Mol Brain [JOURNAL]
Sun
200 papers
Chemogenetic silencing of the subiculum blocks acute chronic temporal lobe epilepsy.
Lin J, Liu J, Zhang Q … +7 more , Liu T, Hong Z, Lu Y, Zhong C, Lu Z, Li Y, Hu Y
Mol Brain · 2024 Nov · PMID 39614352 · Full text
Temporal lobe epilepsy (TLE) is the most common form of medically-intractable epilepsy. Subicular hyperexcitability is frequently observed with TLE, presumably caused by impaired inhibition of local excitatory neurons. H...
Temporal lobe epilepsy (TLE) is the most common form of medically-intractable epilepsy. Subicular hyperexcitability is frequently observed with TLE, presumably caused by impaired inhibition of local excitatory neurons. Here, we evaluated the effectiveness of silencing subicular pyramidal neurons to treat a rodent model of TLE. First, we generated a chronic TLE mouse model via initial intrahippocampal kainic acid (IHKA) injection. In the chronic state after first IHKA injection, behavioral seizures and histological abnormalities were reliably observed. We then injected an adeno-associated viral (AAV) vector carrying an inhibitory chemogenetic element, hM4D, directly into the subiculum. Eight weeks after the first IHKA injection, acute seizures were induced by giving a second dose of kainic acid (KA), which mimicked generalized tonic-clonic seizures. Herein, precise control over generalized tonic-clonic seizure onset was achieved via this two-step process. We found that chemogenetic suppression of subicular pyramidal neurons had a robust anti-epileptogenesis effect in this acute-chronic model of TLE. These data confirm a crucial role of the subiculum in the propagation of hippocampal seizures and highlight the potential for using subicular chemogenetic manipulation to treat generalized tonic-clonic seizures.
Synthetic data-driven overlapped neural spikes sorting: decomposing hidden spikes from overlapping spikes.
Kim MK, Kim SP, Sohn JW
Mol Brain · 2024 Nov · PMID 39609693 · Full text
Sorting spikes from extracellular recordings, obtained by sensing neuronal activity around an electrode tip, is essential for unravelling the complexities of neural coding and its implications across diverse neuroscienti...
Sorting spikes from extracellular recordings, obtained by sensing neuronal activity around an electrode tip, is essential for unravelling the complexities of neural coding and its implications across diverse neuroscientific disciplines. However, the presence of overlapping spikes, originating from neurons firing simultaneously or within a short delay, has been overlooked because of the difficulty in identifying individual neurons due to the lack of ground truth. In this study, we propose a method to identify overlapping spikes in extracellular recordings and to recover hidden spikes by decomposing them. We initially estimate spike waveform templates through a series of steps, including discriminative subspace learning and the isolation forest algorithm. By leveraging these estimated templates, we generate synthetic spikes and train a classifier using their feature components to identify overlapping spikes from observed spike data. The identified overlapping spikes are then decomposed into individual hidden spikes using a particle swarm optimization. Results from the testing of the proposed approach, using the simulation dataset we generated, demonstrated that employing synthetic spikes in the overlapping spike classifier accurately identifies overlapping spikes among the detected ones (the maximum F1 score of 0.88). Additionally, the approach can infer the synchronization between hidden spikes by decomposing the overlapped spikes and reallocating them into distinct clusters. This study advances spike sorting by accurately identifying overlapping spikes, providing a more precise tool for neural activity analysis.
Histamine H receptor inverse agonists/antagonists influence intra-regional cortical activity and inter-regional synchronization during resting state: an exploratory cortex-wide imaging study in mice.
Kaita S, Morishita Y, Kobayashi K … +1 more , Nomura H
Mol Brain · 2024 Nov · PMID 39605021 · Full text
The histaminergic system plays a key role in modulating learning and memory, wakefulness, and energy balance. Histamine H receptors constitutively inhibit the synthesis and release of histamine and other neurotransmitter...
The histaminergic system plays a key role in modulating learning and memory, wakefulness, and energy balance. Histamine H receptors constitutively inhibit the synthesis and release of histamine and other neurotransmitters. Therefore, H receptor inverse agonists/antagonists increase the synthesis and release of these neurotransmitters, enhancing cognitive functions, including memory consolidation and retrieval. Spontaneous neural activity across the cerebral cortex is essential for cognitive function, including memory consolidation. Abnormal spontaneous activity has, in fact, been associated with cognitive dysfunctions and psychiatric disorders. Given the cognitive improvement achieved with the use of H receptor inverse agonists/antagonists, we examined the effects of two inverse agonists/antagonists - thioperamide and pitolisant - on spontaneous cortical activity, using in vivo wide-field Ca imaging. Changes in cortical activity, across multiple cortical regions and in inter-regional connectivity, from pre- to post-administration were evaluated using a linear support vector machine decoder. Thioperamide and pitolisant both modified the amplitude distribution of calcium events across multiple cortical regions, including a reduction in the frequency of low-amplitude calcium events in the somatosensory cortex. Graph theory analysis revealed increases in centrality measures in the somatosensory cortex with the use of both thioperamide and pitolisant, indicative of their importance in the organization of cortical networks. These findings indicate that H receptor inverse agonists/antagonists influence intra-regional cortical activity and inter-regional synchronization of activity in the cerebral cortex during the resting state.
Transcutaneous auricular vagus nerve stimulation in anesthetized mice induces antidepressant effects by activating dopaminergic neurons in the ventral tegmental area.
Choi TY, Kim J, Koo JW
Mol Brain · 2024 Nov · PMID 39604984 · Full text
Depression, a prevalent neuropsychiatric disorder, involves the dysregulation of neurotransmitters such as dopamine (DA). The restoration of DA balance is a pivotal therapeutic target for this condition. Recent studies h...
Depression, a prevalent neuropsychiatric disorder, involves the dysregulation of neurotransmitters such as dopamine (DA). The restoration of DA balance is a pivotal therapeutic target for this condition. Recent studies have indicated that both antidepressant medications and non-pharmacological treatments, such as transcutaneous auricular vagus nerve stimulation (taVNS), can promote recovery from depressive symptoms. Despite the promise of taVNS as a non-invasive depression therapy, its precise mechanism remains unclear. We hypothesized that taVNS exerts antidepressant effects by modulating the DAergic system. To investigate this, we conducted experiments demonstrating that taVNS in anesthetized mice reduced depressive-like behaviors. However, this effect was abolished when DA neurons in the ventral tegmental area (VTA) were inhibited. Additionally, taVNS in anesthetized mice enhanced VTA activity, providing further evidence to support its antidepressant effects. Overall, our findings suggest that taVNS alleviates depression by augmenting VTA activity, thereby contributing to a more comprehensive understanding of its therapeutic mechanisms.
Loss of mitochondrial enzyme GPT2 leads to reprogramming of synaptic glutamate metabolism.
Baytas O, Davidson SM, Kauer JA … +1 more , Morrow EM
Mol Brain · 2024 Nov · PMID 39604975 · Full text
Recessive loss-of-function mutations in the mitochondrial enzyme Glutamate Pyruvate Transaminase 2 (GPT2) cause intellectual disability in children. Given this cognitive disorder, and because glutamate metabolism is tigh...
Recessive loss-of-function mutations in the mitochondrial enzyme Glutamate Pyruvate Transaminase 2 (GPT2) cause intellectual disability in children. Given this cognitive disorder, and because glutamate metabolism is tightly regulated to sustain excitatory neurotransmission, here we investigate the role of GPT2 in synaptic function. GPT2 catalyzes a reversible reaction interconverting glutamate and pyruvate with alanine and alpha-ketoglutarate, a TCA cycle intermediate; thereby, GPT2 may play an important role in linking mitochondrial tricarboxylic acid (TCA) cycle with synaptic transmission. In mouse brain, we find that GPT2 is enriched in mitochondria of synaptosomes (isolated synaptic terminals). Loss of Gpt2 in mouse appears to lead to reprogramming of glutamate and glutamine metabolism, and to decreased glutamatergic synaptic transmission. Whole-cell patch-clamp recordings in pyramidal neurons of CA1 hippocampal slices from Gpt2-null mice reveal decreased excitatory post-synaptic currents (mEPSCs) without changes in mEPSC frequency, or importantly, changes in inhibitory post-synaptic currents (mIPSCs). Additional evidence of defective glutamate release included reduced levels of glutamate released from Gpt2-null synaptosomes measured biochemically. Glutamate release from synaptosomes was rescued to wild-type levels by alpha-ketoglutarate supplementation. Additionally, we observed evidence of altered metabolism in isolated Gpt2-null synaptosomes: decreased TCA cycle intermediates, and increased glutamate dehydrogenase activity. Notably, alterations in the TCA cycle and the glutamine pool were alleviated by alpha-ketoglutarate supplementation. In conclusion, our data support a model whereby GPT2 mitochondrial activity may contribute to glutamate availability in pre-synaptic terminals, thereby highlighting potential interactions between pre-synaptic mitochondrial metabolism and synaptic transmission.
AKAP6 controls NFATc4 activity for BDNF-mediated neuroprotection.
Mackiewicz J, Tomczak J, Lisek M … +2 more , Guo F, Boczek T
Mol Brain · 2024 Nov · PMID 39578909 · Full text
Brain-derived neurotrophic factor (BDNF) is known for its potent prosurvival effect. Despite successfully replicating this effect in various clinical and pre-clinical models, the complete characterization of the molecula...
Brain-derived neurotrophic factor (BDNF) is known for its potent prosurvival effect. Despite successfully replicating this effect in various clinical and pre-clinical models, the complete characterization of the molecular mechanisms underlying its neuroprotective action remains incomplete. Emerging research suggests a vital role for A-kinase anchoring proteins (AKAPs) as central nodal points orchestrating BDNF-dependent signaling. Among the over 50 identified AKAPs, AKAP6 has recently gained special attention due to its involvement in the neurotrophin-mediated survival of injured retinal ganglion cells (RGCs). However, the mechanisms by which AKAP6 responds to pro-survival BDNF signaling remain unknown. In this study, we shown that AKAP6 plays a crucial role in regulating BDNF-mediated NFAT transcriptional activity in neuronal survival by anchoring protein phosphatase calcineurin (CaN) and nuclear factor of activated T cells (NFATc4). Furthermore, we demonstrate that disrupting the anchoring of CaN diminishes the pro-survival effect of BDNF. Lastly, through experiments with NFATc4-/- mice, we provide evidence that NFATc4 acts downstream to BDNF's neuroprotection in vivo. These findings could offer valuable insights for developing neuroprotective strategies aimed at preserving injured neurons from degeneration and promoting their regeneration.
Intravitreal injection of the Galectin-3 inhibitor TD139 provides neuroprotection in a rat model of ocular hypertensive glaucoma.
Rombaut A, Brautaset R, Williams PA … +1 more , Tribble JR
Mol Brain · 2024 Nov · PMID 39574161 · Full text
Neuroinflammation is a significant contributor to the pathology of glaucoma. Targeting key-mediators in this process is a realistic option to slow disease progression. Galectin-3 is a β-galactoside binding lectin that ha...
Neuroinflammation is a significant contributor to the pathology of glaucoma. Targeting key-mediators in this process is a realistic option to slow disease progression. Galectin-3 is a β-galactoside binding lectin that has been associated with inflammation in both systemic and central nervous system diseases. Elevated Galectin-3 has recently been detected in multiple animal models of glaucoma and inhibiting Galectin-3 using an intravitreal injection of TD139 (a Galectin-3 small molecule inhibitor) is neuroprotective. We queried whether this neuroprotective effect was translatable to another animal model and species. TD139 was intravitreally injected, in a rat ocular hypertensive model of glaucoma, 3 days after the induction of ocular hypertension (at peak intraocular pressure). Retinal ganglion cell survival and glial morphological markers were quantified. The degeneration of retinal ganglion cells was prevented by TD139 injection, but gross glial markers remained unaffected. These data confirm that the intravitreal injection of TD139 is neuroprotective in a rat ocular hypertensive model of glaucoma, while suggesting that the inhibition of Galectin-3 is not sufficient to alter the gross inflammatory outcome.
Sonic hedgehog signalling pathway in CNS tumours: its role and therapeutic implications.
Wireko AA, Ben-Jaafar A, Kong JSH … +9 more , Mannan KM, Sanker V, Rosenke SL, Boye ANA, Nkrumah-Boateng PA, Poornaselvan J, Shah MH, Abdul-Rahman T, Atallah O
Mol Brain · 2024 Nov · PMID 39568072 · Full text
CNS tumours encompass a diverse group of neoplasms with significant morbidity and mortality. The SHH signalling pathway plays a critical role in the pathogenesis of several CNS tumours, including gliomas, medulloblastoma...
CNS tumours encompass a diverse group of neoplasms with significant morbidity and mortality. The SHH signalling pathway plays a critical role in the pathogenesis of several CNS tumours, including gliomas, medulloblastomas and others. By influencing cellular proliferation, differentiation and migration in CNS tumours, the SHH pathway has emerged as a promising target for therapeutic intervention. Current strategies such as vismodegib and sonidegib have shown efficacy in targeting SHH pathway activation. However, challenges such as resistance mechanisms and paradoxical effects observed in clinical settings underscore the complexity of effectively targeting this pathway. Advances in gene editing technologies, particularly CRISPR/Cas9, have provided valuable tools for studying SHH pathway biology, validating therapeutic targets and exploring novel treatment modalities. These innovations have paved the way for a better understanding of pathway dynamics and the development of more precise therapeutic interventions. In addition, the identification and validation of biomarkers of SHH pathway activation are critical to guide clinical decision making and improve patient outcomes. Molecular profiling and biomarker discovery efforts are critical steps towards personalised medicine approaches in the treatment of SHH pathway-associated CNS tumours. While significant progress has been made in understanding the role of the SHH pathway in CNS tumorigenesis, ongoing research is essential to overcome current therapeutic challenges and refine treatment strategies. The integration of molecular insights with advanced technologies and clinical expertise holds great promise for developing more effective and personalised therapies for patients with SHH pathway-driven CNS tumours.
A structural analysis of the splice-specific functional impact of the pathogenic familial hemiplegic migraine type 1 S218L mutation on Ca2.1 P/Q-type channel gating.
Sack AS, Samera GJ, Hissen A … +4 more , Wester RJ, Garcia E, Adams PJ, Snutch TP
Mol Brain · 2024 Nov · PMID 39568055 · Full text
P/Q-type (Ca2.1) calcium channels mediate Ca influx essential for neuronal excitability and synaptic transmission. The CACNA1A gene, encoding the Ca2.1 pore forming subunit, is highly expressed throughout the mammalian c...
P/Q-type (Ca2.1) calcium channels mediate Ca influx essential for neuronal excitability and synaptic transmission. The CACNA1A gene, encoding the Ca2.1 pore forming subunit, is highly expressed throughout the mammalian central nervous system. Alternative splicing of Ca2.1 pre-mRNA generates diverse channel isoforms with distinct biophysical properties and drug affinities, which are differentially expressed in nerve tissues. Splicing variants can also affect channel function under pathological conditions although their phenotypic implication concerning inherited neurological disorders linked to CACNA1A mutations remains unknown. Here, we quantified the expression of Ca2.1 exon 24 (e24) spliced transcripts in human nervous system samples, finding different levels of expression within discrete regions. The corresponding Ca2.1 variants, differing by the presence (+) or absence (Δ) of Ser-Ser-Thr-Arg residues (SSTR) in the domain III S3-S4 linker, were functionally characterized using patch clamp recordings. Further, the + /ΔSSTR isoforms were used to demonstrate the differential impact of the Familial Hemiplegic Migraine Type 1 (FHM-1) S218L mutation, located in the domain I S4-S5 linker, on the molecular structure and electrophysiological properties of Ca2.1 isoforms. S218L has a prominent effect on the voltage-dependence of activation of +SSTR channels when compared to ΔSSTR, indicating a differential effect of the mutation depending on splice-variant context. Structural modeling based upon Cav2.1 cryo-EM data provided further insight reflecting independent contributions of amino acids in distant regions of the channel on gating properties. Our modelling indicates that by increasing hydrophobicity the Leu218 mutation contributes to stabilizing a structural conformation in which the domain I S4-S5 linker is oriented alongside the inner plasma membrane, similar to that occurring when S4 is translocated upon activation.The SSTR insertion appears to exert an influence in the local electric field of domain III due to an change in the distribution of positively charged regions surrounding the voltage sensing domain, which we hypothesize impacts its movement during the transition to the open state. In summary, we reveal molecular changes correlated with distinct functional effects provoked by S218L FHM-1 mutation in hCa2.1 splice isoforms whose differential expression could impact the manifestation of the neurological disorder.
NEK7 induces lactylation in Alzheimer's disease to promote pyroptosis in BV-2 cells.
Cheng J, Zhao H
Mol Brain · 2024 Nov · PMID 39563448 · Full text
Alzheimer's disease (AD), an age-related neurodegenerative disorder, is characterized by irreversible brain tissue degeneration. The amyloid-β (Aβ) cascade hypothesis stands as the predominant paradigm explaining AD path...
Alzheimer's disease (AD), an age-related neurodegenerative disorder, is characterized by irreversible brain tissue degeneration. The amyloid-β (Aβ) cascade hypothesis stands as the predominant paradigm explaining AD pathogenesis. This study aimed to elucidate the mechanisms underlying Aβ-induced pyroptosis in AD. AD models were established using amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice and Aβ-treated BV-2 cells (5 µM, 24 h). NEK7 expression was evaluated in vitro and in vivo. Cell pyroptosis was assessed before and after NEK7 expression was inhibited in BV-2 cells. Adeno-associated virus (AAV) vectors carrying short hairpin RNA (shRNA) against NEK7 (AAV-sh-NEK7) were administered to mice to knockdown NEK7 in vivo. Spatial learning and memory abilities were evaluated using the Morris water maze test. The interaction between NEK7 and histone H4 lysine 12 lactylation (H4K12la) were then investigated. The results suggested that NEK7 expression was markedly elevated in both in vitro and in vivo AD models. Treatment with Aβ significantly reduced cell viability and enhanced pyroptosis in BV-2 cells; these effects were reversed by inhibiting NEK7. Furthermore, AD mice with NEK7 knockdown exhibited shorter escape latencies and increased time spent in the target quadrant, suggesting that NEK7 inhibition improved cognitive function and memory retention. Mechanistically, Aβ treatment induced histone lactylation in BV-2 cells, and suppression of lactylation attenuated NEK7 transcriptional activity and mRNA levels. In summary, elevated NEK7 expression promoted histone lactylation in BV-2 cells, thereby facilitating pyroptosis. Inhibition of NEK7 conferred protection against Aβ-induced cellular damage and enhanced cognitive performance and memory retention in AD model mice. Collectively, targeting NEK7 represents a potential therapeutic strategy for alleviating AD symptoms.
Characterization of exosome-mediated propagation of systemic inflammatory responses into the central nervous system.
Kodali MC, Salim C, Ismael S … +3 more , Lebovitz SG, Lin G, Liao FF
Mol Brain · 2024 Nov · PMID 39548504 · Full text
The mechanisms through which systemic inflammation exerts its effect on the central nervous system (CNS) are still not completely understood. Exosomes are small (30 to 100 nm) membrane-bound extracellular vesicles releas...
The mechanisms through which systemic inflammation exerts its effect on the central nervous system (CNS) are still not completely understood. Exosomes are small (30 to 100 nm) membrane-bound extracellular vesicles released by most of the mammalian cells. Exosomes play a vital role in cell-to-cell communication. This includes regulation of inflammatory responses by shuttling mRNAs, miRNAs, and cytokines, both locally and systemically to the neighboring as well as distant cells to further modulate the transcriptional and/or translational states and affect the functional phenotype of those cells that have taken up these exosomes. The role of circulating blood exosomes leading to neuroinflammation during systemic inflammatory conditions was hereby characterized. Serum-derived exosomes from LPS-challenged mice (SDEL) were freshly isolated from the sera of the mice that were earlier treated with LPS and used to study the effects on neuroinflammation. Exosomes isolated from the sera of the mice injected with saline were used as a control. In-vitro studies showed that the SDEL upregulate pro-inflammatory cytokine gene expression in the murine cell lines of microglia (BV-2), astrocytes (C8-D1A), and cerebral microvascular endothelial cells (bEnd.3). To further study their effects in-vivo, SDEL were intravenously injected into normal adult mice. Elevated mRNA expression of pro-inflammatory cytokines was observed in the brains of SDEL recipient mice. Proteomic analysis of the SDEL confirmed the increased expression of inflammatory cytokines in them. Together, these results demonstrate and strengthen the novel role of peripheral circulating exosomes in causing neuroinflammation during systemic inflammatory conditions.
Transcriptomic and de novo proteomic analyses of organotypic entorhino-hippocampal tissue cultures reveal changes in metabolic and signaling regulators in TTX-induced synaptic plasticity.
Lenz M, Turko P, Kruse P … +5 more , Eichler A, Chen ZA, Rappsilber J, Vida I, Vlachos A
Mol Brain · 2024 Nov · PMID 39511688 · Full text
Understanding the mechanisms of synaptic plasticity is crucial for elucidating how the brain adapts to internal and external stimuli. A key objective of plasticity is maintaining physiological activity states during pert...
Understanding the mechanisms of synaptic plasticity is crucial for elucidating how the brain adapts to internal and external stimuli. A key objective of plasticity is maintaining physiological activity states during perturbations by adjusting synaptic transmission through negative feedback mechanisms. However, identifying and characterizing novel molecular targets orchestrating synaptic plasticity remains a significant challenge. This study investigated the effects of tetrodotoxin (TTX)-induced synaptic plasticity within organotypic entorhino-hippocampal tissue cultures, offering insights into the functional, transcriptomic, and proteomic changes associated with network inhibition via voltage-gated sodium channel blockade. Our experiments demonstrate that TTX treatment induces substantial functional plasticity of excitatory synapses, as evidenced by increased miniature excitatory postsynaptic current (mEPSC) amplitudes and frequencies in both dentate granule cells and CA1 pyramidal neurons. Correlating transcriptomic and proteomic data, we identified novel targets for future research into homeostatic plasticity, including cytoglobin, SLIT-ROBO Rho GTPase Activating Protein 3, Transferrin receptor, and 3-Hydroxy-3-Methylglutaryl-CoA Synthase 1. These data provide a valuable resource for future studies aiming to understand the orchestration of homeostatic plasticity by metabolic pathways in distinct cell types of the central nervous system.
Chronic corticosterone exposure causes anxiety- and depression-related behaviors with altered gut microbial and brain metabolomic profiles in adult male C57BL/6J mice.
Shoji H, Maeda Y, Miyakawa T
Mol Brain · 2024 Nov · PMID 39511657 · Full text
Chronic exposure to glucocorticoids in response to long-term stress is thought to be a risk factor for major depression. Depression is associated with disturbances in the gut microbiota composition and peripheral and cen...
Chronic exposure to glucocorticoids in response to long-term stress is thought to be a risk factor for major depression. Depression is associated with disturbances in the gut microbiota composition and peripheral and central energy metabolism. However, the relationship between chronic glucocorticoid exposure, the gut microbiota, and brain metabolism remains largely unknown. In this study, we first investigated the effects of chronic corticosterone exposure on various domains of behavior in adult male C57BL/6J mice treated with the glucocorticoid corticosterone to evaluate them as an animal model of depression. We then examined the gut microbial composition and brain and plasma metabolome in corticosterone-treated mice. Chronic corticosterone treatment resulted in reduced locomotor activity, increased anxiety-like and depression-related behaviors, decreased rotarod latency, reduced acoustic startle response, decreased social behavior, working memory deficits, impaired contextual fear memory, and enhanced cued fear memory. Chronic corticosterone treatment also altered the composition of gut microbiota, which has been reported to be associated with depression, such as increased abundance of Bifidobacterium, Turicibacter, and Corynebacterium and decreased abundance of Barnesiella. Metabolomic data revealed that long-term exposure to corticosterone led to a decrease in brain neurotransmitter metabolites, such as serotonin, 5-hydroxyindoleacetic acid, acetylcholine, and gamma-aminobutyric acid, as well as changes in betaine and methionine metabolism, as indicated by decreased levels of adenosine, dimethylglycine, choline, and methionine in the brain. These results indicate that mice treated with corticosterone have good face and construct validity as an animal model for studying anxiety and depression with altered gut microbial composition and brain metabolism, offering new insights into the neurobiological basis of depression arising from gut-brain axis dysfunction caused by prolonged exposure to excessive glucocorticoids.
NDRG1 upregulation by ubiquitin proteasome system dysfunction aggravates neurodegeneration.
Hoshino T, Mukai A, Yamashita H … +5 more , Misawa H, Urushitani M, Tashiro Y, Matsuzawa SI, Takahashi R
Mol Brain · 2024 Oct · PMID 39444004 · Full text
Protein turnover is crucial for cell survival, and the impairment of proteostasis leads to cell death. Aging is associated with a decline in proteostasis, as the progressive accumulation of damaged proteins is a hallmark...
Protein turnover is crucial for cell survival, and the impairment of proteostasis leads to cell death. Aging is associated with a decline in proteostasis, as the progressive accumulation of damaged proteins is a hallmark of age-related disorders such as neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). We previously discovered that the declining function of the ubiquitin-proteasome system (UPS) in motor neurons contributes to sporadic ALS pathologies, such as progressive motor neuron loss, protein accumulation, and glial activation. However, the mechanisms of UPS dysfunction-induced cell damage, such as cell death and aggregation, are not fully understood. This study used transcriptome analysis of motor neurons with UPS dysfunction and found that the expression of N-myc downstream regulated 1 (NDRG1) gets upregulated by UPS dysfunction. Additionally, the upregulation of NDRG1 induces cell death in the Neuro2a mouse neuroblastoma cell line. These results suggest that NDRG1 is a potential marker for UPS dysfunction and may play a role in neurodegeneration, such as that seen in ALS.
Ultrastructural characterization of hippocampal inhibitory synapses under resting and stimulated conditions.
Tao-Cheng JH, Moreira SL, Winters CA
Mol Brain · 2024 Oct · PMID 39438991 · Full text
The present study uses electron microscopy to document ultrastructural characteristics of hippocampal GABAergic inhibitory synapses under resting and stimulated conditions in three experimental systems. Synaptic profiles...
The present study uses electron microscopy to document ultrastructural characteristics of hippocampal GABAergic inhibitory synapses under resting and stimulated conditions in three experimental systems. Synaptic profiles were sampled from stratum pyramidale and radiatum of the CA1 region from (1) perfusion fixed mouse brains, (2) immersion fixed rat organotypic slice cultures, and from (3) rat dissociated hippocampal cultures of mixed cell types. Synapses were stimulated in the brain by a 5 min delay in perfusion fixation to trigger an ischemia-like excitatory condition, and by treating the two culture systems with 90 mM high K for 2-3 min to depolarize the neurons. Upon such stimulation conditions, the presynaptic terminals of the inhibitory synapses exhibited similar structural changes to those seen in glutamatergic excitatory synapses, with depletion of synaptic vesicles, increase of clathrin-coated vesicles and appearance of synaptic spinules. However, in contrast to excitatory synapses, no structural differences were detected in the postsynaptic compartment of the inhibitory synapses upon stimulation. There were no changes in the appearance of material associated with the postsynaptic membrane or the length and curvature of the membrane. Also no change was detected in the labeling density of gephyrin, a GABAergic synaptic marker, lining the postsynaptic membrane. Furthermore, virtually all inhibitory synaptic clefts remained rigidly apposed, unlike in the case of excitatory synapses where ~ 20-30% of cleft edges were open upon stimulation, presumably to facilitate the clearance of neurotransmitters from the cleft. The fact that no open clefts were induced in inhibitory synapses upon stimulation suggests that inhibitory input may not need to be toned down under these conditions. On the other hand, similar to excitatory synapse, EGTA (a calcium chelator) induced open clefts in ~ 18% of inhibitory synaptic cleft edges, presumably disrupting similar calcium-dependent trans-synaptic bridges in both types of synapses.
Mechanisms of glutamate receptors hypofunction dependent synaptic transmission impairment in the hippocampus of schizophrenia susceptibility gene Opcml-deficient mouse model.
Sun X, Meng H, Lu T … +4 more , Yue W, Zhang D, Wang L, Li J
Mol Brain · 2024 Oct · PMID 39420375 · Full text
Schizophrenia is a severe psychiatric disorder with high heritability, characterized by positive and negative symptoms as well as cognitive abnormalities. Dysfunction in glutamate synapse is strongly implicated in the pa...
Schizophrenia is a severe psychiatric disorder with high heritability, characterized by positive and negative symptoms as well as cognitive abnormalities. Dysfunction in glutamate synapse is strongly implicated in the pathophysiology of schizophrenia. However, the precise role of the perturbed glutamatergic system in contributing to the cognitive abnormalities of schizophrenia at the synaptic level remains largely unknown. Although our previous work found that Opcml promotes spine maturation and Opcml-deficient mice exhibit schizophrenia-related cognitive impairments, the synaptic mechanism remains unclear. By using whole-cell patch clamp recording, we found that decreased neuronal excitability and alterations in intrinsic membrane properties of CA1 PNs in Opcml-deficient mice. Furthermore, Opcml deficiency leads to impaired glutamatergic transmission in hippocampus, which is closely related to postsynaptic AMPA/NMDA receptors dysfunction, resulting in the disturbances of E/I balance. Additionally, we found that the aripiprazole which we used to ameliorate abnormal cognitive behaviors also rescued the impaired glutamatergic transmission in Opcml-deficient mice. These findings will help to understand the synaptic mechanism in schizophrenia pathogenesis, providing insights into schizophrenia therapeutics with glutamatergic disruption.
Theta-gamma-coupling as predictor of working memory performance in young and elderly healthy people.
Abubaker M, Al Qasem W, Pilátová K … +2 more , Ježdík P, Kvašňák E
Mol Brain · 2024 Oct · PMID 39415245 · Full text
The relationship between working memory (WM) and neuronal oscillations can be studied in detail using brain stimulation techniques, which provide a method for modulating these oscillations and thus influencing WM. The en...
The relationship between working memory (WM) and neuronal oscillations can be studied in detail using brain stimulation techniques, which provide a method for modulating these oscillations and thus influencing WM. The endogenous coupling between the amplitude of gamma oscillations and the phase of theta oscillations is crucial for cognitive control. Theta/gamma peak-coupled transcranial alternating current stimulation (TGCp-tACS) can modulate this coupling and thus influence WM performance. This study investigated the effects of TGCp-tACS on WM in older adults and compared their responses with those of younger participants from our previous work who underwent the same experimental design. Twenty-eight older subjects underwent both TGCp-tACS and sham stimulation sessions at least 72 h apart. Resting-state electroencephalography (EEG) was recorded before and after the interventions, and a WM task battery with five different WM tasks was performed during the interventions to assess various WM components. Outcomes measured included WM task performance (e.g., accuracy, reaction time (RT)) and changes in power spectral density (PSD) in different frequency bands. TGCp-tACS significantly decreased accuracy and RT on the 10- and 14-point Sternberg tasks and increased RT on the Digit Symbol Substitution Test in older adults. In contrast, younger participants showed a significant increase in accuracy only on the 14-item Sternberg task. Electrophysiological analysis revealed a decrease in delta and theta PSD and an increase in high gamma PSD in both younger and older participants after verum stimulation. In conclusion, theta-gamma coupling is essential for WM and modulation of this coupling affects WM performance. The effects of TGCp-tACS on WM vary with age due to natural brain changes. To better support older adults, the study suggests several strategies to improve cognitive function, including: Adjusting stimulation parameters, applying stimulation to two sites, conducting multiple sessions, and using brain imaging techniques for precise targeting.
Proteasome inhibition suppresses the induction of lipocalin-2 upon systemic lipopolysaccharide challenge in mice.
Bae JS, Heo JE, Ryu KY
Mol Brain · 2024 Oct · PMID 39363318 · Full text
Lipocalin-2 (Lcn2), a protein secreted by immune-activated cells, including reactive astrocytes, is detrimental to the brain and induces neurodegeneration. We previously showed that Lcn2 levels are reduced in primary mou...
Lipocalin-2 (Lcn2), a protein secreted by immune-activated cells, including reactive astrocytes, is detrimental to the brain and induces neurodegeneration. We previously showed that Lcn2 levels are reduced in primary mouse astrocytes after treatment with the proteasome inhibitor bortezomib (BTZ). However, it remains unknown whether a decrease in Lcn2 levels after BTZ treatment can also be observed in vivo and whether it reduces neurotoxicity during lipopolysaccharide (LPS)-induced systemic inflammation in vivo. To answer these questions, we performed LPS challenge experiments by intraperitoneal injection in mice and found that Lcn2 levels were significantly increased in the brain, recapitulating in vitro experiments using astrocytes. Co-administration of LPS and BTZ reduced the Lcn2 levels compared to the levels in LPS-treated controls. Upon LPS challenge, the expression levels of glial marker genes were upregulated in the mouse brain. Of note, this upregulation was hampered by the co-administration of BTZ. Taken together, our results suggested that BTZ can reduce LPS-induced Lcn2 levels and may alleviate LPS-induced neuroinflammation and neurotoxicity in mice.
Improving working memory by electrical stimulation and cross-frequency coupling.
Al Qasem W, Abubaker M, Pilátová K … +2 more , Ježdík P, Kvašňák E
Mol Brain · 2024 Oct · PMID 39354549 · Full text
Working memory (WM) is essential for the temporary storage and processing of information required for complex cognitive tasks and relies on neuronal theta and gamma oscillations. Given the limited capacity of WM, researc...
Working memory (WM) is essential for the temporary storage and processing of information required for complex cognitive tasks and relies on neuronal theta and gamma oscillations. Given the limited capacity of WM, researchers have investigated various methods to improve it, including transcranial alternating current stimulation (tACS), which modulates brain activity at specific frequencies. One particularly promising approach is theta-gamma peak-coupled-tACS (TGCp-tACS), which simulates the natural interaction between theta and gamma oscillations that occurs during cognitive control in the brain. The aim of this study was to improve WM in healthy young adults with TGCp-tACS, focusing on both behavioral and neurophysiological outcomes. Thirty-one participants completed five WM tasks under both sham and verum stimulation conditions. Electroencephalography (EEG) recordings before and after stimulation showed that TGCp-tACS increased power spectral density (PSD) in the high-gamma region at the stimulation site, while PSD decreased in the theta and delta regions throughout the cortex. From a behavioral perspective, although no significant changes were observed in most tasks, there was a significant improvement in accuracy in the 14-item Sternberg task, indicating an improvement in phonological WM. In conclusion, TGCp-tACS has the potential to promote and improve the phonological component of WM. To fully realize the cognitive benefits, further research is needed to refine the stimulation parameters and account for individual differences, such as baseline cognitive status and hormonal factors.
Shank3 deficiency alters midbrain GABAergic neuron morphology, GABAergic markers and synaptic activity in primary striatal neurons.
Bačová Z, Jurkovičová-Tarabová B, Havránek T … +6 more , Mihalj D, Borbélyová V, Pirnik Z, Mravec B, Ostatníková D, Bakoš J
Mol Brain · 2024 Sep · PMID 39334399 · Full text
Abnormalities in gamma-aminobutyric acid (GABA)ergic neurotransmission play a role in the pathogenesis of autism, although the mechanisms responsible for alterations in specific brain regions remain unclear. Deficits in...
Abnormalities in gamma-aminobutyric acid (GABA)ergic neurotransmission play a role in the pathogenesis of autism, although the mechanisms responsible for alterations in specific brain regions remain unclear. Deficits in social motivation and interactions are core symptoms of autism, likely due to defects in dopaminergic neural pathways. Therefore, investigating the morphology and functional roles of GABAergic neurons within dopaminergic projection areas could elucidate the underlying etiology of autism. The aim of this study was to (1) compare the morphology and arborization of glutamate decarboxylase (GAD)-positive neurons from the midbrain tegmentum; (2) evaluate synaptic activity in primary neurons from the striatum; and (3) assess GABAergic postsynaptic puncta in the ventral striatum of wild-type (WT) and Shank3-deficient mice. We found a significant decrease in the number of short neurites in GAD positive primary neurons from the midbrain tegmentum in Shank3-deficient mice. The application of a specific blocker of GABA receptors (GABAR) revealed significantly increased frequency of spontaneous postsynaptic currents (sPSCs) in Shank3-deficient striatal neurons compared to their WT counterparts. The mean absolute amplitude of the events was significantly higher in striatal neurons from Shank3-deficient compared to WT mice. We also observed a significant reduction in gephyrin/GABAR γ2 colocalization in the striatum of adult male Shank3-deficient mice. The gene expression of collybistin was significantly lower in the nucleus accumbens while gephyrin and GABAR γ2 were lower in the ventral tegmental area (VTA) in male Shank3-deficient compared to WT mice. In conclusion, Shank3 deficiency leads to alterations in GABAergic neurons and impaired GABAergic function in dopaminergic brain areas. These changes may underlie autistic symptoms, and potential interventions modulating GABAergic activity in dopaminergic pathways may represent new treatment modality.
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