One of the most intriguing features of the brain is its ability to be malleable, allowing it to adapt continually to changes in the environment. Specific neuronal activity patterns drive long‐lasting increases or decreases in the strength of synaptic connections, referred to as long‐term potentiation and long‐term depression, respectively. Such phenomena have been described in a variety of model organisms, which are used to study molecular, structural, and functional aspects of synaptic plasticity. This review originated from the first International Society for Neurochemistry (ISN) and Journal of Neurochemistry (JNC) Flagship School held in Alpbach, Austria (Sep 2016), and will use its curriculum and discussions as a framework to review some of the current knowledge in the field of synaptic plasticity. First, we describe the role of plasticity during development and the persistent changes of neural circuitry occurring when sensory input is altered during critical developmental stages. We then outline the signaling cascades resulting in the synthesis of new plasticity‐related proteins, which ultimately enable sustained changes in synaptic strength. Going beyond the traditional understanding of synaptic plasticity conceptualized by long‐term potentiation and long‐term depression, we discuss system‐wide modifications and recently unveiled homeostatic mechanisms, such as synaptic scaling. Finally, we describe the neural circuits and synaptic plasticity mechanisms driving associative memory and motor learning. Evidence summarized in this review provides a current view of synaptic plasticity in its various forms, offers new insights into the underlying mechanisms and behavioral relevance, and provides directions for future research in the field of synaptic plasticity. image Read the Editorial Highlight for this article on page 788.Cover Image for this issue: doi: 10.1111/jnc.13815.

Nullomers are the shortest strings of absent amino acid (aa) sequences in a species or group of species. Primes are those nullomers that have not been detected in the genome of any species. 9S1R is a 5-aa peptide prime sequence attached to 5-arginine aa, used to treat triple negative breast cancer (TNBC) in an in vivo mouse model. This unique peptide, administered with a trehalose carrier (9S1R-NulloPT), offers enhanced solubility and exhibits distinct anti-cancer effects against TNBC. In our study, we investigated the effect of 9S1R-NulloPT on tumor growth, metabolism, metastatic burden, tumor immune-microenvironment (TME), and transcriptome of aggressive mouse TNBC tumors. Notably, treated mice had smaller tumors in the initial phase of the treatment, as compared to untreated control, and diminished in vivo and ex vivo bioluminescence at later-stages - indicative of metabolically quiescent, dying tumors. The treatment also caused changes in TME with increased infiltration of immune cells and altered tumor transcriptome, with 365 upregulated genes and 710 downregulated genes. Consistent with in vitro data, downregulated genes were enriched in cellular metabolic processes (179), specifically mitochondrial TCA cycle/oxidative phosphorylation (44), and translation machinery/ribosome biogenesis (45). The upregulated genes were associated with the developmental (13), ECM organization (12) and focal adhesion pathways (7). In conclusion, our study demonstrates that 9S1R-NulloPT effectively reduced tumor growth during its initial phase, altering the TME and tumor transcriptome. The treatment induced mitochondrial pathology which led to a metabolic deceleration in tumors, aligning with in vitro observations.

Systemic mitochondrial dysfunction, dopamine loss, sustained structural changes in the basal ganglia including reduced tyrosine hydroxylase, and altered gait- these effects observed in space-flown animals and astronauts mirrors Parkinson’s disease (PD). Evidence of mitochondrial changes in space-flown human cells, examined through the lens of PD, suggests that spaceflight-induced PD-like molecular changes are important to monitor during deep space exploration. These changes, may potentially elevate the risk of PD in astronauts.

This review article focuses on current and emerging therapeutics for CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy). CADASIL is a genetic vascular disease characterized by mutations in the NOTCH3 gene, which disrupts small cerebral blood vessels and leads to strokes and neurological decline. This article discusses how NOTCH3 mutations alter cysteine residues in the protein's extracellular domain, contributing to the disease's underlying pathology. It highlights promising disease-modifying approaches such as gene editing, cell therapies, and immune-based strategies. Ongoing clinical trials, recent patents, diagnostic methods, and molecular mechanisms related to CADASIL and its prospective treatments are also described. Finally, the article highlights the translational potential of current research and experimental models, aiming to provide a comprehensive overview of promising therapies to improve long-term outcomes. Graphical abstract