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Neuropsychopharmacology : Official... Jun 2024Synaptic plasticity occurs via multiple mechanisms to regulate synaptic efficacy. Homeostatic and Hebbian plasticity are two such mechanisms by which neuronal synapses...
Synaptic plasticity occurs via multiple mechanisms to regulate synaptic efficacy. Homeostatic and Hebbian plasticity are two such mechanisms by which neuronal synapses can be altered. Although these two processes are mechanistically distinct, they converge on downstream regulation of AMPA receptor activity to modify glutamatergic neurotransmission. However, much remains to be explored regarding how these two prominent forms of plasticity interact. Ketamine, a rapidly acting antidepressant, increases glutamatergic transmission via pharmacologically-induced homeostatic plasticity. Here, we demonstrate that Hebbian plasticity mechanisms are still intact in synapses that have undergone homeostatic scaling by ketamine after either systemic injection or perfusion onto hippocampal brain slices. We also investigated this relationship in the context of stress induced by chronic exposure to corticosterone (CORT) to better model the circumstances under which ketamine may be used as an antidepressant. We found that CORT induced an anhedonia-like behavioral phenotype in mice but did not impair long-term potentiation (LTP) induction. Furthermore, corticosterone exposure does not impact the intersection of homeostatic and Hebbian plasticity mechanisms, as synapses from CORT-exposed mice also demonstrated intact ketamine-induced plasticity and LTP in succession. These results provide a mechanistic explanation for how ketamine used for the treatment of depression does not impair the integrity of learning and memory processes encoded by mechanisms such as LTP.
PubMed: 38898206
DOI: 10.1038/s41386-024-01895-2 -
Nature Methods Jun 2024Volumetric imaging of synaptic transmission in vivo requires high spatial and high temporal resolution. Shaping the wavefront of two-photon fluorescence excitation...
Volumetric imaging of synaptic transmission in vivo requires high spatial and high temporal resolution. Shaping the wavefront of two-photon fluorescence excitation light, we developed Bessel-droplet foci for high-contrast and high-resolution volumetric imaging of synapses. Applying our method to imaging glutamate release, we demonstrated high-throughput mapping of excitatory inputs at >1,000 synapses per volume and >500 dendritic spines per neuron in vivo and unveiled previously unseen features of functional synaptic organization in the mouse primary visual cortex.
PubMed: 38898094
DOI: 10.1038/s41592-024-02309-3 -
International Immunopharmacology Jun 2024Chronic stress-induced neuroinflammation plays a pivotal role in the development and exacerbation of mental disorders, such as anxiety and depression. Dimethyl Fumarate...
BACKGROUND
Chronic stress-induced neuroinflammation plays a pivotal role in the development and exacerbation of mental disorders, such as anxiety and depression. Dimethyl Fumarate (DMF), an effective therapeutic agent approved for the treatment of multiple sclerosis, has been widely reported to display anti-inflammatory and anti-oxidative effects. However, the impact of DMF on chronic stress-induced anxiety disorders and the exact underlying mechanisms remain largely unknown.
METHODS
We established a mouse model of chronic social defeat stress (CSDS). DMF was administered orally 1 h before daily stress session for 10 days in CSDS + DMF group. qRT-PCR and western blotting were used to analyze mRNA and protein expression of NLRP3, Caspase-1 and IL-1β. Immunofluorescence staining was carried out to detect the expression of Iba 1 and c-fos positive cells as well as morphological change of Iba 1 microglia. Whole-cell patch-clamp recording was applied to evaluate synaptic transmission and intrinsic excitability of neurons.
RESULTS
DMF treatment significantly alleviated CSDS-induced anxiety-like behaviors in mice. Mechanistically, DMF treatment prevented CSDS-induced neuroinflammation by inhibiting the activation of microglia and NLRP3/Caspase-1/IL-1β signaling pathway in basolateral amygdala (BLA), a brain region important for emotional processing. Furthermore, DMF treatment effectively reversed the CSDS-caused disruption of excitatory and inhibitory synaptic transmission balance, as well as the increased intrinsic excitability of BLA neurons.
CONCLUSIONS
Our findings provide new evidence that DMF may exert anxiolytic effect by preventing CSDS-induced activation of NLRP3/Caspase-1/IL-1β signaling pathway and alleviating hyperactivity of BLA neurons.
PubMed: 38897132
DOI: 10.1016/j.intimp.2024.112414 -
The Journal of Comparative Neurology Jun 2024The hypothalamic suprachiasmatic nucleus (SCN) is the central pacemaker for mammalian circadian rhythms. As such, this ensemble of cell-autonomous neuronal oscillators...
The hypothalamic suprachiasmatic nucleus (SCN) is the central pacemaker for mammalian circadian rhythms. As such, this ensemble of cell-autonomous neuronal oscillators with divergent periods must maintain coordinated oscillations. To investigate ultrastructural features enabling such synchronization, 805 coronal ultrathin sections of mouse SCN tissue were imaged with electron microscopy and aligned into a volumetric stack, from which selected neurons within the SCN core were reconstructed in silico. We found that clustered SCN core neurons were physically connected to each other via multiple large soma-to-soma plate-like contacts. In some cases, a sliver of a glial process was interleaved. These contacts were large, covering on average ∼21% of apposing neuronal somata. It is possible that contacts may be the electrophysiological substrate for synchronization between SCN neurons. Such plate-like contacts may explain why the synchronization of SCN neurons is maintained even when chemical synaptic transmission or electrical synaptic transmission via gap junctions is blocked. Such ephaptic contact-mediated synchronization among nearby neurons may therefore contribute to the wave-like oscillations of circadian core clock genes and calcium signals observed in the SCN.
Topics: Animals; Mice; Mice, Inbred C57BL; Suprachiasmatic Nucleus Neurons; Male; Suprachiasmatic Nucleus; Neurons
PubMed: 38896499
DOI: 10.1002/cne.25624 -
Synapse (New York, N.Y.) Jul 2024The goal of this report is to explore how K2P channels modulate axonal excitability by using the crayfish ventral superficial flexor preparation. This preparation allows...
The goal of this report is to explore how K2P channels modulate axonal excitability by using the crayfish ventral superficial flexor preparation. This preparation allows for simultaneous recording of motor nerve extracellular action potentials (eAP) and intracellular excitatory junctional potential (EJP) from a muscle fiber. Previous pharmacological studies have demonstrated the presence of K2P-like channels in crayfish. Fluoxetine (50 µM) was used to block K2P channels in this study. The blocker caused a gradual decline, and eventually complete block, of motor axon action potentials. At an intermediate stage of the block, when the peak-to-peak amplitude of eAP decreased to ∼60%-80% of the control value, the amplitude of the initial positive component of eAP declined at a faster rate than that of the negative peak representing sodium influx. Furthermore, the second positive peak following this sodium influx, which corresponds to the after-hyperpolarizing phase of intracellularly recorded action potentials (iAP), became larger during the intermediate stage of eAP block. Finally, EJP recorded simultaneously with eAP showed no change in amplitude, but did show a significant increase in synaptic delay. These changes in eAP shape and EJP delay are interpreted as the consequence of depolarized resting membrane potential after K2P channel block. In addition to providing insights to possible functions of K2P channels in unmyelinated axons, results presented here also serve as an example of how changes in eAP shape contain information that can be used to infer alterations in intracellular events. This type of eAP-iAP cross-inference is valuable for gaining mechanistic insights here and may also be applicable to other model systems.
Topics: Animals; Astacoidea; Fluoxetine; Action Potentials; Motor Neurons; Axons
PubMed: 38896000
DOI: 10.1002/syn.22304 -
Frontiers in Pharmacology 2024Neurodegenerative disorders represent a significant and growing health burden worldwide. Unfortunately, limited therapeutic options are currently available despite... (Review)
Review
Neurodegenerative disorders represent a significant and growing health burden worldwide. Unfortunately, limited therapeutic options are currently available despite ongoing efforts. Over the past decades, research efforts have increasingly focused on understanding the molecular mechanisms underlying these devastating conditions. Orphan receptors, a class of receptors with no known endogenous ligands, emerge as promising druggable targets for diverse diseases. This review aims to direct attention to a subgroup of orphan GPCRs, in particular class A orphans that have roles in neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and Multiple sclerosis. We highlight the diverse roles orphan receptors play in regulating critical cellular processes such as synaptic transmission, neuronal survival and neuro-inflammation. Moreover, we discuss the therapeutic potential of targeting orphan receptors for the treatment of neurodegenerative disorders, emphasizing recent advances in drug discovery and preclinical studies. Finally, we outline future directions and challenges in orphan receptor research.
PubMed: 38895631
DOI: 10.3389/fphar.2024.1394516 -
BioRxiv : the Preprint Server For... Jun 2024Dynamin-1 (DNM1) consolidates memory through synaptic transmission and modulation and has been explored as a therapeutic target in Alzheimer's disease. Through a...
Dynamin-1 (DNM1) consolidates memory through synaptic transmission and modulation and has been explored as a therapeutic target in Alzheimer's disease. Through a two-prong approach, this study examined its role in cancer-related cognitive impairment (CRCI) pathogenesis using human and animal models. The human study recruited newly diagnosed, chemotherapy-naïve adolescent and young adult cancer and non-cancer controls to complete a cognitive instrument (FACT-Cog) and blood draws for up to three time points. Concurrently, a syngeneic young-adult WT (C57BL/6 female) mouse model of breast cancer was developed to study DNM1 expression in the brain. Samples from eighty-six participants with 30 adolescent and young adult (AYA) cancer and 56 non-cancer participants were analyzed. DNM1 levels were significantly lower among cancer participants compared to non-cancer prior to treatment. While receiving cancer treatment, cognitively impaired patients were found with a significant downregulation of DNM1, but not among those without impairment. In murine breast cancer-bearing mice receiving chemotherapy, we consistently found a significant decline in DNM1 immunoreactivity in the hippocampal CA1 and CA3 subregions. Observed in both human and animal studies, the downregulation of DNM1 is linked with the onset of CRCI. Future research should explore the potential of DNM1 in CRCI pathogenesis and therapeutics development.
PubMed: 38895481
DOI: 10.1101/2024.06.04.597349 -
BioRxiv : the Preprint Server For... Jun 2024The basal ganglia (BG) are an evolutionarily conserved and phylogenetically old set of sub-cortical nuclei that guide action selection, evaluation, and reinforcement....
The basal ganglia (BG) are an evolutionarily conserved and phylogenetically old set of sub-cortical nuclei that guide action selection, evaluation, and reinforcement. The entopeduncular nucleus (EP) is a major BG output nucleus that contains a population of GABA/glutamate cotransmitting neurons (EP ) that specifically target the lateral habenula (LHb) and whose function in behavior remains mysterious. Here we use a probabilistic switching task that requires an animal to maintain flexible relationships between action selection and evaluation to examine when and how GABA/glutamate cotransmitting neurons contribute to behavior. We find that EP neurons are strongly engaged during this task and show bidirectional changes in activity during the choice and outcome periods of a trial. We then tested the effects of either permanently blocking cotransmission or modifying the GABA/glutamate ratio on behavior in well-trained animals. Neither manipulation produced detectable changes in behavior despite significant changes in synaptic transmission in the LHb, demonstrating that the outputs of these neurons are not required for on-going action-outcome updating in a probabilistic switching task.
PubMed: 38895480
DOI: 10.1101/2024.06.07.597980 -
BioRxiv : the Preprint Server For... Jun 2024Premature infants often experience frequent hypoxic episodes due to immaturity of respiratory control that may result in disturbances of gray and white matter...
BACKGROUND
Premature infants often experience frequent hypoxic episodes due to immaturity of respiratory control that may result in disturbances of gray and white matter development and long-term cognitive and behavioral abnormalities. We hypothesize that neonatal intermittent hypoxia alters cortical maturation of excitatory and inhibitory circuits that can be detected early with functional MRI.
METHODS
C57BL/6 mouse pups were exposed to an intermittent hypoxia (IH) regimen consisting of 12 to 20 daily hypoxic episodes of 5% oxygen exposure for 2 min at 37C from P3 to P7, followed by MRI at P12 and electrophysiological recordings in cortical slices and in vivo at several time points between P7 and P13. Behavioral tests were conducted at P41-P50 to assess animal activity and motor learning.
RESULTS
Adult mice after neonatal IH exhibited hyperactivity in open field test and impaired motor learning in complex wheel tasks. Patch clamp and evoked field potential electrophysiology revealed increased glutamatergic transmission accompanied by elevation of tonic inhibition. A decreased synaptic inhibitory drive was evidenced by miniature IPSC frequency on pyramidal cells, multi-unit activity recording in vivo in the motor cortex with selective GABA receptor inhibitor picrotoxin injection, as well as by the decreased interneuron density at P13. There was also an increased tonic depolarizing effect of picrotoxin after IH on principal cells' membrane potential on patch clamp and direct current potential in extracellular recordings. The amplitude of low-frequency fluctuation on resting-state fMRI was larger, with a larger increase after picrotoxin injection in the IH group.
CONCLUSIONS
Increased excitatory glutamatergic transmission, decreased numbers, and activity of inhibitory interneurons after neonatal IH may affect the maturation of connectivity in cortical networks, resulting in long-term cognitive and behavioral changes, including impaired motor learning and hyperactivity. Functional MRI reveals increased intrinsic connectivity in the sensorimotor cortex, suggesting neuronal dysfunction in cortical maturation after neonatal IH. The increased tonic inhibition, presumably due to tonic extrasynaptic GABA receptor drive, may be compensatory to the elevated excitatory glutamatergic transmission.
PubMed: 38895332
DOI: 10.1101/2024.06.04.596449 -
BioRxiv : the Preprint Server For... Jun 2024The ketogenic diet is an effective treatment for drug-resistant epilepsy, but the therapeutic mechanisms are poorly understood. Although ketones are able to fuel the...
The ketogenic diet is an effective treatment for drug-resistant epilepsy, but the therapeutic mechanisms are poorly understood. Although ketones are able to fuel the brain, it is not known whether ketones are directly metabolized by neurons on a time scale sufficiently rapid to fuel the bioenergetic demands of sustained synaptic transmission. Here, we show that nerve terminals can use the ketone β-hydroxybutyrate in a cell- autonomous fashion to support neurotransmission in both excitatory and inhibitory nerve terminals and that this flexibility relies on Ca dependent upregulation of mitochondrial metabolism. Using a genetically encoded ATP sensor, we show that inhibitory axons fueled by ketones sustain much higher ATP levels under steady state conditions than excitatory axons, but that the kinetics of ATP production following activity are slower when using ketones as fuel compared to lactate/pyruvate for both excitatory and inhibitory neurons.
PubMed: 38895313
DOI: 10.1101/2024.06.08.598077