Sustained antidepressant effects of ketamine metabolite involve GABAergic inhibition-mediated molecular dynamics in aPVT glutamatergic neurons.

Despite the rapid and sustained antidepressant effects of ketamine and its metabolites, their underlying cellular and molecular mechanisms are not fully understood. Here, we demonstrate that the sustained antidepressant-like behavioral effects of (2S,6S)-hydroxynorketamine (HNK) in repeatedly stressed animal models involve neurobiological changes in the anterior paraventricular nucleus of the thalamus (aPVT). Mechanistically, (2S,6S)-HNK induces mRNA expression of extrasynaptic GABA receptors and subsequently enhances GABA-receptor-mediated tonic currents, leading to the nuclear export of histone demethylase KDM6 and its replacement by histone methyltransferase EZH2.

Microglia-triggered hypoexcitability plasticity of pyramidal neurons in the rat medial prefrontal cortex.

Lipopolysaccharide (LPS), an outer component of Gram-negative bacteria, induces a strong response of innate immunity via microglia, which triggers a modulation of the intrinsic excitability of neurons. However, it is unclear whether the modulation of neurophysiological properties is similar among neurons. Here, we found the hypoexcitability of layer 5 (L5) pyramidal neurons after exposure to LPS in the medial prefrontal cortex (mPFC) of juvenile rats.

Immune-Triggered Forms of Plasticity Across Brain Regions.

Immune cells play numerous roles in the host defense against the invasion of microorganisms and pathogens, which induces the release of inflammatory mediators (e.g., cytokines and chemokines).

Insights from a computational analysis of the SARS-CoV-2 Omicron variant: Host-pathogen interaction, pathogenicity, and possible drug therapeutics.

Introduction: Prominently accountable for the upsurge of COVID-19 cases as the world attempts to recover from the previous two waves, Omicron has further threatened the conventional therapeutic approaches. The lack of extensive research regarding Omicron has raised the need to establish correlations to understand this variant by structural comparisons. Here, we evaluate, correlate, and compare its genomic sequences through an immunoinformatic approach to understand its epidemiological characteristics and responses to existing drugs.

Acute Cerebellar Inflammation and Related Ataxia: Mechanisms and Pathophysiology.

The cerebellum governs motor coordination and motor learning. Infection with external microorganisms, such as viruses, bacteria, and fungi, induces the release and production of inflammatory mediators, which drive acute cerebellar inflammation. The clinical observation of acute cerebellitis is associated with the emergence of cerebellar ataxia.

A Destruction Model of the Vascular and Lymphatic Systems in the Emergence of Psychiatric Symptoms.

The lymphatic system is important for antigen presentation and immune surveillance. The lymphatic system in the brain was originally introduced by Giovanni Mascagni in 1787, while the rediscovery of it by Jonathan Kipnis and Kari Kustaa Alitalo now opens the door for a new interpretation of neurological diseases and therapeutic applications. The glymphatic system for the exchanges of cerebrospinal fluid (CSF) and interstitial fluid (ISF) is associated with the blood-brain barrier (BBB), which is involved in the maintenance of immune privilege and homeostasis in the brain.

Synergistic excitability plasticity in cerebellar functioning.

The cerebellum, a universal processor for sensory acquisition and internal models, and its association with synaptic and nonsynaptic plasticity have been envisioned as the biological correlates of learning, perception, and even thought. Indeed, the cerebellum is no longer considered merely as the locus of motor coordination and its learning. Here, we introduce the mechanisms underlying the induction of multiple types of plasticity in cerebellar circuit and give an overview focusing on the plasticity of nonsynaptic intrinsic excitability.

Modification of Synaptic-Input Clustering by Intrinsic Excitability Plasticity on Cerebellar Purkinje Cell Dendrites.

The role of dendrites in the integration of widespread synaptic activity has been studied in experiments and theories (Johnston et al., 1996; Magee, 2007). However, whether the conduction of synaptic currents from dendrites to the soma depends on excitability of those dendritic branches is unclear.

Microglia-Triggered Plasticity of Intrinsic Excitability Modulates Psychomotor Behaviors in Acute Cerebellar Inflammation.

Cerebellar dysfunction relates to various psychiatric disorders, including autism spectrum and depressive disorders. However, the physiological aspect is less advanced. Here, we investigate the immune-triggered hyperexcitability in the cerebellum on a wider scope.

Synaptic Potential and Plasticity of an SK2 Channel Gate Regulate Spike Burst Activity in Cerebellar Purkinje Cells.

Neurons store information and participate in memory engrams as a result of experience-dependent changes in synaptic weights and in membrane excitability. Here, we examine excitatory postsynaptic potential (EPSP) amplitude and neuronal excitability in relation to these two mechanisms of plasticity. We analyze somato-dendritic double-patch recordings from cerebellar Purkinje cells while inducing intrinsic, SK2 channel-dependent plasticity or blocking SK channels with bath application of apamin.

Activity-Dependent Plasticity of Spike Pauses in Cerebellar Purkinje Cells.

The plasticity of intrinsic excitability has been described in several types of neurons, but the significance of non-synaptic mechanisms in brain plasticity and learning remains elusive. Cerebellar Purkinje cells are inhibitory neurons that spontaneously fire action potentials at high frequencies and regulate activity in their target cells in the cerebellar nuclei by generating a characteristic spike burst-pause sequence upon synaptic activation. Using patch-clamp recordings from mouse Purkinje cells, we find that depolarization-triggered intrinsic plasticity enhances spike firing and shortens the duration of spike pauses.

The Spontaneous Ataxic Mouse Mutant Tippy is Characterized by a Novel Purkinje Cell Morphogenesis and Degeneration Phenotype.

This study represents the first detailed analysis of the spontaneous neurological mouse mutant, tippy, uncovering its unique cerebellar phenotype. Homozygous tippy mutant mice are small, ataxic, and die around weaning. Although the cerebellum shows grossly normal foliation, tippy mutants display a complex cerebellar Purkinje cell phenotype consisting of abnormal dendritic branching with immature spine features and patchy, non-apoptotic cell death that is associated with widespread dystrophy and degeneration of the Purkinje cell axons throughout the white matter, the cerebellar nuclei, and the vestibular nuclei.

SK2 channel modulation contributes to compartment-specific dendritic plasticity in cerebellar Purkinje cells.

Small-conductance Ca(2+)-activated K(+) channels (SK channels) modulate excitability and curtail excitatory postsynaptic potentials (EPSPs) in neuronal dendrites. Here, we demonstrate long-lasting plasticity of intrinsic excitability (IE) in dendrites that results from changes in the gain of this regulatory mechanism. Using dendritic patch-clamp recordings from rat cerebellar Purkinje cells, we find that somatic depolarization or parallel fiber (PF) burst stimulation induce long-term amplification of synaptic responses to climbing fiber (CF) or PF stimulation and enhance the amplitude of passively propagated sodium spikes.

Similarity of visual selectivity among clonally related neurons in visual cortex.

Neurons in rodent visual cortex are organized in a salt-and-pepper fashion for orientation selectivity, but it is still unknown how this functional architecture develops. A recent study reported that the progeny of single cortical progenitor cells are preferentially connected in the postnatal cortex. If these neurons acquire similar selectivity through their connections, a salt-and-pepper organization may be generated, because neurons derived from different progenitors are intermingled in rodents.

Purkinje cell NMDA receptors assume a key role in synaptic gain control in the mature cerebellum.

A classic view in cerebellar physiology holds that Purkinje cells do not express functional NMDA receptors and that, therefore, postsynaptic NMDA receptors are not involved in the induction of long-term depression (LTD) at parallel fiber (PF) to Purkinje cell synapses. Recently, it has been demonstrated that functional NMDA receptors are postsynaptically expressed at climbing fiber (CF) to Purkinje cell synapses in mice, reaching full expression levels at ∼2 months after birth. Here, we show that in the mature mouse cerebellum LTD (induced by paired PF and CF activation), but not long-term potentiation (LTP; PF stimulation alone) at PF to Purkinje cell synapses is blocked by bath application of the NMDA receptor antagonist D-2-amino-5-phosphonovaleric acid (D-APV).

Intrinsic plasticity complements long-term potentiation in parallel fiber input gain control in cerebellar Purkinje cells.

Synaptic gain control and information storage in neural networks are mediated by alterations in synaptic transmission, such as in long-term potentiation (LTP). Here, we show using both in vitro and in vivo recordings from the rat cerebellum that tetanization protocols for the induction of LTP at parallel fiber (PF)-to-Purkinje cell synapses can also evoke increases in intrinsic excitability. This form of intrinsic plasticity shares with LTP a requirement for the activation of protein phosphatases 1, 2A, and 2B for induction.

Climbing fiber signaling and cerebellar gain control.

The physiology of climbing fiber signals in cerebellar Purkinje cells has been studied since the early days of electrophysiology. Both the climbing fiber-evoked complex spike and the role of climbing fiber activity in the induction of long-term depression (LTD) at parallel fiber-Purkinje cell synapses have become hallmark features of cerebellar physiology. However, the key role of climbing fiber signaling in cerebellar motor learning has been challenged by recent reports of forms of synaptic and non-synaptic plasticity in the cerebellar cortex that do not involve climbing fiber activity, but might well play a role in cerebellar learning.

Bidirectional plasticity at developing climbing fiber-Purkinje neuron synapses.

Climbing fibers provide one of the two major excitatory inputs to the cerebellar cortex. In an immature animal, several climbing fibers form synapses with one Purkinje neuron. During postnatal development most climbing fiber innervations with a Purkinje neuron are eliminated and only one strong fiber remains.

Enhancement of both long-term depression induction and optokinetic response adaptation in mice lacking delphilin.

In the cerebellum, Delphilin is expressed selectively in Purkinje cells (PCs) and is localized exclusively at parallel fiber (PF) synapses, where it interacts with glutamate receptor (GluR) delta2 that is essential for long-term depression (LTD), motor learning and cerebellar wiring. Delphilin ablation exerted little effect on the synaptic localization of GluRdelta2. There were no detectable abnormalities in cerebellar histology, PC cytology and PC synapse formation in contrast to GluRdelta2 mutant mice.

Enhanced inhibitory synaptic transmission in the cerebellar molecular layer of the GluRdelta2 knock-out mouse.

A novel ionotropic glutamate receptor subunit delta2 (GluRdelta2), which is specifically expressed in cerebellar Purkinje neurons (PNs), is implicated in the induction of long-term depression. Mutant mice deficient in GluRdelta2 (delta2-/-) have abnormal cerebellar synaptic organization and impaired motor coordination and learning. Previous in vivo extracellular recordings indelta2-/- revealed that PN activity distinct from that in wild-type (WT) mice is attributable to enhanced climbing fiber activity.

Oscillating Purkinje neuron activity causing involuntary eye movement in a mutant mouse deficient in the glutamate receptor delta2 subunit.

How failures in regulation of synaptic transmission in the mammalian CNS affect neuronal activity and disturb motor coordination is addressed. The mutant mouse deficient in the glutamate receptor delta2 subunit, specifically expressed in cerebellar Purkinje neurons, has defects in synaptic regulations such as synaptic plasticity, stabilization, and elimination of synaptic connections and shows failures in motor coordination and learning. In this study, the cause of motor discoordination of the delta2 mutant mouse was analyzed by comparing its motor control ability with those of the wild-type mouse and the lurcher mutant mouse, which loses all Purkinje neurons, the sole output neurons in the cerebellar cortex.