Biomolecules

Epilepsy is a neurological disorder characterized by a long-lasting predisposition to recurrently generate unprovoked seizures. Epilepsy affects over 70 million people worldwide, with approximately one-third suffering from pharmacoresistant seizures. Currently, the clinical antiseizure drugs lack efficacy in preventing epileptogenesis. Adenosine, as an endogenous anticonvulsant, inhibits the development of epilepsy via interaction with the molecular epileptogenic network on several levels: (i) Activation of A1 receptor inhibits glutamate release via presynaptic inhibition, and hyperpolarizes the synaptic potentials in postsynaptic neurons. (ii) The A2A receptor on astrocytes interacts with astroglial glutamate transporter GLT-1, controlling glial glutamate homeostasis. (iii) Activation of the A3 receptor inhibits GABA transporter type 1-mediated GABA uptake. (iv) Adenosine kinase (ADK) is highlighted as a pathological hallmark of epilepsy, with its distinct isoforms driving different mechanisms. The cytoplasmic short isoform (ADK-S) in astrocytes controls extracellular adenosine and receptor-mediated pathways, whereas the nuclear long isoform (ADK-L) in astrocytes and specific neurons regulates epigenetic mechanisms without relying on adenosine receptors. Collectively, this review clarifies the adenosine system’s critical regulatory role in the epileptogenic network, highlights adenosine receptors and ADK isoforms as promising therapeutic targets for epilepsy, and provides a theoretical basis for developing novel disease-modifying therapies for pharmacoresistant epilepsy while laying a foundation for subsequent preclinical and clinical translation.

Early-life adversity (ELA) disrupts brain development and is linked to poor health outcomes across species, including humans and rodents. A growing body of work suggests that impaired attachment to a caregiver—arising from erratic, neglectful, or abusive parenting—mediates a substantial portion of ELA’s long-term effects. Despite the conceptual and clinical appeal of this idea, the neural mechanisms by which ELA disrupts attachment and how altered attachment in turn produces diverse psychiatric and medical sequelae remain incompletely understood. In this review, we synthesize recent randomized controlled trials showing that strengthening caregiver–child attachment can ameliorate a broad range of ELA-related outcomes. We also highlight key animal studies that illuminate the biology of attachment and outline critical priorities for future research.

The second messenger cyclic AMP (cAMP) is very likely involved in phototactic as well as gravitactic behavior of the unicellular flagellate Euglena gracilis. A slight but significant increase in cAMP was observed when cells encountered sub-threshold acceleration (0.16 × g) force after microgravity [µg]. No differences in cAMP levels were found between cells on a clinostat and 1x-controls. This observation is consistent with the ones of earlier studies. Illumination of cells resulted in a significant increase in cellular cAMP levels. After RNAi-mediated knockdown or CRISPR-Cas9 knockout of the photoactivated adenylyl cyclases PACα and/or PACβ in the photoreceptor, light-induced changes in cAMP levels were no longer observed. In parallel, phototactic behavior was abolished, supporting the essential role of photoactivated adenylyl cyclases in phototaxis. Cells spin around their length axis during locomotion (1–2 Hz). In order to generate a signal in the light direction, the cells should be capable of synthesizing and degrading cAMP within 0.5–1 s. The rapid fixation of cells upon transition from dark to light or light to dark revealed that detectable changes in cAMP-levels (increase or decrease) occur within a 100–200 ms time window, which is sufficiently fast to account for the proposed theoretical kinetics of cAMP oscillations.