Adenosine receptors are the on-and-off switch of astrocytic cannabinoid type 1 (CB1) receptor effect upon synaptic plasticity in the medial prefrontal cortex.

The medial prefrontal cortex (mPFC) is involved in cognitive functions such as working memory. Astrocytic cannabinoid type 1 receptor (CB1R) induces cytosolic calcium (Ca2+) concentration changes with an impact on neuronal function. mPFC astrocytes also express adenosine A1 and A2A receptors (A1R, A2AR), being unknown the crosstalk between CB1R and adenosine receptors in these cells. We show here that a further level of regulation of astrocyte Ca2+ signaling occurs through CB1R-A2AR or CB1R-A1R heteromers that ultimately impact mPFC synaptic plasticity. CB1R-mediated Ca2+ transients increased and decreased when A1R and A2AR were activated, respectively, unveiling adenosine receptors as modulators of astrocytic CB1R. CB1R activation leads to an enhancement of long-term potentiation (LTP) in the mPFC, under the control of A1R but not of A2AR. Notably, in IP3R2KO mice, that do not show astrocytic Ca2+ level elevations, CB1R activation decreases LTP, which is not modified by A1R or A2AR. The present work suggests that CB1R has a homeostatic role on mPFC LTP, under the control of A1R, probably due to physical crosstalk between these receptors in astrocytes that ultimately alters CB1R Ca2+ signaling.

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.

Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases.

Excitotoxicity is a phenomenon that describes the toxic actions of excitatory neurotransmitters, primarily glutamate, where the exacerbated or prolonged activation of glutamate receptors starts a cascade of neurotoxicity that ultimately leads to the loss of neuronal function and cell death. In this process, the shift between normal physiological function and excitotoxicity is largely controlled by astrocytes since they can control the levels of glutamate on the synaptic cleft. This control is achieved through glutamate clearance from the synaptic cleft and its underlying recycling through the glutamate-glutamine cycle. The molecular mechanism that triggers excitotoxicity involves alterations in glutamate and calcium metabolism, dysfunction of glutamate transporters, and malfunction of glutamate receptors, particularly N-methyl-D-aspartic acid receptors (NMDAR). On the other hand, excitotoxicity can be regarded as a consequence of other cellular phenomena, such as mitochondrial dysfunction, physical neuronal damage, and oxidative stress. Regardless, it is known that the excessive activation of NMDAR results in the sustained influx of calcium into neurons and leads to several deleterious consequences, including mitochondrial dysfunction, reactive oxygen species (ROS) overproduction, impairment of calcium buffering, the release of pro-apoptotic factors, among others, that inevitably contribute to neuronal loss. A large body of evidence implicates NMDAR-mediated excitotoxicity as a central mechanism in the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and epilepsy. In this review article, we explore different causes and consequences of excitotoxicity, discuss the involvement of NMDAR-mediated excitotoxicity and its downstream effects on several neurodegenerative disorders, and identify possible strategies to study new aspects of these diseases that may lead to the discovery of new therapeutic approaches. With the understanding that excitotoxicity is a common denominator in neurodegenerative diseases and other disorders, a new perspective on therapy can be considered, where the targets are not specific symptoms, but the underlying cellular phenomena of the disease.

Controlling deformations of gel-based composites by electromagnetic signals within the GHz frequency range.

Using theoretical and computational modeling, we focus on dynamics of gels filled with uniformly dispersed ferromagnetic nanoparticles subjected to electromagnetic (EM) irradiation within the GHz frequency range. As a polymer matrix, we choose poly(N-isopropylacrylamide) gel, which has a low critical solution temperature and shrinks upon heating. When these composites are irradiated with a frequency close to the Ferro-Magnetic Resonance (FMR) frequency, the heating rate increases dramatically. The energy dissipation of EM signals within the magnetic nanoparticles results in the heating of the gel matrix. We show that the EM signal causes volume phase transitions, leading to large deformations of the sample for a range of system parameters. We propose a model that accounts for the dynamic coupling between the elastodynamics of the polymer gel and the FMR heating of magnetic nanoparticles. This coupling is nonlinear: when the system is heated, the gel shrinks during the volume phase transition, and the particle concentration increases, which in turn results in an increase of the heating rates as long as the concentration of nanoparticles does not exceed a critical value. We show that the system exhibits high selectivity to the frequency of the incident EM signal and can result in a large mechanical feedback in response to a small change in the applied signal. These results suggest the design of a new class of soft active gel-based materials remotely controlled by low power EM signals within the GHz frequency range.