapeutic potential of lithium in other brain diseases. This review offers a comprehensive examination of contemporary understanding and predominant theories concerning the diverse mechanisms underlying lithium's effects. These findings are based on investigations utilizing cellular and animal models of neurodegenerative and psychiatric disorders. Recent studies have provided additional support for the significance of glycogen synthase kinase-3 (GSK3) inhibition as a crucial mechanism. Furthermore, research has shed more light on the interconnections between GSK3-mediated neuroprotective, antioxidant, and neuroplasticity processes. Moreover, recent advancements in animal and human models have provided valuable insights into how lithium-induced modifications at the homeostatic synaptic plasticity level may play a pivotal role in its clinical effectiveness. We focused on findings from translational studies suggesting that lithium may interface with microRNA expression. Finally, we are exploring the repurposing potential of lithium beyond bipolar disorder. These recent findings on the therapeutic mechanisms of lithium have provided important clues toward developing predictive models of response to lithium treatment and identifying new biologic targets. SIGNIFICANCE STATEMENT: Lithium is the drug of choice for the treatment of bipolar disorder, but its mechanism of action in stabilizing mood remains elusive. This review presents the latest evidence on lithium's various mechanisms of action. Recent evidence has strengthened glycogen synthase kinase-3 (GSK3) inhibition, changes at the level of homeostatic synaptic plasticity, and regulation of microRNA expression as key mechanisms, providing an intriguing perspective that may help bridge the mechanistic gap between molecular functions and its clinical efficacy as a mood stabilizer.
Topics: Humans; Animals; Lithium Compounds; Antimanic Agents; Bipolar Disorder; Neuronal Plasticity; Glycogen Synthase Kinase 3
PubMed: 38697859
DOI: 10.1124/pharmrev.120.000007