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Pathogenic variants in UNC13A underlie a novel neurodevelopmental syndrome, with three subtypes defined by distinct genotypes with varying clinical and functional impacts characterized in cellular and animal models.

The active zone is a brain signaling hub critical for synaptic information transfer and the encoding of behaviors. The authors identify Blobby as an assembly factor required for proper active zone nanoscale protein architecture and memory formation.

The role of macroautophagy in neuronal processes mediating brain maintenance remains enigmatic. Authors show here that impairing autophagy within the major learning related brain center of Drosophila, and not other regions, triggered a form of presynaptic metaplasticity that was invariably connected to the absence of the specific component of aversive olfactory memory, which normally only declines in the course of aging process

Coupling distances between synaptic vesicles and Ca²⁺ channels determine the efficacy of neurotransmission. Böhme et al. find that presynaptic scaffold complexes spatiotemporally control Unc13 isoforms to establish two independent release pathways at subsynaptic active zones: Unc13B defines nascent, loosely coupled synapses whereas Unc13A facilitates release at mature synapses by tight coupling between Ca²⁺ channels and synaptic vesicles.

Synaptic plasticity ensures functionality during perturbations and enables memory formation. Here, the authors describe homeostatic functional and nano-modular active zone modifications for immediate and long-lasting enhancement of neurotransmitter release, and identify Unc13 as a presynaptic molecular target for homeostatic potentiation and learning.

The physical distance between synaptic Ca²⁺ channels and sensors modulates short-term plasticity (STP). Here, the authors show that synaptic release factors Unc13A and Unc13B distinctly couple with Ca²⁺ channels and contribute to the neural decoding of distinct sensory information in Drosophila.

A nanocolumn spans the synaptic cleft between neurons, connecting regions of neurotransmitter molecule release and capture. This discovery informs on mechanisms of synaptic organization and regulation. See Letter p.210

Hofer et al. show that fasting promotes the synthesis of spermidine, which stimulates eIF5A hypusination to induce autophagy and increase lifespan in various species in a conserved manner.

The α₂δ-3 auxiliary subunit of voltage-dependent calcium channels promotes the formation of synaptic boutons in Drosophila neuromuscular junction independently of its role in channel localization.

Synaptic assembly depends on trans-synaptic Neurexin/Neuroligin signalling. Here, Muhammad et al. show that Spinophilin, a pre-synaptic scaffolding protein, interacts with Neurexin, in competition with Syd-1, to regulate the formation and function of synaptic active zones at Drosophilaneuromuscular junctions.

Hunger makes Drosophila larvae move faster to find food. A new study suggests the underlying functional and structural plasticity, showing that hunger increases release of octopamine and branching of motor neurons.

The Drosophila proteins Neuroligin (Nlg1) and Neurexin (Nrx-1) form a trans-synaptic complex that regulates synapse formation at the neuromuscular junction. Here the authors show that Syd-1, also known to regulate active zone formation, interacts with presynaptic Nrx-1, promoting synaptic clustering and immobilization of Nrx-1, and subsequent glutamate receptor incorporation.

Polyamines such as spermidine and putrescine are known to promote autophagy and longevity in fruit flies. Similar to many other organisms, Drosophila also display age-induced memory impairment. Here, Gupta et al. find that a decrease in brain polyamines in aging Drosophila is correlated with age-dependent memory impairment. They also find that polyamines in flies' diet can alleviate this impairment, demonstrating a link between polyamines, autophagy and memory decline.

Although ageing is the most important risk factor for chronic ailments, effective interventions remain rare. Here, the authors identify the flavonoid 4,4’-dimethoxychalcone and demonstrate that it extends lifespan and promotes health in multiple organisms by inducing autophagy.

It is unclear how circuit specificity and function are maintained during organismal growth. In this study, authors show that connectivity between primary nociceptors and their downstream neurons scales with animal size and that Ste20-like kinase Tao acts as a negative regulator of synaptic growth required for maintenance of circuit specificity and connectivity.

Palmitoylation is a post translational modification that regulates GPCR activity. Here the authors show that palmitoylation of 5-HT1AR by the palmitoyltransferase enzyme ZDHHC21 contributes to depression-like behaviour in rodents and might be implicated in major depressive disorder.

Presynaptic homeostatic plasticity adaptively enhances neurotransmitter release following diminished postsynaptic glutamate receptor functionality. Here the authors identify a calcium-independent signaling system where active CaMKII detects a short domain encoded in a glutamate receptor C-tail, which gates retrograde homeostatic communication at a model glutamatergic synapse.

Spermidine, a naturally occurring polyamine, extends the lifespan of mice and is cardioprotective in both aged mice and hypertensive rats. In humans, high dietary spermidine intake is associated with reduced blood pressure and a lower incidence of cardiovascular disease.

Faithful transmission of information within and between neural circuits is underpinned by tight coupling between exocytosis and endocytosis at individual synapses. In this Review, Haucke and colleagues unravel the mechanisms underlying this coupling and explain how it is crucial to robust neurotransmission.

A deep-learning-based approach enables automatic identification of synaptically connected neurons in electron microscopy datasets of the fly brain.

Temporally stochastic STED nanoscopy with electro-optical deflector–based scanning allows ultrafast super-resolution imaging. The method was used to monitor vesicles and viruses moving at ~2 μm/s with no motion blur.

Standard light microscopy techniques cannot resolve the subcellular structures of neurons: axons, presynaptic active zones, postsynaptic densities and dendritic spines. In this review, the authors discuss the use of recently developed super-resolution light microscopic techniques to resolve these structures, and how such techniques can be most effectively used in the future.

Biochemical methods have typically been underused in Drosophila research owing to technical challenges. Here Depner et al. describe a simple CNS fractionation method that yields ∼4 mg of synaptic membrane protein per 1 g of adult fly heads.