Cytoprotective Small Compound M109S Attenuated Retinal Ganglion Cell Degeneration Induced by Optic Nerve Crush in Mice.

BAX plays an essential role in retinal ganglion cell (RGC) death induced by optic nerve injury. Recently, we developed M109S, an orally bioactive and cytoprotective small compound (CPSC) that inhibits BAX-mediated cell death. We examined whether M109S can protect RGC from optic nerve crush (ONC)-induced apoptosis.

Atypical electrophysiological and behavioral responses to diazepam in a leading mouse model of Down syndrome.

Mounting evidence implicates dysfunctional GABAR-mediated neurotransmission as one of the underlying causes of learning and memory deficits observed in the Ts65Dn mouse model of Down syndrome (DS). The specific origin and nature of such dysfunction is still under investigation, which is an issue with practical consequences to preclinical and clinical research, as well as to the care of individuals with DS and anxiety disorder or those experiencing seizures in emergency room settings. Here, we investigated the effects of GABAR positive allosteric modulation (PAM) by diazepam on brain activity, synaptic plasticity, and behavior in Ts65Dn mice.

Microcapillary Reactors via Coaxial Electrospinning: Fabrication of Small Poly(Acrylic Acid) Gel Beads and Thin Threads of Biological Cell Dimensions.

Poly(acrylic acid) (PAA) bulk gels and threads, typically derived via free-radical polymerization, are of interest as anionic polyelectrolyte mimics of cellular cytosol and as models for early protocells. The thread dimensions have been limited by the diameters of readily-available glass or plastic capillaries, and threads with diameters of less than 50 µm have been difficult to achieve. Here, we report a useful approach for achieving crosslinked, partially neutralized PAA, namely poly(acrylate), gel threads with diameters of a few microns when dry.

Quantitative Analysis of Retinal Structure and Function in Two Chromosomally Altered Mouse Models of Down Syndrome.

Purpose: Ophthalmic disorders are among the most prevalent Down syndrome (DS) comorbidities. Therefore, when studying mouse models of DS, ignoring how vision is affected can lead to misinterpretation of results from assessments dependent on the integrity of the visual system. Here, we used imaging and electroretinography (ERG) to study eye structure and function in two important mouse models of DS: Ts65Dn and Dp(16)1Yey/+.

Pharmacological Modulation of Three Modalities of CA1 Hippocampal Long-Term Potentiation in the Ts65Dn Mouse Model of Down Syndrome.

The Ts65Dn mouse is the most studied animal model of Down syndrome. Past research has shown a significant reduction in CA1 hippocampal long-term potentiation (LTP) induced by theta-burst stimulation (TBS), but not in LTP induced by high-frequency stimulation (HFS), in slices from Ts65Dn mice compared with euploid mouse-derived slices. Additionally, therapeutically relevant doses of the drug memantine were shown to rescue learning and memory deficits in Ts65Dn mice.

Generation of Integration-Free Induced Pluripotent Stem Cells from Urine-Derived Cells Isolated from Individuals with Down Syndrome.

Down syndrome (DS) is a genetic disorder caused by trisomy 21 (T21). Over the past two decades, the use of mouse models has led to significant advances in the understanding of mechanisms underlying various phenotypic features and comorbidities secondary to T21 and even informed the design of clinical trials aimed at enhancing the cognitive abilities of persons with DS. In spite of its success, this approach has been plagued by all the typical limitations of rodent modeling of human disorders and diseases.

Soluble prion protein and its N-terminal fragment prevent impairment of synaptic plasticity by Aβ oligomers: Implications for novel therapeutic strategy in Alzheimer's disease.

The pathogenic process in Alzheimer's disease (AD) appears to be closely linked to the neurotoxic action of amyloid-β (Aβ) oligomers. Recent studies have shown that these oligomers bind with high affinity to the membrane-anchored cellular prion protein (PrP(C)). It has also been proposed that this binding might mediate some of the toxic effects of the oligomers.

Prospects for improving brain function in individuals with Down syndrome.

Down syndrome (DS), which results from an extra copy of chromosome 21 (trisomy 21), is the most common genetically defined cause of intellectual disability. Although no pharmacotherapy aimed at counteracting the cognitive and adaptive deficits associated with this genetic disorder has been approved at present, there have been several new promising studies on pharmacological agents capable of rescuing learning/memory deficits seen in mouse models of DS. Here, we will review the available mouse models for DS and provide a comprehensive, albeit not exhaustive review of the following preclinical research strategies: (1) SOD1 and antioxidant agents; (2) APP and γ-secretase inhibitors; (3) DYRK1A and the polyphenol epigallocatechin gallate (EGCG); (4) GIRK2 and fluoxetine; (5) adrenergic receptor agonists; (6) modulation of GABAA and GABAB receptors; (7) agonism of the hedgehog signaling pathway; (8) nerve growth factor (NGF) and other neurotrophic factors; (9) anticholinesterase (AChE) agents; and (10) antagonism of NMDA receptors.

Human sensory neurons derived from induced pluripotent stem cells support varicella-zoster virus infection.

After primary infection, varicella-zoster virus (VZV) establishes latency in neurons of the dorsal root and trigeminal ganglia. Many questions concerning the mechanism of VZV pathogenesis remain unanswered, due in part to the strict host tropism and inconsistent availability of human tissue obtained from autopsies and abortions. The recent development of induced pluripotent stem (iPS) cells provides great potential for the study of many diseases.

Exaggerated NMDA mediated LTD in a mouse model of Down syndrome and pharmacological rescuing by memantine.

The Ts65Dn mouse is the best-studied animal model for Down syndrome. In the experiments described here, NMDA-mediated or mGluR-mediated LTD was induced in the CA1 region of hippocampal slices from Ts65Dn and euploid control mice by bath application of 20 µM NMDA for 3 min and 50 µM DHPG for 5 min, respectively. We found that Ts65Dn mice display exaggerated NMDA-induced, but not mGluR-induced, LTD in the CA1 region of the hippocampus compared with euploid control animals.

The mouse model of Down syndrome Ts65Dn presents visual deficits as assessed by pattern visual evoked potentials.

Purpose: The Ts65Dn mouse is the most complete widely available animal model of Down syndrome (DS). Quantitative information was generated about visual function in the Ts65Dn mouse by investigating their visual capabilities by means of electroretinography (ERG) and patterned visual evoked potentials (pVEPs).

Methods: pVEPs were recorded directly from specific regions of the binocular visual cortex of anesthetized mice in response to horizontal sinusoidal gratings of different spatial frequency, contrast, and luminance generated by a specialized video card and presented on a 21-in.

Sustained hippocampal IL-1beta overexpression impairs contextual and spatial memory in transgenic mice.

Neuroinflammatory conditions such as traumatic brain injury, aging, Alzheimer's disease, and Down syndrome are often associated with cognitive dysfunction. Much research has targeted inflammation as a causative mediator of these deficits, although the diverse cellular and molecular changes that accompany these disorders obscure the link between inflammation and impaired memory. Therefore, we used a transgenic mouse model with a dormant human IL-1beta excisional activation transgene to direct overexpression of IL-1beta with temporal and regional control.

5-HT(1A) Receptor Null Mutant Mice Responding Under a Differential-Reinforcement-of-Low-Rate 72-Second Schedule of Reinforcement.

Over the last two decades, our ever-increasing ability to manipulate the mouse genome has resulted in a variety of genetically defined mouse models of depression and other psychiatric and neurological disorders. However, it is still the case that some relevant rodent models for depression and antidepressant action have been validated experimentally in rats only and not in mice. An important example of such models is the operant model of antidepressant action known as differential-reinforcement-of-low-rates 72-second (DRL 72-s).

Acute injections of the NMDA receptor antagonist memantine rescue performance deficits of the Ts65Dn mouse model of Down syndrome on a fear conditioning test.

Individuals with Down syndrome (DS) and Ts65Dn mice (a major animal model of DS) carry an extra copy of the DSCR1 (Down Syndrome Critical Region 1) gene, which encodes for a protein that inhibits calcineurin. Calcineurin itself has been shown to modulate N-methyl-D-aspartate (NMDA) receptor (NMDAR) activation kinetics by decreasing channel mean open time and opening probability. We hypothesize that the overexpression of DSCR1 in persons with DS and Ts65Dn mice would inhibit normal calcineurin activity and produce pathological increases in NMDAR mean open time and opening probability.

Hypothermic responses to 8-OH-DPAT in the Ts65Dn mouse model of Down syndrome.

Recently, we have demonstrated that potassium channels containing G-protein-activated potassium channel 2 (GIRK2) subunits play a significant role in hypothermia induced by several neurotransmitter receptor agonists, including the serotonin (5-HT)1A/5-HT7 receptor agonist 8-OH-DPAT [R-(+)-8-hydroxy-2-(di-n-propylamino) tetralin]. The GIRK2 gene is located in human chromosome 21 (its mouse ortholog, Girk2, is in mouse chromosome 16). Down syndrome is produced by the trisomy of chromosome 21.

G-protein-gated potassium (GIRK) channels containing the GIRK2 subunit are control hubs for pharmacologically induced hypothermic responses.

Hypothermic responses of rodents to the peripheral or intraventricular injection of many individual neurotransmitter receptor agonists have been well documented. Because many hypothermia-inducing agonists are also known to activate G-protein-gated potassium (GIRK) channels, we investigated the hypothermic response to several of these agents on Girk2 null mutant mice. Core body temperatures were measured through radiotelemetry, and animals were maintained in special temperature-regulated chambers to ensure the accuracy of the measurements.