bioRxiv Subject Collection: Neuroscience's Journal
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Saturday, April 19th, 2025
| Time |
Event |
| 6:18a |
N1 cassette-lacking NMDA receptors mediate the antidepressant activity of ketamine
Ketamine has emerged as a rapid-acting and robust antidepressant1,2. However, the mechanism of its antidepressant action remains enigmatic. The core issue that has yet to be resolved is whether NMDA receptors (NMDARs), which are subject to open channel blockade by ketamine3,4, mediate the antidepressant effect. NMDARs naturally undergo alternative splicing of the obligatory GluN1 subunit5, producing receptor diversity in the brain that has not been considered in the actions of ketamine. Here we discover that alternative splicing of Grin1 exon 5, which leads to exclusion (GluN1a) or inclusion (GluN1b) of the N1 cassette, located in the N-terminal domain of GluN1 distant from the pore, unexpectedly dictates the level and dynamics of NMDAR blockade by ketamine and gates its antidepressant activity. We find that ketamine prevents NMDAR-dependent long-term potentiation (LTP) in the CA1 region of the hippocampus in mice engineered to exclude Grin1 exon 5 (GluN1a mice), but ketamine has no effect on LTP in mice engineered to include this exon (GluN1b mice). Ketamine inhibits synaptic NMDARs in CA1 pyramidal neurons in both GluN1a and GluN1b mice, with the level of steady-state blockade marginally greater in GluN1a- than in GluN1b-containing NMDARs. However, the rate of relief of ketamine blockade upon membrane depolarization is markedly slower in GluN1a than in GluN1b neurons such that GluN1a-containing receptors remain blocked during bursting activity, whereas those containing GluN1b escape the ketamine blockade. Furthermore, ketamine treatment, either via systemic administration or local infusion into the hippocampus, induces an antidepressant effect in GluN1a mice but has no effect in GluN1b mice. Collectively, we identify GluN1a-containing NMDARs, which are persistently blocked by ketamine during neuronal firing activity, to be selectively responsible for the antidepressant effect. | | 6:18a |
First vs recurrent episode symptomatology in Major Depressive Disorder and its relation to brain function and structure: a network approach.
Background: Major Depressive Disorder (MDD) is a prevalent psychiatric disorder. At least half of the patients who recover from a first depressive episode, will experience a relapse. Therefore, understanding the underlying mechanisms supporting relapse is a clinical urgency that could be informed by studying complex brain-behavior associations. Here, we investigated how the relationships between depressive symptomatology and regional brain characteristics differed between people with first depressive episode vs recurrent depression. Methods: We used REST-meta-MDD data from the DIRECT consortium. We focused on comparing global and local network properties between first (n=239) and recurrent episode (n=179) on: (i) symptom network, (ii) brain structural (VBM) and functional networks (ALFF, ReHO), and (iii) integrated symptoms network and brain characteristics using the psychopathology and multimodal network approach. Results: Symptom network analysis showed high values of strength centrality for Insomnia: Early Hours of the Morning and General somatic symptoms at recurrence compared to the first episode. Also, differences in global strength in the integrated symptom-brain network (measured with ReHo metric) (S=2.09 p= 0.042). Finally, we found the edge of specific symptom-brain links, including insomnia and somatic symptoms-, to differ between the first episode and recurrence. Conclusions: For symptom networks, local but not global properties differentiated first from recurrent episode MDD, with specially stronger relations of insomnia and somatic symptoms in recurrent episode depression. For integrated symptom-brain networks, global strength of the network reflecting regional functional integrity (ReHO) was related to recurrence. This suggests that symptoms have relevance for understanding the complex brain-symptom relations underpinning recurrence of depression. | | 8:15a |
Alpha-synuclein aggregation and dopaminergic neuron death in a new mouse model of Parkinson disease expressing human full-length and C-terminally truncated 1-120 alpha-synuclein.
Parkinson disease (PD) is neuropathologically characterized by the presence of Lewy bodies and Lewy neurites made of aggregated alpha-synuclein (aSyn). Several studies have shown that Lewy bodies contain C-terminally truncated aSyn which is more prone to fibrillation and enhances the aggregation of human full-length aSyn in vitro. Nevertheless, in vivo studies addressing whether and how human C-terminally truncated aSyn may exacerbate the pathological aggregation and toxicity of human full-length aSyn are currently lacking. In the present study we aimed to determine whether the co-expression of human full-length and 1-120 truncated aSyn would enhance human full-length aSyn aggregation and toxicity. To this end we generated and characterized two novel alpha-synuclein mouse models. Specifically, we first produced a mouse line expressing full-length human aSyn under its own promoter (BACo mice) in the absence of endogenous mouse aSyn. Then, the BACo mice were crossed with the previously described MI2 mice, which express human 1-120 truncated aSyn under the control of the tyrosine hydroxylase (TH) promoter on a mouse aSyn null backgroundin order to obtain the MI2BACo mice, which express both human 1-120 truncated and full-length aSyn in a mouse aSyn null background. We found that aSyn aggregation was present and increased with age in both mouse lines but was significantly higher in the MI2BACo mice. These mice exhibited progressive nigrostriatal accumulation of aSyn aggregates which were often composed of full-length and 1-120haSyn, the latter being specifically recognized by using a novel antibody raised against the 1-120haSyn. In addition, we observed that the presence of both truncated and full-length aSyn in MI2BACo mice led to a faster and more pronounced aSyn aggregation which associated with more severe dopaminergic striatal fiber degeneration and nigral neuron loss. Collectively, our results indicate that the expression of human C-terminally truncated aSyn exacerbates human full-length aSyn pathology and support that the novel MI2BACo transgenic mouse line represents an innovative experimental model to study the biological basis of PD and test novel therapeutic approaches. | | 9:30a |
Developmental, neuroanatomical and cellular expression of genes causing dystonia
Objective Dystonia is one of the most common forms of movement disorder with >50 genes identified as causative. However, an understanding of which developmental stages, brain regions and cell types are most relevant is crucial for developing relevant disease models and therapeutics. One approach is to examine the timing and anatomical expression of dystonia-causing genes, on the assumption that deleterious variants have a greater impact where higher levels of expression are observed. Methods We investigated the expression patterns of 44 dystonia-causing genes across two bulk- and two single-nuclei RNA-sequencing datasets, derived from prenatal and postnatal human brain tissue. Results Dystonia genes were most strongly enriched in those with higher expression in the striatum, cerebral cortex, hippocampus, amygdala and substantia nigra, and for higher postnatal expression. Individual genes exhibiting differences in expression across adult brain regions include SQSTM1, SGCE, KMT2B, PRKRA, YY1, DNAJC12, KCNA1, CACNA1A (highest expression in cerebellum), ADCY5, GNAL, ANO3 (highest expression in striatum), RHOBTB2, FOXG1 (highest expression in cerebral cortex). Single-nuclei RNA-sequencing data analyses from human frontal cortex, striatum and cerebellum indicated that dystonia genes are predominantly expressed in neurons (both glutamatergic and GABAergic), rather than glia. Gene Ontology analysis showed prominent enrichment in biological processes such as dopamine biosynthetic and metabolic processes, and in the cellular components axons, presynapse and neuron projection. Interpretation These analyses provide important insights into the anatomical, developmental and cellular expression patterns of dystonia-causing genes, potentially guiding the development of disease-relevant models and improving the timing and targeting of future therapeutic interventions. | | 3:18p |
Neural Gain Modulation Propagates from Posterior to Anterior Brain Regions to Optimize Orientation Perception in Chronic Astigmatism
While visual impairments commonly occur daily, many individuals fail to recognize these distortions. Yet, the brain's role in adapting to distorted sensory inputs remains largely unknown. In this study, we focused on how the brain recalibrates physical orientation-specific blur after chronic exposure to astigmatism. By reconstructing the population orientation tuning response from electroencephalogram activity patterns and estimating neural gain modulation using an optics-based computational model (data from 42 participants, including 15 females), we found enhanced neural gain for underrepresented orientations and reduced gain for overrepresented ones, especially in individuals with long-term astigmatism. The strength of the gain modulation correlated with the optimization of orientation perception in these participants. Furthermore, this push-pull neural gain modulation dynamically propagated from the posterior brain regions to others, and the strength of the propagation correlated with the degree of perceptual optimization. In contrast, short-term exposure resulted in transient and short-lived neural optimization, characterized by a relatively stronger anterior-to-posterior transference pattern. These results show how feature-specific information is modified across the entire brain in response to systematic visual distortion, revealing duration-dependent strategies the brain employs to handle sensory impairments. | | 10:33p |
Advancing Mobile Neuroscience: A Novel Wearable Backpack for Multi-Sensor Research in Urban Environments
The rapid global urbanisation has intensified the need to understand the complex interactions and impacts that city environments have on human physical or mental health and well-being. Traditional indoor laboratory-based approaches conduct experiments in well controlled settings but, while advantageous for their controlled conditions, they often lack ecological validity. To address this gap, we present the "eMOTIONAL Cities Walker Backpack" - a wearable unit developed for synchronously collecting multi-modal data in dynamic real-world settings. Designed for both indoor and outdoor use, the backpack integrates environmental (for microclimate, air pollution and noise) and physiological sensors (including electroencephalography, eye-tracking and wrist-based biosensors for cardiovascular monitoring) to enable the study of human experience in naturalistic urban environments. In this paper, we describe the technical specifications and implementation of this technology during outdoor acquisitions across selected urban locations in the city of Lisbon. We also highlight its potential for methodological comparison with traditional lab-based tasks (particularly through the use of equivalent sensing technologies), and thus advancing the field of translational research in mental health and urban studies. | | 10:33p |
Dysregulated Proline Metabolism Contributes to Subretinal Fibrosis in Neovascular AMD: Therapeutic Potential of Prolyl-4-Hydroxylase Inhibition
Subretinal fibrosis, a major cause of irreversible vision loss in neovascular age-related macular degeneration (nAMD), is driven by excessive deposition of extracellular matrix such as collagens. While proline metabolism is known to play a critical role in collagen biosynthesis and fibrosis, its involvement in subretinal fibrosis remains unclear. Here, we characterized the progression of fibrovascular lesions in JR5558 mice, observing significant molecular alterations as early as 4 weeks of age and phenotypic changes by 8 weeks. Transcriptomic and metabolomic analyses revealed elevated levels of 4-hydroxyproline, an essential component of collagen, alongside significant alterations of other fibrosis-related pathways. P4HA1, a catalytic subunit of prolyl-4-hydroxylase essential for 4-hydroxyproline biosynthesis, was prominently expressed in fibrotic lesions in retinas of JR5558 and two-stage laser-induced murine models, as well as human eyes with nAMD. Targeting P4HA1 with the small- molecule inhibitor diethyl pythiDC significantly attenuated fibrovascular lesion growth in the JR5558 murine models and reduced collagen turnover in human retinal pigment epithelium cells. Combining diethyl pythiDC with aflibercept had a stronger antifibrotic effect than aflibercept monotherapy in JR5558 mice. These findings suggest a key contribution of proline metabolism, particularly proline hydroxylation, in subretinal fibrosis. Inhibiting P4HA1 with diethyl pythiDC inhibited fibrosis in the models we studied, offering a novel therapeutic strategy. Further research is warranted to explore the potential benefits of combining existing anti-angiogenic therapies with drugs that inhibit proline metabolism for the management of nAMD-associated fibrosis. |
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