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Biological Psychiatry Global Open... Oct 2023Schizophrenia is a heritable psychiatric disorder with a polygenic architecture. Genome-wide association studies have reported that an increasing number of...
BACKGROUND
Schizophrenia is a heritable psychiatric disorder with a polygenic architecture. Genome-wide association studies have reported that an increasing number of risk-associated variants and polygenic risk scores (PRSs) explain 17% of the variance in the disorder. Substantial heterogeneity exists in the effect of these variants, and aggregating them based on biologically relevant functions may provide mechanistic insight into the disorder.
METHODS
Using the largest schizophrenia genome-wide association study conducted to date, we associated PRSs based on 5 gene sets previously found to contribute to schizophrenia pathophysiology-postsynaptic density of excitatory synapses, postsynaptic membrane, dendritic spine, axon, and histone H3-K4 methylation-along with respective whole-genome PRSs, with neuroimaging ( > 29,000) and reported psychotic-like experiences ( > 119,000) variables in healthy UK Biobank subjects.
RESULTS
Several variables were significantly associated with the axon gene-set (psychotic-like communications, parahippocampal gyrus volume, fractional anisotropy thalamic radiations, and fractional anisotropy posterior thalamic radiations (β range -0.016 to 0.0916, false discovery rate-corrected [] ≤ .05), postsynaptic density gene-set (psychotic-like experiences distress, global surface area, and cingulate lobe surface area [β range -0.014 to 0.0588, ≤ .05]), and histone gene set (entorhinal surface area: β = -0.016, = .035). From these, whole-genome PRSs were significantly associated with psychotic-like communications (β = 0.2218, = 1.34 × 10), distress (β = 0.1943, = 7.28 × 10), and fractional anisotropy thalamic radiations (β = -0.0143, = .036). Permutation analysis revealed that these associations were not due to chance.
CONCLUSIONS
Our results indicate that genetic variation in 3 gene sets relevant to schizophrenia may confer risk for the disorder through effects on previously implicated neuroimaging variables. Because associations were stronger overall for whole-genome PRSs, findings here highlight that selection of biologically relevant variants is not yet sufficient to address the heterogeneity of the disorder.
PubMed: 37881537
DOI: 10.1016/j.bpsgos.2023.03.004 -
Nature Nov 2023Vision enables both image-forming perception, driven by a contrast-based pathway, and unconscious non-image-forming circadian photoentrainment, driven by an...
Vision enables both image-forming perception, driven by a contrast-based pathway, and unconscious non-image-forming circadian photoentrainment, driven by an irradiance-based pathway. Although two distinct photoreceptor populations are specialized for each visual task, image-forming photoreceptors can additionally contribute to photoentrainment of the circadian clock in different species. However, it is unknown how the image-forming photoreceptor pathway can functionally implement the segregation of irradiance signals required for circadian photoentrainment from contrast signals required for image perception. Here we report that the Drosophila R8 photoreceptor separates image-forming and irradiance signals by co-transmitting two neurotransmitters, histamine and acetylcholine. This segregation is further established postsynaptically by histamine-receptor-expressing unicolumnar retinotopic neurons and acetylcholine-receptor-expressing multicolumnar integration neurons. The acetylcholine transmission from R8 photoreceptors is sustained by an autocrine negative feedback of the cotransmitted histamine during the light phase of light-dark cycles. At the behavioural level, elimination of histamine and acetylcholine transmission impairs R8-driven motion detection and circadian photoentrainment, respectively. Thus, a single type of photoreceptor can achieve the dichotomy of visual perception and circadian photoentrainment as early as the first visual synapses, revealing a simple yet robust mechanism to segregate and translate distinct sensory features into different animal behaviours.
Topics: Animals; Acetylcholine; Biological Clocks; Circadian Rhythm; Drosophila melanogaster; Feedback, Physiological; Histamine; Neurotransmitter Agents; Photoreceptor Cells, Invertebrate; Receptors, Cholinergic; Receptors, Histamine; Visual Perception
PubMed: 37880372
DOI: 10.1038/s41586-023-06681-6 -
Patterns (New York, N.Y.) Oct 2023Mapping functional connectivity between neurons is an essential step toward probing the neural computations mediating behavior. Accurately determining synaptic...
Mapping functional connectivity between neurons is an essential step toward probing the neural computations mediating behavior. Accurately determining synaptic connectivity maps in populations of neurons is challenging in terms of yield, accuracy, and experimental time. Here, we developed a compressive sensing approach to reconstruct synaptic connectivity maps based on random two-photon cell-targeted optogenetic stimulation and membrane voltage readout of many putative postsynaptic neurons. Using a biophysical network model of interconnected populations of excitatory and inhibitory neurons, we characterized mapping recall and precision as a function of network observability, sparsity, number of neurons stimulated, off-target stimulation, synaptic reliability, propagation latency, and network topology. We found that mapping can be achieved with far fewer measurements than the standard pairwise sequential approach, with network sparsity and synaptic reliability serving as primary determinants of the performance. Our results suggest a rapid and efficient method to reconstruct functional connectivity of sparsely connected neuronal networks.
PubMed: 37876895
DOI: 10.1016/j.patter.2023.100845 -
Heliyon Oct 2023Isoliquiritigenin (ILTG) is a chalcone compound that exhibits hypnotic effects via gamma-aminobutyric acid type A (GABA) receptors. The ventrolateral preoptic area...
OBJECTIVE
Isoliquiritigenin (ILTG) is a chalcone compound that exhibits hypnotic effects via gamma-aminobutyric acid type A (GABA) receptors. The ventrolateral preoptic area (VLPO) is a sleep-promoting center that contains a large number of GABA-releasing cells. There are two cell types in the VLPO: one generates a low-threshold spike (LTS), whereas the other lacks an LTS (non-LTS).
METHOD
Whole-cell patch-clamp technology was used to detect the firing and currents of LTS and non-LTS cells in the VLPO.
RESULTS
Bath administration of ILTG (10 μM) increased the firing rate of VLPO LTS cells, reversed by flumazenil (5 μM), a GABA benzodiazepine site antagonist. However, the firing rate of VLPO non-LTS cells was inhibited by ILTG (10 μM), also reversed by flumazenil (5 μM). No differences were detected regarding resting membrane potential (RMP) amplitude, spike threshold, afterhyperpolarization (AHP) amplitude, or action potential duration (APD) after ILTG (10 μM) perfusion in VLPO LTS cells. RMP amplitude was more hyperpolarized and spike threshold was higher after ILTG (10 μM) application in VLPO non-LTS cells. In addition, ILTG significantly reduced the frequency of miniature inhibitory postsynaptic currents (mIPSCs) in VLPO LTS cells. ILTG significantly increased the amplitude of mIPSCs in VLPO non-LTS cells.
CONCLUSIONS
This study revealed that ILTG suppresses presynaptic GABA release on VLPO LTS cells, thereby increasing their excitability. ILTG enhances postsynaptic GABA receptor function on VLPO non-LTS cells, thereby decreasing their excitability. These results suggest that ILTG may produce hypnotic effects by modulating the GABAergic synaptic transmission properties of these two cell types.
PubMed: 37876454
DOI: 10.1016/j.heliyon.2023.e20620 -
BioRxiv : the Preprint Server For... Oct 2023In a chemical synapse, information flow occurs via the release of neurotransmitters from a presynaptic neuron that triggers an Action potential (AP) in the postsynaptic...
In a chemical synapse, information flow occurs via the release of neurotransmitters from a presynaptic neuron that triggers an Action potential (AP) in the postsynaptic neuron. At its core, this occurs via the postsynaptic membrane potential integrating neurotransmitter-induced synaptic currents, and AP generation occurs when potential reaches a critical threshold. This manuscript investigates feedback implementation via an autapse, where the axon from the postsynaptic neuron forms an inhibitory synapse onto itself. Using a stochastic model of neuronal synaptic transmission, we formulate AP generation as a first-passage time problem and derive expressions for both the mean and noise of AP-firing times. Our analytical results supported by stochastic simulations identify parameter regimes where autaptic feedback transmission enhances the precision of AP firing times consistent with experimental data. These noise attenuating regimes are intuitively based on two orthogonal mechanisms - either expanding the time window to integrate noisy upstream signals; or by linearizing the mean voltage increase over time. Interestingly, we find regimes for noise amplification that specifically occur when the inhibitory synapse has a low probability of release for synaptic vesicles. In summary, this work explores feedback modulation of the stochastic dynamics of autaptic neurotransmission and reveals its function of creating more regular AP firing patterns.
PubMed: 37873216
DOI: 10.1101/2023.10.06.561207 -
Proceedings of the National Academy of... Oct 2023Pre- and postsynaptic forms of long-term potentiation (LTP) are candidate synaptic mechanisms underlying learning and memory. At layer 5 pyramidal neurons, LTP increases...
Pre- and postsynaptic forms of long-term potentiation (LTP) are candidate synaptic mechanisms underlying learning and memory. At layer 5 pyramidal neurons, LTP increases the initial synaptic strength but also short-term depression during high-frequency transmission. This classical form of presynaptic LTP has been referred to as redistribution of synaptic efficacy. However, the underlying mechanisms remain unclear. We therefore performed whole-cell recordings from layer 5 pyramidal neurons in acute cortical slices of rats and analyzed presynaptic function before and after LTP induction by paired pre- and postsynaptic neuronal activity. LTP was successfully induced in about half of the synaptic connections tested and resulted in increased synaptic short-term depression during high-frequency transmission and a decelerated recovery from short-term depression due to an increased fraction of a slow recovery component. Analysis with a recently established sequential two-step vesicle priming model indicates an increase in the abundance of fully-primed and slowly-recovering vesicles. A systematic analysis of short-term plasticity and synapse-to-synapse variability of synaptic strength at various types of synapses revealed that stronger synapses generally recover more slowly from synaptic short-term depression. Finally, pharmacological stimulation of the cyclic adenosine monophosphate and diacylglycerol signaling pathways, which are both known to promote synaptic vesicle priming, mimicked LTP and slowed the recovery from short-term depression. Our data thus demonstrate that LTP at layer 5 pyramidal neurons increases synaptic strength primarily by enlarging a subpool of fully-primed slowly-recovering vesicles.
Topics: Rats; Animals; Long-Term Potentiation; Neocortex; Neurons; Synapses; Synaptic Transmission; Neuronal Plasticity; Hippocampus
PubMed: 37856547
DOI: 10.1073/pnas.2305460120 -
Frontiers in Synaptic Neuroscience 2023The synaptic cleft is the extracellular part of the synapse, bridging the pre- and postsynaptic membranes. The geometry and molecular organization of the cleft is...
The synaptic cleft is the extracellular part of the synapse, bridging the pre- and postsynaptic membranes. The geometry and molecular organization of the cleft is gaining increased attention as an important determinant of synaptic efficacy. The present study by electron microscopy focuses on short-term morphological changes at the synaptic cleft under excitatory conditions. Depolarization of cultured hippocampal neurons with high K results in an increased frequency of synaptic profiles with clefts widened at the periphery (open clefts), typically exhibiting patches of membranes lined by postsynaptic density, but lacking associated presynaptic membranes (18.0% open clefts in high K compared to 1.8% in controls). Similarly, higher frequencies of open clefts were observed in adult brain upon a delay of perfusion fixation to promote excitatory/ischemic conditions. Inhibition of basal activity in cultured neurons through the application of TTX results in the disappearance of open clefts whereas application of NMDA increases their frequency (19.0% in NMDA vs. 5.3% in control and 2.6% in APV). Depletion of extracellular Ca with EGTA also promotes an increase in the frequency of open clefts (16.6% in EGTA vs. 4.0% in controls), comparable to that by depolarization or NMDA, implicating dissociation of Ca-dependent trans-synaptic bridges. Dissociation of transsynaptic bridges under excitatory conditions may allow perisynaptic mobile elements, such as AMPA receptors to enter the cleft. In addition, peripheral opening of the cleft would facilitate neurotransmitter clearance and thus may have a homeostatic and/or protective function.
PubMed: 37840571
DOI: 10.3389/fnsyn.2023.1239098 -
Bioorganic Chemistry Dec 2023The serotonin 1A (5-HT) receptors and serotonin transporter (SERT) are important biological targets in the treatment of diseases of the central nervous system,...
The serotonin 1A (5-HT) receptors and serotonin transporter (SERT) are important biological targets in the treatment of diseases of the central nervous system, especially for depression. In this study, new 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives linked with the 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole moiety were synthesised and evaluated for their affinity for 5-HT receptor and serotonin reuptake inhibition. Selected compounds were then tested for their affinity for D, 5-HT, 5-HT and 5-HT receptors, and also in in vitro metabolic stability assays in human microsomes. Finally, in vivo assays allowed us to evaluate the agonist-antagonist properties of pre- and postsynaptic 5-HT receptors. 3-(1-(4-(3-(5-methoxy-1H-indol-3-yl)-2,5-dioxopyrrolidin-1-yl)butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-5-carbonitrile (4f) emerged as the most promising compound from the series, due to its favourable receptor binding profile (K = 10.0 nM; K = 2.8 nM), good microsomal stability and 5-HT receptor agonistic activity.
Topics: Humans; Serotonin Plasma Membrane Transport Proteins; Serotonin; Receptor, Serotonin, 5-HT1A; Indoles; Serotonin Receptor Agonists; Structure-Activity Relationship
PubMed: 37827015
DOI: 10.1016/j.bioorg.2023.106903 -
Journal of Translational Medicine Oct 2023Seizures are associated with a decrease in γ-aminobutyric type A acid receptors (GABAaRs) on the neuronal surface, which may be regulated by enhanced internalization of...
BACKGROUND
Seizures are associated with a decrease in γ-aminobutyric type A acid receptors (GABAaRs) on the neuronal surface, which may be regulated by enhanced internalization of GABAaRs. When interactions between GABAaR subunit α-1 (GABRA1) and postsynaptic scaffold proteins are weakened, the α1-containing GABAaRs leave the postsynaptic membrane and are internalized. Previous evidence suggested that neuroplastin (NPTN) promotes the localization of GABRA1 on the postsynaptic membrane. However, the association between NPTN and GABRA1 in seizures and its effect on the internalization of α1-containing GABAaRs on the neuronal surface has not been studied before.
METHODS
An in vitro seizure model was constructed using magnesium-free extracellular fluid, and an in vivo model of status epilepticus (SE) was constructed using pentylenetetrazole (PTZ). Additionally, in vitro and in vivo NPTN-overexpression models were constructed. Electrophysiological recordings and internalization assays were performed to evaluate the action potentials and miniature inhibitory postsynaptic currents of neurons, as well as the intracellular accumulation ratio of α1-containing GABAaRs in neurons. Western blot analysis was performed to detect the expression of GABRA1 and NPTN both in vitro and in vivo. Immunofluorescence co-localization analysis and co-immunoprecipitation were performed to evaluate the interaction between GABRA1 and NPTN.
RESULTS
The expression of GABRA1 was found to be decreased on the neuronal surface both in vivo and in vitro seizure models. In the in vitro seizure model, α1-containing GABAaRs showed increased internalization. NPTN expression was found to be positively correlated with GABRA1 expression on the neuronal surface both in vivo and in vitro seizure models. In addition, NPTN overexpression alleviated seizures and NPTN was shown to bind to GABRA1 to form protein complexes that can be disrupted during seizures in both in vivo and in vitro models. Furthermore, NPTN was found to inhibit the internalization of α1-containing GABAaRs in the in vitro seizure model.
CONCLUSION
Our findings provide evidence that NPTN may exert antiepileptic effects by binding to GABRA1 to inhibit the internalization of α1-containing GABAaRs.
Topics: Humans; Anticonvulsants; Carrier Proteins; gamma-Aminobutyric Acid; Neurons; Receptors, GABA-A; Seizures
PubMed: 37814294
DOI: 10.1186/s12967-023-04596-4 -
Cureus Sep 2023Myasthenia gravis (MG) is a neuromuscular junction disorder involving autoantibodies affecting the postsynaptic muscle membrane. We report an 81-year-old man who...
Myasthenia gravis (MG) is a neuromuscular junction disorder involving autoantibodies affecting the postsynaptic muscle membrane. We report an 81-year-old man who presented to the emergency department with three days of left facial droop, who later developed worsening bilateral ptosis, cervical weakness, dysphagia, and dysarthria following an assessment for Bell's palsy. Ultimately, he was diagnosed with MG. This patient's presentation was atypical and challenging. Specifically, the patient had droopy eyelids from a redundancy of skin and an anatomical neck droop, non-specific findings in older adults, which obscured the development of bilateral ptosis and cervical weakness, a classic sign of bulbar disease. The patient also presented with unilateral facial weakness, a rare finding in MG and concerning stroke in the elderly population. Our aim is to discuss the challenges of identifying MG in older populations and to discuss pharmacological challenges in assessing elderly patients with suspected bulbar palsies.
PubMed: 37809196
DOI: 10.7759/cureus.44737