Tau disengages from the proteosome core complex and neurogranin coincident with enhanced neuronal network excitability.

Tauopathies are characterised by the pathological accumulation of misfolded tau. The emerging view is that toxic tau species drive synaptic dysfunction and potentially tau propagation before measurable neurodegeneration is evident, but the underlying molecular events are not well defined. Human non-mutated 0N4R tau (tau) and P301L mutant 0N4R tau (tau) were expressed in mouse primary cortical neurons using adeno-associated viruses to monitor early molecular changes and synaptic function before the onset of neuronal loss.

Tau isoform-specific enhancement of L-type calcium current and augmentation of afterhyperpolarization in rat hippocampal neurons.

Accumulation of tau is observed in dementia, with human tau displaying 6 isoforms grouped by whether they display either 3 or 4 C-terminal repeat domains (3R or 4R) and exhibit no (0N), one (1N) or two (2N) N terminal repeats. Overexpression of 4R0N-tau in rat hippocampal slices enhanced the L-type calcium (Ca) current-dependent components of the medium and slow afterhyperpolarizations (AHPs). Overexpression of both 4R0N-tau and 4R2N-tau augmented Ca1.

Oral (-)-Epicatechin Inhibits Progressive Tau Pathology in rTg4510 Mice Independent of Direct Actions at GSK3β.

Aggregation of the microtubule-associated protein tau into paired helical filaments (PHFs) and neurofibrillary tangles is a defining characteristic of Alzheimer's Disease. Various plant polyphenols disrupt tau aggregation but display poor bioavailability and low potency, challenging their therapeutic translation. We previously reported that oral administration of the flavonoid (-)-epicatechin (EC) reduced Amyloid-β (Aβ) plaque pathology in APP/PS1 transgenic mice.

EEG microstate complexity for aiding early diagnosis of Alzheimer's disease.

The dynamics of the resting brain exhibit transitions between a small number of discrete networks, each remaining stable for tens to hundreds of milliseconds. These functional microstates are thought to be the building blocks of spontaneous consciousness. The electroencephalogram (EEG) is a useful tool for imaging microstates, and EEG microstate analysis can potentially give insight into altered brain dynamics underpinning cognitive impairment in disorders such as Alzheimer's disease (AD).

The Impact of COVID-19 on Telemedicine Utilization Across Multiple Service Lines in the United States.

The impact of COVID-19 on the U.S. healthcare industry cannot be overstated.

Neurophysiological alterations in the nucleus reuniens of a mouse model of Alzheimer's disease.

Recently, increased neuronal activity in nucleus reuniens (Re) has been linked to hyperexcitability within hippocampal-thalamo-cortical networks in the J20 mouse model of amyloidopathy. Here in vitro whole-cell patch clamp recordings were used to compare old pathology-bearing J20 mice and wild-type controls to examine whether altered intrinsic electrophysiological properties could contribute to the amyloidopathy-associated Re hyperactivity. A greater proportion of Re neurons display hyperpolarized membrane potentials in J20 mice without changes to the incidence or frequency of spontaneous action potentials.

Network substrates of cognitive impairment in Alzheimer's Disease.

Objectives: Functional and structural disconnection of the brain is a prevailing hypothesis to explain cognitive impairment in Alzheimer's Disease (AD). We aim to understand the link between alterations to networks and cognitive impairment using functional connectivity analysis and modelling.

Methods: EEG was recorded from 21 AD patients and 26 controls, mapped into source space using eLORETA, and functional connectivity was calculated using phase locking factor.

β-Adrenergic receptor-dependent modulation of the medium afterhyperpolarization in rat hippocampal CA1 pyramidal neurons.

Action potential firing in hippocampal pyramidal neurons is regulated by generation of an afterhyperpolarization (AHP). Three phases of AHP are recognized, with the fast AHP regulating action potential firing at the onset of a burst and the medium and slow AHPs supressing action potential firing over hundreds of milliseconds and seconds, respectively. Activation of β-adrenergic receptors suppresses the slow AHP by a protein kinase A-dependent pathway.

Control of clustered action potential firing in a mathematical model of entorhinal cortex stellate cells.

The entorhinal cortex is a crucial component of our memory and spatial navigation systems and is one of the first areas to be affected in dementias featuring tau pathology, such as Alzheimer's disease and frontotemporal dementia. Electrophysiological recordings from principle cells of medial entorhinal cortex (layer II stellate cells, mEC-SCs) demonstrate a number of key identifying properties including subthreshold oscillations in the theta (4-12 Hz) range and clustered action potential firing. These single cell properties are correlated with network activity such as grid firing and coupling between theta and gamma rhythms, suggesting they are important for spatial memory.

Aging-Associated Changes to Intrinsic Neuronal Excitability in the Bed Nucleus of the Stria Terminalis Is Cell Type-Dependent.

Intrinsic neuronal excitability has been reported to change during normal aging. The bed nucleus of the stria terminalis (BNST), a limbic forebrain structure, is involved in fear, stress and anxiety; behavioral features that exhibit age-dependent properties. To examine the effect of aging on intrinsic neuronal properties in BNST we compared patch clamp recordings from cohorts of female mice at two ages, 3-4 months (Young) and 29-30 months (Aged) focusing on 2 types of BNST neurons.

Hippocampal neurophysiology is modified by a disease-associated C-terminal fragment of tau protein.

The accumulation of cleaved tau fragments in the brain is associated with several tauopathies. For this reason, we recently developed a transgenic mouse that selectively accumulates a C-Terminal 35 kDa human tau fragment (Tau35). These animals develop progressive motor and spatial memory impairment, paralleled by increased hippocampal glycogen synthase kinase 3β activity.

Minocycline reduces microgliosis and improves subcortical white matter function in a model of cerebral vascular disease.

Chronic cerebral hypoperfusion is a key mechanism associated with white matter disruption in cerebral vascular disease and dementia. In a mouse model relevant to studying cerebral vascular disease, we have previously shown that cerebral hypoperfusion disrupts axon-glial integrity and the distribution of key paranodal and internodal proteins in subcortical myelinated axons. This disruption of myelinated axons is accompanied by increased microglia and cognitive decline.

Forced cell cycle exit and modulation of GABAA, CREB, and GSK3β signaling promote functional maturation of induced pluripotent stem cell-derived neurons.

Although numerous protocols have been developed for differentiation of neurons from a variety of pluripotent stem cells, most have concentrated on being able to specify effectively appropriate neuronal subtypes and few have been designed to enhance or accelerate functional maturity. Of those that have, most employ time courses of functional maturation that are rather protracted, and none have fully characterized all aspects of neuronal function, from spontaneous action potential generation through to postsynaptic receptor maturation. Here, we describe a simple protocol that employs the sequential addition of just two supplemented media that have been formulated to separate the two key phases of neural differentiation, the neurogenesis and synaptogenesis, each characterized by different signaling requirements.

Altered intrinsic excitability of hippocampal CA1 pyramidal neurons in aged PDAPP mice.

Amyloidopathy involves the accumulation of insoluble amyloid β (Aβ) species in the brain's parenchyma and is a key histopathological hallmark of Alzheimer's disease (AD). Work on transgenic mice that overexpress Aβ suggests that elevated Aβ levels in the brain are associated with aberrant epileptiform activity and increased intrinsic excitability (IE) of CA1 hippocampal neurons. In this study we examined if similar changes could be observed in hippocampal CA1 pyramidal neurons from aged PDAPP mice (20-23 month old, Indiana mutation: V717F on APP gene) compared to their age-matched wild-type littermate controls.

Disruption of hippocampal-prefrontal cortex activity by dopamine D2R-dependent LTD of NMDAR transmission.

Functional connectivity between the hippocampus and prefrontal cortex (PFC) is essential for associative recognition memory and working memory. Disruption of hippocampal-PFC synchrony occurs in schizophrenia, which is characterized by hypofunction of NMDA receptor (NMDAR)-mediated transmission. We demonstrate that activity of dopamine D2-like receptors (D2Rs) leads selectively to long-term depression (LTD) of hippocampal-PFC NMDAR-mediated synaptic transmission.

Preferential assembly of heteromeric small conductance calcium-activated potassium channels.

The activation of small conductance calcium-dependent (SK) channels regulates membrane excitability by causing membrane hyperpolarization. Three subtypes (SK1-3) have been cloned, with each subtype expressed within the nervous system. The locations of channel subunits overlap, with SK1 and SK2 subunits often expressed in the same brain region.

Disrupted in schizophrenia 1 and synaptic function in the mammalian central nervous system.

The disrupted in schizophrenia 1 (DISC1) gene is found at the breakpoint of an inherited chromosomal translocation, and segregates with major mental illnesses. Its potential role in central nervous system (CNS) malfunction has triggered intensive investigation of the biological roles played by DISC1, with the hope that this may shed new light on the pathobiology of psychiatric disease. Such work has ranged from investigations of animal behavior to detailed molecular-level analysis of the assemblies that DISC1 forms with other proteins.

Randomized controlled trial: targeted neck cooling in the treatment of the migraine patient.

Cold therapy has long been the number one self-care treatment employed for migraine without aura and the second most common for migraine with aura, yet its mechanism remains elusive. In this study, a mechanism by which this time-tested therapy works is proposed (by cooling the blood passing through intracranial vessels) in an attempt to further elucidate its beneficial effects. The study is designed as a randomized, controlled, crossover clinical trial utilizing an adjustable wrap containing two freezable ice packs targeting the carotid arteries at the neck, where they come close to the skin surface.

Sodium channel cleavage is associated with aberrant neuronal activity and cognitive deficits in a mouse model of Alzheimer's disease.

BACE1 is the rate-limiting enzyme that cleaves amyloid precursor protein (APP) to produce the amyloid β peptides that accumulate in Alzheimer's disease (AD). BACE1, which is elevated in AD patients and APP transgenic mice, also cleaves the β2-subunit of voltage-gated sodium channels (Navβ2). Although increased BACE1 levels are associated with Navβ2 cleavage in AD patients, whether Navβ2 cleavage occurs in APP mice had not yet been examined.

Whole-cell patch-clamp recording of voltage-sensitive Ca²⁺ channel currents in single cells: heterologous expression systems and neurones.

Voltage-sensitive calcium channels (VSCC) are vital to the normal physiology of many cell types, including neurones, skeletal, cardiac and smooth muscle cells, heart pacemaker tissue and endocrine cells. Whole-cell recording is a functional electrophysiological assay that allows real-time measurement of macroscopic VSCC activity at the level of single cells. Using this technique, it is possible to probe the molecular physiology, pharmacology, and biophysics of VSCC proteins with a level of precision rarely surpassed in cell biological studies.

Age-related changes to Na+ channel gating contribute to modified intrinsic neuronal excitability.

Cognitive decline occurs during normal aging and is likely to be reflected in the neurophysiological properties of neural circuits with key roles in cognition, for example those of the limbic system. To identify candidate neurophysiological changes we used patch clamp methods to compare the intrinsic excitability properties of hippocampal CA1 pyramidal neurons of mature adult (8-10 month) and aged (22-24 month) mice. Resting potential, input resistance, and the "sag" observed on injection of hyperpolarizing current were not age-dependent.

Voltage- and Temperature-Dependent Allosteric Modulation of α7 Nicotinic Receptors by PNU120596.

Alpha7 nicotinic acetylcholine receptors (α7 nAChR) are widely distributed throughout the central nervous system and are found at particularly high levels in the hippocampus and cortex. Several lines of evidence indicate that pharmacological enhancement of α7 nAChRs function could be a potential therapeutic route to alleviate disease-related cognitive deficits. A recent pharmacological approach adopted to increase α7 nAChR activity has been to identify selective positive allosteric modulators (PAMs).

Profiles of SUMO and ubiquitin conjugation in an Alzheimer's disease model.

Alzheimer's disease (AD) is a major cause of disability in the elderly. The formation of senile plaques and neurofibrillary tangles are the main hallmarks of the disorder, whereas synaptic loss best correlates to the progressive cognitive decline. Interestingly, some of the proteins involved in these pathophysiological processes have been reported to be subject to posttranslational modification by ubiquitin and/or the small ubiquitin-like modifier (SUMO).