Communication defects with astroglia contribute to early impairments in the motor cortex plasticity of SOD1G93A mice.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, involving the selective degeneration of cortical upper synapses in the primary motor cortex (M1). Excitotoxicity in ALS occurs due to an imbalance between excitation and inhibition, closely linked to the loss/gain of astrocytic function. Using the ALS SOD1G93A mice, we investigated the astrocytic contribution for the electrophysiological alterations observed in the M1 of SOD1G93A mice, throughout disease progression. Results showed that astrocytes are involved in synaptic dysfunction observed in presymptomatic SOD1G93A mice, since astrocytic glutamate transport currents are diminished and pharmacological inhibition of astrocytes only impaired long-term potentiation and basal transmission in wild-type mice. Proteomic analysis revealed major differences in neuronal transmission, metabolism, and immune system in upper synapses, confirming early communication deficits between neurons and astroglia. These results provide valuable insights into the early impact of upper synapses in ALS and the lack of supportive functions of cortical astrocytes, highlighting the possibility of manipulating astrocytes to improve synaptic function.

Manganese dioxide nanosheet-containing reactors as antioxidant support for neuroblastoma cells.

Supporting mammalian cells against reactive oxygen species such as hydrogen peroxide (H2O2) is essential. Bottom-up synthetic biology aims to integrate designed artificial units with mammalian cells. Here, we used manganese dioxide nanosheets (MnO2-NSs) as catalytically active entities that have superoxide dismutase-like and catalase-like activities. The integration of these MnO2-NSs into 7 µm reactors was able to assist SH-SY5Y neuroblastoma cells when stressed with H2O2. Complementary, Janus-shaped 800 nm reactors with one hemisphere coated with MnO2-NSs showed directed locomotion in cell media with top speeds up to 50 µm s-1 when exposed to 300 mM H2O2 as a fuel, while reactors homogeneously coated with MnO2-NSs were not able to outperform Brownian motion. These Janus-shaped reactors were able to remove H2O2 from the media, protecting cells cultured in the proximity. This effort advanced the use of bottom-up synthetic biology concepts in neuroscience.

Memory deficits induced by chronic cannabinoid exposure are prevented by adenosine A2AR receptor antagonism.

Patients under cannabis-based therapies are usually chronically exposed to cannabinoids. Chronic treatment with a cannabinoid receptor agonist, WIN 55,212-2, affects brain metabolism and modifies functional connectivity between brain areas responsible for memory and learning. Therefore, it is of uttermost importance to discover strategies to mitigate the negative side-effects of cannabinoid-based therapies. Previously, we showed that a single treatment with the synthetic cannabinoid WIN 55,212-2 disrupts recognition memory, an effect mediated by cannabinoid receptor 1 (CB1R) and cancelled by concomitant administration of adenosine A2A receptor (A2AR) antagonists. We herein evaluate if memory deficits induced by chronic exposure to WIN 55,212-2 can also be reverted by A2AR antagonism, and assessed the synaptic mechanisms that could be involved in that reversal. We show that chronic administration of KW-6002 (istradefylline) (3 mg/kg/28days) reverts memory deficits (evaluated through the Novel Object Recognition Test) induced by chronic cannabinoid exposure (WIN 55,212-2, 1 mg/kg/28 days). Long Term Potentiation (LTP) of synaptic potentials recorded from the CA1 area of the hippocampus was impaired by WIN 55,212-2 (300 nM), an effect partially rescued by the A2AR antagonist, SCH 58261 (100 nM). Chronic administration of KW-6002 or WIN 55,212-2 did not affect A2AR or CB1R binding in the hippocampus and in the prefrontal cortex. These results, showing that A2AR antagonism can still revert memory deficits after chronic administration of a cannabinoid, an effect that involves mitigation of synaptic plasticity impairment, strongly indicate that adenosine A2ARs are appropriate targets to tackle side-effects of putative therapies involving the activation of cannabinoid receptors.

Anxiety Assessment in Pre-clinical Tests and in Clinical Trials: A Critical Review.

The identification of anxious symptoms is crucial to diagnose anxiety disorders, as well as to monitor their treatment in clinical practice and research. The aim of this review is to discuss the different ways of assessing anxiety in clinical research, including clinical trials, and the different kinds of animal behavioral tests used to study anxiety and test the efficacy of anxiolytics in pre-clinical studies. In clinical practice, a categorical classification (such as the Diagnostic and Statistical Manual of Mental Disorders and the International Statistical Classification of Diseases and Related Health Problems) distinguishes the cases of the disease versus non-disease. Some structured and semi-structured interviews can be used to arrive at these diagnoses. On the other hand, anxiety can also be assessed using a dimensional approach, through self-report or hetero-evaluation questionnaires. Regarding the assessment of anxiety in animals, several behavioral tests are described and evaluated, namely the Social Interaction Test, Elevated Plus Maze and Open Field Test. Under a critical view, these two approaches are presented and discussed, in order to improve the outcome of research in this field.

Depression Assessment in Clinical Trials and Pre-clinical Tests: A Critical Review.

Depression is deeply rooted in human behavior. The development of new antidepressants demands the creation of animal models to investigate new drugs, which potentially could work as antidepressants. The aim of this review is to discuss the different ways of assessing depression in clinical research, including clinical trials, and the different animal behavioral tests used to study depression and test the efficacy of antidepressants in pre-clinical studies. In clinical practice, a categorical classification, such as the Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Statistical Classification of Diseases and Related Health Problems (ICD) can be used for diagnosis, through the use of structured and semi-structured interviews. On the other hand, depression can also be assessed using a dimensional approach, through self- or clinicianrated questionnaires. Regarding the assessment of the efficacy of antidepressants in animal models, several tests are routinely used, namely the Forced Swim Test, the Modified Forced Swim Test, the Tail Suspension Test and the Sucrose Preference Test. These tests are informative, providing that the following rules are taken into account: 1) more than one test is used, with coherent results; 2) secondary drug effects, the most frequent being putative changes in motor activity, are taken into account and properly controlled with specific tests run concomitantly; 3) each test and specific protocol is validated with data from at least a gold standard antidepressant drug. We herein briefly discuss the potential and limitations of each of those tests.