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The involvement of astroglia in long-term potentiation (LTP) of synaptic transmission remains controversial. Clamping internal Ca²⁺ in individual astrocytes in the CA1 area of the hippocampus is now shown to block LTP induction at nearby excitatory synapses through an effect on the N-methyl-D-aspartate receptor. This LTP blockade can be reversed by exogenous D-serine, normally released in a Ca²⁺-dependent manner from astrocytes.

Noonan syndrome (NS) is an autosomal dominant genetic disease that is co-morbid with cognitive deficits in a subset of patients. Using mouse models of NS, a study now shows that the synaptic plasticity and memory deficits in mouse models of NS are due primarily to the dysfunction in the MEK-Erk kinase pathways, and pharmacological intervention that alters MEK-Ras function can alleviate physiological and behavioral deficits in the mouse models of NS.

Molecular mechanisms of attention-deficit hyperactivity disorder (ADHD) are not fully understood. Here the authors demonstrate a mutation in CDH2, encoding N-cadherin, that is associated with ADHD, and in a mouse model, delineate molecular electrophysiological characteristics associated with this mutation.

The authors show in an animal model and in a study in patients with dementia with Lewy bodies (DLB) that the drug neflamapimod has potential to treat diseases, such as DLB, associated with loss of neurons that produce the neurotransmitter acetylcholine.

A mouse model containing a GFP-tagged ryanodine receptor 2 (RyR2) has shed light on the precise subcellular localization of hippocampal RyR2 and mechanisms underlying neuronal excitability, learning, and memory.

Two new phosphorylation sites, p-tau₂₆₂ and p-tau₃₅₆, detect the formation of prefibrillar tau aggregates and may serve as early-stage biofluid-based biomarkers of tau neurofibrillary tangle pathology in Alzheimer’s disease.

The role of lactate in the control of microglial function remains poorly investigated. Here, the authors show that lactate promotes lysosomal acidification in microglia, and that mice lacking the lactate transporter MCT4 in these cells display defective brain development and anxiety-like behavior.

The biology of Alzheimer’s disease (AD) remains unknown. We propose AD is a protein connectivity-based dysfunction disorder whereby a switch of the chaperome into epichaperomes rewires proteome-wide connectivity, leading to brain circuitry malfunction that can be corrected by novel therapeutics.

Suprachiasmatic nucleus circadian oscillatory protein (SCOP) is implicated in long-term potentiation. Here, the authors show that μ-calpain-mediated SCOP degradation contributes to long-term potentiation induction, whereas m-calpain-mediated stimulation of SCOP synthesis restricts long-term potentiation.

Cognitive decline in Huntington’s disease (HD) may be due to impaired hippocampal synaptic plasticity. In this study the authors show that AMPA receptor surface diffusion, a key player in synaptic plasticity, is deregulated in multiple HD mouse models as a result of impaired BDNF signalling that underlies the memory deficits, and can be pharmacologically rescued.

Gawrzak et al. show that MSK1 regulates bone metastatic dormancy of ER⁺ breast cancer. MSK1 affects histone modifications at luminal transcription factor promoters to prevent cell differentiation and bone homing.

Auxiliary AMPA receptor subunits can affect gating and surface mobility. Here the authors show that Shisa6 traps AMPA receptors at postsynaptic sites via PSD-95, and keeps them in an activated state in the presence of glutamate, preventing full desensitization and consequently synaptic depression.

Sex-discordant selection causes intralocus sexual conflict as different alleles are favoured in each sex. Here, the authors show that the evolution of body size dimorphism—a trait with strong correlation between males and females—is arrested in Drosophila for many generations due to intralocus sexual conflict.

Surface diffusion of AMPA receptors, from extra-synaptic to synaptic sites at the plasma membrane, is essential for full long-term potentiation in hippocampal neurons and for fear conditioning in living mice.

Chun et al. find that a severe model of reactive astrocytes overproduces hydrogen peroxide, leading to the development of Alzheimer’s disease-like pathologies, including neurodegeneration, tauopathy and memory impairment.

The molecular mechanisms underlying deficits in Down syndrome remain unclear. Here, the authors show that copy number restoration of a chromatin remodeler in trisomic mice is sufficient to rescue epigenomic, physiological and cognitive deficits.

Null GRIN2A human patients display a largely transient seizure burden that resolves with age, which may be attributable to a transient delay in the developmental maturation of parvalbumin-positive interneurons in CA1 as is observed in Grin2a^+/− and Grin2a^-/- mice.

In aged mice, inhibition of prostaglandin E₂ (PGE₂) signalling through its receptor EP2 improves cellular bioenergetics, reduces inflammatory responses and restores hippocampal plasticity to youthful levels, resulting in an improvement in spatial memory and cognition.

The R138Q mutation in the Fragile X Mental Retardation 1 (FMR1) gene has been associated with Fragile X syndrome (FXS). Here, the authors present a Fmr1^R138Q Knock-In mouse model and show that R138Q mutation results in impaired long-term potentiation and socio-cognitive performance in these mice.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by loss of the translational repressor protein FMRP. Now, Joel D. Richter and his colleagues report that knocking down the expression of the translational activator protein CPEB can restore normal levels of translation and rescue behavioral deficits in a mouse model of FXS.

The failure of a broad fringing coral reef to protect the village of Hemani from a tsunami-like wave during Typhoon Haiyan came as a destructive surprise. Here, the authors present results from a phase-resolving wave model and show that the steep reef face facilitated the release of energetic infragravity waves.

The molecular interplay between metabolic and synaptic functions of astrocytes is underexplored. Here, the authors show that astrocyte cannabinoid type-1 receptors integrate lactate and D-serine signaling to promote NMDA receptor-dependent cognition.

Russo et al. show that context-specific place cell assemblies support hippocampal integration of past experiences into future plans during goal-directed behavior and propose a biophysical mechanism behind the formation of goal dependent theta sequences.

Analysis of 1.32 billion records of medication data from England, Scotland and Wales reveals that the COVID-19 pandemic led to substantial declines in dispensing of antihypertensive and lipid-lowering medications, leading to increased risks for future cardiovascular disease.

Local circuit GABAergic inhibitory interneurons regulate almost all aspects of cortical and hippocampal circuitry. In this Review, Overstreet-Wadiche and McBain discuss how neurogliaform cells are emerging as an inhibitory interneuron type with unique cellular and signalling properties that diverge from canonical roles for interneurons.

A technique to ‘lift out’ samples of interest from high-pressure-frozen specimens expands applications of cryo-electron tomography to multicellular organisms and tissue.

Proper brain function depends on the correct assembly of excitatory and inhibitory neurons into neural circuits. Here the authors show that during early postnatal development in mice, NMDAR signaling via activity of long-range synaptic inputs onto neurogliaform cells is required for their appropriate integration into the hippocampal circuitry.

Mutations in the gene encoding Shrm4 are associated with epilepsy and intellectual disability. The authors show that Shrm4 interacts with GABA_Breceptors and regulates tonic inhibition in the hippocampus, and knockdown of Shrm4 in rats leads to anxiety-like behaviour and seizures.

Dopaminergic dysfunction occurs in Alzheimer’s disease (AD). The authors show that in a mouse model of AD, loss of dopaminergic neurons in the ventral tegmental area, but not the substantia nigra, occurs at early pre-plaque stages, and may contribute to impaired cognition and reward processing.

Xu et al. use single-cell transcriptomics to reveal that targeted and systemic partial reprogramming restore the production of neuronal progenitors and new neurons in old mice and show a cell-autonomous effect of reprogramming in cultures of aged neural stem cells.