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Astrocytes play crucial roles in brain homeostasis and are regulatory elements of neuronal and synaptic physiology. Astrocytic alterations have been found in Major Depressive Disorder (MDD) patients; however, the consequences of astrocyte Ca 2+ signaling in MDD are poorly understood. Here, we found that corticosterone-treated juvenile mice (Cort-mice) showed altered astrocytic Ca 2+ dynamics in mPFC both in resting conditions and during social interactions, in line with altered mice behavior. Additionally, Cort-mice displayed reduced serotonin (5-HT)-mediated Ca 2+ signaling in mPFC astrocytes, and aberrant 5-HT-driven synaptic plasticity in layer 2/3 mPFC neurons. Downregulation of astrocyte Ca 2+ signaling in naïve animals mimicked the synaptic deficits found in Cort-mice. Remarkably, boosting astrocyte Ca 2+ signaling with Gq-DREADDS restored to the control levels mood and cognitive abilities in Cort-mice. This study highlights the important role of astrocyte Ca 2+ signaling for homeostatic control of brain circuits and behavior, but also reveals its potential therapeutic value for depressive-like states., (© 2023. The Author(s).)

E2F4 was initially described as a transcription factor with a key function in the regulation of cell quiescence. Nevertheless, a number of recent studies have established that E2F4 can also play a relevant role in cell and tissue homeostasis, as well as tissue regeneration. For these non-canonical functions, E2F4 can also act in the cytoplasm, where it is able to interact with many homeostatic and synaptic regulators. Since E2F4 is expressed in the nervous system, it may fulfill a crucial role in brain function and homeostasis, being a promising multifactorial target for neurodegenerative diseases and brain aging. The regulation of E2F4 is complex, as it can be chemically modified through acetylation, from which we present evidence in the brain, as well as methylation, and phosphorylation. The phosphorylation of E2F4 within a conserved threonine motif induces cell cycle re-entry in neurons, while a dominant negative form of E2F4 (E2F4DN), in which the conserved threonines have been substituted by alanines, has been shown to act as a multifactorial therapeutic agent for Alzheimer's disease (AD). We generated transgenic mice neuronally expressing E2F4DN. We have recently shown using this mouse strain that expression of E2F4DN in 5xFAD mice, a known murine model of AD, improved cognitive function, reduced neuronal tetraploidization, and induced a transcriptional program consistent with modulation of amyloid-β (Aβ) peptide proteostasis and brain homeostasis recovery. 5xFAD/E2F4DN mice also showed reduced microgliosis and astrogliosis in both the cerebral cortex and hippocampus at 3-6 months of age. Here, we analyzed the immune response in 1 year-old 5xFAD/E2F4DN mice, concluding that reduced microgliosis and astrogliosis is maintained at this late stage. In addition, the expression of E2F4DN also reduced age-associated microgliosis in wild-type mice, thus stressing its role as a brain homeostatic agent. We conclude that E2F4DN transgenic mice represent a promising tool for the evaluation of E2F4 as a therapeutic target in neuropathology and brain aging.

GABA interneurons play a critical role in higher brain functions. Astrocytic glial cells interact with synapses throughout the whole brain and are recognized as regulatory elements of excitatory synaptic transmission. However, it is largely unknown how GABAergic interneurons and astrocytes interact and contribute to stable performance of complex behaviors. Here, we found that genetic ablation of GABA B receptors in medial prefrontal cortex astrocytes altered low-gamma oscillations and firing properties of cortical neurons, which affected goal-directed behaviors. Remarkably, working memory deficits were restored by optogenetic stimulation of astrocytes with melanopsin. Furthermore, melanopsin-activated astrocytes in wild-type mice enhanced the firing rate of cortical neurons and gamma oscillations, as well as improved cognition. Therefore, our work identifies astrocytes as a hub for controlling inhibition in cortical circuits, providing a novel pathway for the behaviorally relevant midrange time-scale regulation of cortical information processing and consistent goal-directed behaviors.

Phosphatase and tensin homolog on chromosome 10 (PTEN) is a tumor suppressor and autism-associated gene that exerts an important influence over neuronal structure and function during development. In addition, it participates in synaptic plasticity processes in adulthood. As an attempt to assess synaptic and developmental mechanisms by which PTEN can modulate cognitive function, we studied the consequences of 2 different genetic manipulations in mice: presence of additional genomic copies of the Pten gene (Ptentg) and knock-in of a truncated Pten gene lacking its PDZ motif (Pten-ΔPDZ), which is required for interaction with synaptic proteins. Ptentg mice exhibit substantial microcephaly, structural hypoconnectivity, enhanced synaptic depression at cortico-amygdala synapses, reduced anxiety, and intensified social interactions. In contrast, Pten-ΔPDZ mice have a much more restricted phenotype, with normal synaptic connectivity, but impaired synaptic depression at cortico-amygdala synapses and virtually abolished social interactions. These results suggest that synaptic actions of PTEN in the amygdala contribute to specific behavioral traits, such as sociability. Also, PTEN appears to function as a bidirectional rheostat in the amygdala: reduction in PTEN activity at synapses is associated with less sociability, whereas enhanced PTEN activity accompanies hypersocial behavior., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The expression of certain genes involved in response to oxidative stress is likely related to aging-related outcomes, such as frailty in old age. Given nutrition's substantial impact in aging and age-related diseases, one of its mechanisms might be through influencing gene expression., Objective: This study aimed to investigate the association between nutrition and the expression of 15 genes related to cellular response to stress in older community-dwelling individuals., Methods: A nested case-control study of 350 participants (mean ± SEM age: 76.5 ± 6.9 y, 42.9% men, 22% frail according to Fried's criteria) was selected from the Toledo Study for Healthy Aging. Blood-derived RNA was retro-transcribed into complementary DNA. TaqMan Arrays were used for determining gene expression. The Mini Nutritional Assessment (MNA) and the PREDIMED (PREvención con DIeta MEDiterranea) questionnaire measured nutritional status and adherence to the Mediterranean diet (MD), respectively. Data were reweighed so that inference from linear and logistic regression models applied to the original sampling population., Results: Higher MNA scores were associated with higher expressions of the gene coding for sirtuin-1 (SIRT1), regardless of age, sex, and Charlson comorbidity score (P = 0.04) and even after adjusting for frailty status (P = 0.016) and level of adherence to the MD (P = 0.04). Malnutrition risk and SIRT1 gene expression were inversely associated (P = 0.0045) independently of frailty status (P = 0.0045) and level of adherence to the MD (P = 0.0075)., Conclusions: In older individuals, improvement in nutritional status is positively associated with SIRT1 gene expression independently of frailty status or adherence to the MD. These findings may provide potential biomarkers and targets for health interventions among the elderly.

Dyshomeostasis of amyloid-β peptide (Aβ) is responsible for synaptic malfunctions leading to cognitive deficits ranging from mild impairment to full-blown dementia in Alzheimer's disease. Aβ appears to skew synaptic plasticity events toward depression. We found that inhibition of PTEN, a lipid phosphatase that is essential to long-term depression, rescued normal synaptic function and cognition in cellular and animal models of Alzheimer's disease. Conversely, transgenic mice that overexpressed PTEN displayed synaptic depression that mimicked and occluded Aβ-induced depression. Mechanistically, Aβ triggers a PDZ-dependent recruitment of PTEN into the postsynaptic compartment. Using a PTEN knock-in mouse lacking the PDZ motif, and a cell-permeable interfering peptide, we found that this mechanism is crucial for Aβ-induced synaptic toxicity and cognitive dysfunction. Our results provide fundamental information on the molecular mechanisms of Aβ-induced synaptic malfunction and may offer new mechanism-based therapeutic targets to counteract downstream Aβ signaling.

Cell adhesion molecules and downstream growth factor-dependent signaling are critical for brain development and synaptic plasticity, and they have been linked to cognitive function in adult animals. We have previously developed a mimetic peptide (FGL) from the neural cell adhesion molecule (NCAM) that enhances spatial learning and memory in rats. We have now investigated the cellular and molecular basis of this cognitive enhancement, using biochemical, morphological, electrophysiological, and behavioral analyses. We have found that FGL triggers a long-lasting enhancement of synaptic transmission in hippocampal CA1 neurons. This effect is mediated by a facilitated synaptic delivery of AMPA receptors, which is accompanied by enhanced NMDA receptor-dependent long-term potentiation (LTP). Both LTP and cognitive enhancement are mediated by an initial PKC activation, which is followed by persistent CaMKII activation. These results provide a mechanistic link between facilitation of AMPA receptor synaptic delivery and improved hippocampal-dependent learning, induced by a pharmacological cognitive enhancer., Competing Interests: I have read the journal's policy and have the following conflicts. E. Bock and V. Berezin are shareholders of ENKAM Pharmaceuticals A/S, which owns the FGL peptide (less than 0.01% shares each). Nevertheless, this does not alter our adherence to all the PLoS Biology policies on sharing data and materials.