Alzheimer's disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression.

The synapse has consistently been considered a vulnerable and critical target within Alzheimer's disease, and synapse loss is, to date, one of the main biological correlates of cognitive decline within Alzheimer's disease. This occurs prior to neuronal loss with ample evidence that synaptic dysfunction precedes this, in support of the idea that synaptic failure is a crucial stage within disease pathogenesis. The two main pathological hallmarks of Alzheimer's disease, abnormal aggregates of amyloid or tau proteins, have had demonstrable effects on synaptic physiology in animal and cellular models of Alzheimer's disease.

Gas7 Is a Novel Dendritic Spine Initiation Factor.

Brain stores new information by modifying connections between neurons. When new information is learnt, a group of neurons gets activated and they are connected to each other via synapses. Dendritic spines are protrusions along neuronal dendrites where excitatory synapses are located.

Unexpected phenotypic and molecular changes of combined glucocerebrosidase and acid sphingomyelinase deficiency.

Heterozygous variants in GBA1, encoding glucocerebrosidase (GCase), are the most common genetic risk factor for Parkinson's disease (PD). Moreover, sporadic PD patients also have a substantial reduction of GCase activity. Genetic variants of SMPD1 are also overrepresented in PD cohorts, whereas a reduction of its encoded enzyme (acid sphingomyelinase or ASM) activity is linked to an earlier age of PD onset.

Localized microglia dysregulation impairs central nervous system myelination in development.

Myelination of neuronal axons is a critical aspect of central nervous system development and function. However, the fundamental cellular and molecular mechanisms influencing human developmental myelination and its failure are not fully understood. Here, we used digital spatial transcriptomics of a rare bank of human developing white matter to uncover that a localized dysregulated innate immune response is associated with impeded myelination.

Rapid Testing of Gene Function in Axonal Regeneration After Spinal Cord Injury Using Larval Zebrafish.

Larval zebrafish show axonal regrowth over a complex spinal injury site and recovery of function within days after injury. Here we describe a simple protocol to disrupt gene function in this model using acute injections of highly active synthetic gRNAs to rapidly detect loss-of-function phenotypes without the need for breeding.

A cranial implant for stabilizing whole-cell patch-clamp recordings in behaving rodents.

Background: In vivo patch-clamp recording techniques provide access to the sub- and suprathreshold membrane potential dynamics of individual neurons during behavior. However, maintaining recording stability throughout behavior is a significant challenge, and while methods for head restraint are commonly used to enhance stability, behaviorally related brain movement relative to the skull can severely impact the success rate and duration of whole-cell patch-clamp recordings.

New Method: We developed a low-cost, biocompatible, and 3D-printable cranial implant capable of locally stabilizing brain movement, while permitting equivalent access to the brain when compared to a conventional craniotomy.

Astrocyte Endfeet in Brain Function and Pathology: Open Questions.

Astrocyte endfeet enwrap the entire vascular tree within the central nervous system, where they perform important functions in regulating the blood-brain barrier (BBB), cerebral blood flow, nutrient uptake, and waste clearance. Accordingly, astrocyte endfeet contain specialized organelles and proteins, including local protein translation machinery and highly organized scaffold proteins, which anchor channels, transporters, receptors, and enzymes critical for astrocyte-vascular interactions. Many neurological diseases are characterized by the loss of polarization of specific endfoot proteins, vascular dysregulation, BBB disruption, altered waste clearance, or, in extreme cases, loss of endfoot coverage.

LGI3/2-ADAM23 interactions cluster Kv1 channels in myelinated axons to regulate refractory period.

Along myelinated axons, Shaker-type potassium channels (Kv1) accumulate at high density in the juxtaparanodal region, directly adjacent to the paranodal axon-glia junctions that flank the nodes of Ranvier. However, the mechanisms that control the clustering of Kv1 channels, as well as their function at this site, are still poorly understood. Here we demonstrate that axonal ADAM23 is essential for both the accumulation and stability of juxtaparanodal Kv1 complexes.

16p11.2 deletion accelerates subpallial maturation and increases variability in human iPSC-derived ventral telencephalic organoids.

Inhibitory interneurons regulate cortical circuit activity, and their dysfunction has been implicated in autism spectrum disorder (ASD). 16p11.2 microdeletions are genetically linked to 1% of ASD cases.

The medial entorhinal cortex is necessary for the stimulus control over hippocampal place fields by distal, but not proximal, landmarks.

A fundamental property of place cells in the hippocampus is the anchoring of their firing fields to salient landmarks within the environment. However, it is unclear how such information reaches the hippocampus. In the current experiment, we tested the hypothesis that the stimulus control exerted by distal visual landmarks requires input from the medial entorhinal cortex (MEC).

Execution of new trajectories toward a stable goal without a functional hippocampus.

The hippocampus is a critical component of a mammalian spatial navigation system, with the firing sequences of hippocampal place cells during sleep or immobility constituting a "replay" of an animal's past trajectories. A novel spatial navigation task recently revealed that such "replay" sequences of place fields can also prospectively map onto imminent new paths to a goal that occupies a stable location during each session. It was hypothesized that such "prospective replay" sequences may play a causal role in goal-directed navigation.

Epilepsy-Related CDKL5 Deficiency Slows Synaptic Vesicle Endocytosis in Central Nerve Terminals.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a severe early-onset epileptic encephalopathy resulting mainly from mutations in the X-linked gene. To determine whether loss of presynaptic CDKL5 function contributes to CDD, we examined synaptic vesicle (SV) recycling in primary hippocampal neurons generated from knockout rat males. Using a genetically encoded reporter, we revealed that CDKL5 is selectively required for efficient SV endocytosis.

Abstinence-Induced Nicotine Seeking Relays on a Persistent Hypoglutamatergic State within the Amygdalo-Striatal Neurocircuitry.

Nicotine robustly sustains smoking behavior by acting as a primary reinforcer and by enhancing the incentive salience of the nicotine-associated stimuli. The motivational effects produced by environmental cues associated with nicotine delivery can progressively manifest during abstinence resulting in reinstatement of nicotine seeking. However, how the activity in reward neuronal circuits is transformed during abstinence-induced nicotine seeking is not yet fully understood.

Oxidation modulates LINGO2-induced inactivation of large conductance, Ca-activated potassium channels.

Ca and voltage-activated K (BK) channels are ubiquitous ion channels that can be modulated by accessory proteins, including β, γ, and LINGO1 BK subunits. In this study, we utilized a combination of site-directed mutagenesis, patch clamp electrophysiology, and molecular modeling to investigate if the biophysical properties of BK currents were affected by coexpression of LINGO2 and to examine how they are regulated by oxidation. We demonstrate that LINGO2 is a regulator of BK channels, since its coexpression with BK channels yields rapid inactivating currents, the activation of which is shifted ∼-30 mV compared to that of BKα currents.

Increased basolateral amygdala metabolic activity during flavor familiarization: an experimental study.

Background: Novel flavors elicit a cautious neophobic response which is attenuated as the flavor becomes familiar and safe. The attenuation of neophobia reveals the formation of a safe memory. Previous lesion studies in rats have reported that basolateral amygdala integrity is required for taste neophobia, but not neophobia to flavor, i.

Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus.

Objectives: Motor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART: NCT04302870), an adaptive platform trial.

Long-term plasticity of astrocytic phenotypes and their control by neurons in health and disease.

The brain is a complex organ even when viewed from a cell biological perspective. Neuronal networks are embedded in a dense milieu of diverse and specialised cell types, including several types of vascular, immune, and macroglial cells. To view each cell as a small cog in a highly complex machine is itself an oversimplification.

Identifying foetal forebrain interneurons as a target for monogenic autism risk factors and the polygenic 16p11.2 microdeletion.

Background: Autism spectrum condition or 'autism' is associated with numerous genetic risk factors including the polygenic 16p11.2 microdeletion. The balance between excitatory and inhibitory neurons in the cerebral cortex is hypothesised to be critical for the aetiology of autism making improved understanding of how risk factors impact on the development of these cells an important area of research.

Human adenylyl cyclase 9 is auto-stimulated by its isoform-specific C-terminal domain.

Human transmembrane adenylyl cyclase 9 (AC9) is not regulated by heterotrimeric G proteins. Key to the resistance to stimulation by Gs-coupled receptors (GsRs) is auto-inhibition by the COOH-terminal domain (C2b). The present study investigated the role of the C2b domain in the regulation of cyclic AMP production by AC9 in HEK293FT cells expressing the GloSensor22F cyclic AMP-reporter protein.

Haemorrhage of human foetal cortex associated with SARS-CoV-2 infection.

Maternal viral infection and immune response are known to increase the risk of altered development of the foetal brain. Given the ongoing global pandemic of coronavirus disease 2019 (COVID-19), investigating the impact of SARS-CoV-2 on foetal brain health is of critical importance. Here, we report the presence of SARS-CoV-2 in first and second trimester foetal brain tissue in association with cortical haemorrhages.

Glucocorticoid action in the anterior pituitary gland: Insights from corticotroph physiology.

The anterior pituitary is exposed to ultradian, circadian and stress-induced rhythms of circulating glucocorticoid hormones. Glucocorticoids feedback at the level of the pituitary corticotroph to control their own production through multiple mechanisms. This review highlights key insights from analysis of the dynamics of rapid and early glucocorticoid feedback that reveal both non-genomic and genomic mechanisms mediated by glucocorticoid receptors.

Mathematical modelling of the oxytocin and vasopressin secretory system.

Magnocellular oxytocin and vasopressin neurons of the hypothalamus project to the posterior pituitary where they secrete their peptide hormone signals directly into the bloodstream. Their large anatomically distinct secretory mechanisms provide a uniquely accessible system in which to unite experimental and modelling approaches in the investigation of how input signals and electrophysiological properties of neurons relate to physiological function. We describe how the mechanisms have been translated and assembled into a mathematical model representation that can explain and simulate the complex and highly non-linear stimulus-secretion coupling of these neurons, and how this model has been applied to further understand these systems.

Fast dynamics in the HPA axis: Insight from mathematical and experimental studies.

The activity of the hypothalamic-pituitary-adrenal (HPA) axis is characterised by complex dynamics spanning several timescales. This ranges from slow circadian rhythms in blood hormone concentration to faster ultradian pulses of hormone secretion and even more rapid oscillations in electrical and calcium activity in neuroendocrine cells of the hypothalamus and pituitary gland. Here, we focus on the system's oscillations on the short timescale.