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Brain Communications 2024Synapse loss is currently the best biological correlate of cognitive decline in Alzheimer's disease and other tauopathies. Synapses seem to be highly vulnerable to...
Synapse loss is currently the best biological correlate of cognitive decline in Alzheimer's disease and other tauopathies. Synapses seem to be highly vulnerable to tau-mediated disruption in neurodegenerative tauopathies. However, it is unclear how and when this leads to alterations in function related to the progression of tauopathy and neurodegeneration. We used the well-characterized rTg4510 mouse model of tauopathy at 5-6 months and 7-8 months of age, respectively, to study the functional impact of cortical synapse loss. The earlier age was used as a model of prodromal tauopathy, with the later age corresponding to more advanced tau pathology and presumed progression of neurodegeneration. Analysis of synaptic protein expression in the somatosensory cortex showed significant reductions in synaptic proteins and NMDA and AMPA receptor subunit expression in rTg4510 mice. Surprisingly, whole-cell patch clamp electrophysiology from putative pyramidal neurons in layer 2/3 of the somatosensory cortex suggested no functional alterations in layer 4 to layer 2/3 synaptic transmission at 5-6 months. From these same neurons, however, there were alterations in dendritic structure, with increased branching proximal to the soma in rTg4510 neurons. Therefore, whole-cell patch clamp recordings were utilized to investigate synaptic function and integration in putative pyramidal neurons in layer 2/3 of the somatosensory cortex. These recordings revealed a significant increase in the peak response to synaptically driven sensory stimulation-evoked activity and a loss of temporal fidelity of the evoked signal to the input stimulus in rTg4510 neurons. Together, these data suggest that loss of synapses, changes in receptor expression and dendritic restructuring may lead to alterations in synaptic integration at a network level. Understanding these compensatory processes could identify targets to help delay symptomatic onset of dementia.
PubMed: 38712321
DOI: 10.1093/braincomms/fcae134 -
Cureus Apr 2024Borderline personality disorder (BPD) and treatment-resistant depression (TRD) are common mental disorders that are challenging to treat. Ketamine is an...
Borderline personality disorder (BPD) and treatment-resistant depression (TRD) are common mental disorders that are challenging to treat. Ketamine is an N-methyl-D-aspartate receptor antagonist that has shown promise as a rapid-acting antidepressant when administered intravenously. BPD symptoms have also been demonstrated to improve with repeated intravenous administration of ketamine, and a single case report described improvement in BPD following the intranasal administration of esketamine. We present a case report of a woman with BPD and TRD who responded to treatment with very low-dose sublingual ketamine. Very low-dose sublingual ketamine may be effective for the treatment of psychiatric disorders such as BPD and/or comorbid TRD.
PubMed: 38707115
DOI: 10.7759/cureus.57654 -
Clinical and Translational Science May 2024This parallel-arm, phase I study investigated the potential cytochrome P450 (CYP)3A induction effect of NBI-1065845 (TAK-653), an investigational... (Randomized Controlled Trial)
Randomized Controlled Trial
This parallel-arm, phase I study investigated the potential cytochrome P450 (CYP)3A induction effect of NBI-1065845 (TAK-653), an investigational α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiator in phase II development for major depressive disorder. The midazolam treatment arm received the sensitive CYP3A substrate midazolam on Day 1, followed by NBI-1065845 alone on Days 5-13; on Day 14, NBI-1065845 was administered with midazolam, then NBI-1065845 alone on Day 15. The oral contraceptive treatment arm received ethinyl estradiol-levonorgestrel on Day 1, then NBI-1065845 alone on Days 5-13; on Day 14, NBI-1065845 was administered with ethinyl estradiol-levonorgestrel, then NBI-1065845 alone on Days 15-17. Blood samples were collected for pharmacokinetic analyses. The midazolam treatment arm comprised 14 men and 4 women, of whom 16 completed the study. Sixteen of the 17 healthy women completed the oral contraceptive treatment arm. After multiple daily doses of NBI-1065845, the geometric mean ratios (GMRs) (90% confidence interval) for maximum observed concentration were: midazolam, 0.94 (0.79-1.13); ethinyl estradiol, 1.00 (0.87-1.15); and levonorgestrel, 0.99 (0.87-1.13). For area under the plasma concentration-time curve (AUC) from time 0 to infinity, the GMRs were as follows: midazolam, 0.88 (0.78-0.98); and ethinyl estradiol, 1.01 (0.88-1.15). For levonorgestrel, the GMR for AUC from time 0 to the last quantifiable concentration was 0.87 (0.78-0.96). These findings indicate that NBI-1065845 is not a CYP3A inducer and support its administration with CYP3A substrates. NBI-1065845 was generally well tolerated, with no new safety signals observed after coadministration of midazolam, ethinyl estradiol, or levonorgestrel.
Topics: Humans; Midazolam; Ethinyl Estradiol; Female; Adult; Male; Young Adult; Contraceptives, Oral, Combined; Levonorgestrel; Drug Interactions; Drug Combinations; Healthy Volunteers; Adolescent; Cytochrome P-450 CYP3A; Middle Aged; Area Under Curve; Cytochrome P-450 CYP3A Inducers
PubMed: 38700236
DOI: 10.1111/cts.13791 -
Cell Reports May 2024Recent findings show that effective integration of novel information in the brain requires coordinated processes of homo- and heterosynaptic plasticity. In this work, we...
Recent findings show that effective integration of novel information in the brain requires coordinated processes of homo- and heterosynaptic plasticity. In this work, we hypothesize that activity-dependent remodeling of the peri-synaptic extracellular matrix (ECM) contributes to these processes. We show that clusters of the peri-synaptic ECM, recognized by CS56 antibody, emerge in response to sensory stimuli, showing temporal and spatial coincidence with dendritic spine plasticity. Using CS56 co-immunoprecipitation of synaptosomal proteins, we identify several molecules involved in Ca signaling, vesicle cycling, and AMPA-receptor exocytosis, thus suggesting a role in long-term potentiation (LTP). Finally, we show that, in the CA1 hippocampal region, the attenuation of CS56 glycoepitopes, through the depletion of versican as one of its main carriers, impairs LTP and object location memory in mice. These findings show that activity-dependent remodeling of the peri-synaptic ECM regulates the induction and consolidation of LTP, contributing to hippocampal-dependent memory.
Topics: Animals; Extracellular Matrix; Long-Term Potentiation; Mice; Neuronal Plasticity; Memory; Synapses; Mice, Inbred C57BL; Male; CA1 Region, Hippocampal; Hippocampus
PubMed: 38676925
DOI: 10.1016/j.celrep.2024.114112 -
Biomedicines Apr 2024Glutamate is the major excitatory neurotransmitter in the central nervous system. Glutamatergic transmission can be mediated by ionotropic glutamate receptors (iGluRs),... (Review)
Review
Glutamate is the major excitatory neurotransmitter in the central nervous system. Glutamatergic transmission can be mediated by ionotropic glutamate receptors (iGluRs), which mediate rapid synaptic depolarization that can be associated with Ca entry and activity-dependent change in the strength of synaptic transmission, as well as by metabotropic glutamate receptors (mGluRs), which mediate slower postsynaptic responses through the recruitment of second messenger systems. A wealth of evidence reported over the last three decades has shown that this dogmatic subdivision between iGluRs and mGluRs may not reflect the actual physiological signaling mode of the iGluRs, i.e., α-amino-3-hydroxy-5-methyl-4-isoxasolepropionic acid (AMPA) receptors (AMPAR), kainate receptors (KARs), and N-methyl-D-aspartate (NMDA) receptors (NMDARs). Herein, we review the evidence available supporting the notion that the canonical iGluRs can recruit flux-independent signaling pathways not only in neurons, but also in brain astrocytes and cerebrovascular endothelial cells. Understanding the signaling versatility of iGluRs can exert a profound impact on our understanding of glutamatergic synapses. Furthermore, it may shed light on novel neuroprotective strategies against brain disorders.
PubMed: 38672234
DOI: 10.3390/biomedicines12040880 -
Brain Sciences Apr 2024To determine the critical timing for learning and the associated synaptic plasticity, we analyzed developmental changes in learning together with training-induced...
To determine the critical timing for learning and the associated synaptic plasticity, we analyzed developmental changes in learning together with training-induced plasticity. Rats were subjected to an inhibitory avoidance (IA) task prior to weaning. While IA training did not alter latency at postnatal day (PN) 16, there was a significant increase in latency from PN 17, indicating a critical day for IA learning between PN 16 and 17. One hour after training, acute hippocampal slices were prepared for whole-cell patch clamp analysis following the retrieval test. In the presence of tetrodotoxin (0.5 µM), miniature excitatory postsynaptic currents (mEPSCs) and inhibitory postsynaptic currents (mIPSCs) were sequentially recorded from the same CA1 neuron. Although no changes in the amplitude of mEPSCs or mIPSCs were observed at PN 16 and 21, significant increases in both excitatory and inhibitory currents were observed at PN 23, suggesting a specific critical day for training-induced plasticity between PN 21 and 23. Training also increased the diversity of postsynaptic currents at PN 23 but not at PN 16 and 21, demonstrating a critical day for training-induced increase in the information entropy of CA1 neurons. Finally, we analyzed the plasticity at entorhinal cortex layer III (ECIII)-CA1 or CA3-CA1 synapses for each individual rat. At either ECIII-CA1 or CA3-CA1 synapses, a significant correlation between mean α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/N-methyl-D-aspartic acid (AMPA/NMDA) ratio and learning outcomes emerged at PN 23 at both synapses, demonstrating a critical timing for the direct link between AMPA receptor-mediated synaptic plasticity and learning efficacy. Here, we identified multiple critical periods with respect to training-induced synaptic plasticity and delineated developmental trajectories of learning mechanisms at hippocampal CA1 synapses.
PubMed: 38672030
DOI: 10.3390/brainsci14040382 -
Frontiers in Synaptic Neuroscience 2024Rapid, synapse-specific neurotransmission requires the precise alignment of presynaptic neurotransmitter release and postsynaptic receptors. How postsynaptic glutamate...
Rapid, synapse-specific neurotransmission requires the precise alignment of presynaptic neurotransmitter release and postsynaptic receptors. How postsynaptic glutamate receptor accumulation is induced during maturation is not well understood. We find that in cultures of dissociated hippocampal neurons at 11 days (DIV) numerous synaptic contacts already exhibit pronounced accumulations of the pre- and postsynaptic markers synaptotagmin, synaptophysin, synapsin, bassoon, VGluT1, PSD-95, and Shank. The presence of an initial set of AMPARs and NMDARs is indicated by miniature excitatory postsynaptic currents (mEPSCs). However, AMPAR and NMDAR immunostainings reveal rather smooth distributions throughout dendrites and synaptic enrichment is not obvious. We found that brief periods of Ca influx through NMDARs induced a surprisingly rapid accumulation of NMDARs within 1 min, followed by accumulation of CaMKII and then AMPARs within 2-5 min. Postsynaptic clustering of NMDARs and AMPARs was paralleled by an increase in their mEPSC amplitudes. A peptide that blocked the interaction of NMDAR subunits with PSD-95 prevented the NMDAR clustering. NMDAR clustering persisted for 3 days indicating that brief periods of elevated glutamate fosters permanent accumulation of NMDARs at postsynaptic sites in maturing synapses. These data support the model that strong glutamatergic stimulation of immature glutamatergic synapses results in a fast and substantial increase in postsynaptic NMDAR content that required NMDAR binding to PSD-95 or its homologues and is followed by recruitment of CaMKII and subsequently AMPARs.
PubMed: 38660466
DOI: 10.3389/fnsyn.2024.1291262 -
BioRxiv : the Preprint Server For... Apr 2024AMPA-type glutamate receptors (AMPAR) mediate excitatory cochlear transmission. However, the unique roles of AMPAR subunits are unresolved. Lack of subunit GluA3 () in...
AMPA-type glutamate receptors (AMPAR) mediate excitatory cochlear transmission. However, the unique roles of AMPAR subunits are unresolved. Lack of subunit GluA3 () in male mice reduced cochlear output by 8-weeks of age. Since is X-linked and considering sex differences in hearing vulnerability, we hypothesized accelerated presbycusis in females. Here, auditory brainstem responses (ABR) were similar in 3-week-old female and mice. However, when raised in ambient sound, ABR thresholds were elevated and wave-1 amplitudes were diminished at 5-weeks and older in . In contrast, these metrics were similar between genotypes when raised in quiet. Paired synapses were similar in number, but lone ribbons and ribbonless synapses were increased in female mice in ambient sound compared to or to either genotype raised in quiet. Synaptic GluA4:GluA2 ratios increased relative to , particularly in ambient sound, suggesting an activity-dependent increase in calcium-permeable AMPARs in . Swollen afferent terminals were observed by 5-weeks only in females reared in ambient sound. We propose that lack of GluA3 induces sex-dependent vulnerability to AMPAR-mediated excitotoxicity.
PubMed: 38659964
DOI: 10.1101/2024.02.21.581467 -
IScience Apr 2024In vertebrates, retinal neural circuitry for visual perception is organized in specific layers. The outer plexiform layer is the first synaptic region in the visual...
In vertebrates, retinal neural circuitry for visual perception is organized in specific layers. The outer plexiform layer is the first synaptic region in the visual pathway, where photoreceptor synaptic terminals connect with bipolar and horizontal cell processes. However, molecular mechanisms underlying cone synapse formation to mediate OFF pathways remain unknown. This study reveals that Necl-1/CADM3 is localized at S- and S/M-opsin-containing cones and dendrites of type 4 OFF cone bipolar cells (CBCs). In mouse retina, synapses between cones and type 4 OFF CBCs were dislocated, horizontal cell distribution became abnormal, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors were dislocated. mice exhibited aberrant short-wavelength-light-elicited signal transmission from cones to OFF CBCs, which was rescued by AMPA receptor potentiator. Additionally, mice showed impaired optokinetic responses. These findings suggest that Necl-1 regulates cone synapse formation to mediate OFF cone pathways elicited by short-wavelength light in mouse retina.
PubMed: 38623325
DOI: 10.1016/j.isci.2024.109577 -
International Journal of Molecular... Mar 2024Patients with systemic lupus erythematosus (SLE) frequently experience chronic pain due to the limited effectiveness and safety profiles of current analgesics.... (Review)
Review
Patients with systemic lupus erythematosus (SLE) frequently experience chronic pain due to the limited effectiveness and safety profiles of current analgesics. Understanding the molecular and synaptic mechanisms underlying abnormal neuronal activation along the pain signaling pathway is essential for developing new analgesics to address SLE-induced chronic pain. Recent studies, including those conducted by our team and others using the SLE animal model (/ lupus-prone mice), have unveiled heightened excitability in nociceptive primary sensory neurons within the dorsal root ganglia and increased glutamatergic synaptic activity in spinal dorsal horn neurons, contributing to the development of chronic pain in mice with SLE. Nociceptive primary sensory neurons in lupus animals exhibit elevated resting membrane potentials, and reduced thresholds and rheobases of action potentials. These changes coincide with the elevated production of TNFα and IL-1β, as well as increased ERK activity in the dorsal root ganglion, coupled with decreased AMPK activity in the same region. Dysregulated AMPK activity is linked to heightened excitability in nociceptive sensory neurons in lupus animals. Additionally, the increased glutamatergic synaptic activity in the spinal dorsal horn in lupus mice with chronic pain is characterized by enhanced presynaptic glutamate release and postsynaptic AMPA receptor activation, alongside the reduced activity of glial glutamate transporters. These alterations are caused by the elevated activities of IL-1β, IL-18, CSF-1, and thrombin, and reduced AMPK activities in the dorsal horn. Furthermore, the pharmacological activation of spinal GPR109A receptors in microglia in lupus mice suppresses chronic pain by inhibiting p38 MAPK activity and the production of both IL-1β and IL-18, as well as reducing glutamatergic synaptic activity in the spinal dorsal horn. These findings collectively unveil crucial signaling molecular and synaptic targets for modulating abnormal neuronal activation in both the periphery and spinal dorsal horn, offering insights into the development of analgesics for managing SLE-induced chronic pain.
Topics: Humans; Animals; Mice; Mice, Inbred MRL lpr; Chronic Pain; Interleukin-18; AMP-Activated Protein Kinases; Glutamic Acid; Interleukin-1beta; Lupus Erythematosus, Systemic; Analgesics
PubMed: 38612414
DOI: 10.3390/ijms25073602