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It is not fully understood if the probability of synaptic vesicle release is homogenous or varies between individual boutons. Here the authors perform optical quantal analyses of individual Schaffer collateral synapses, showing that multivesicular release enables a tenfold increase in glutamate output and that the vesicular release probability is not uniform between synapses.

The authors selectively target a population of hippocampal interneurons called oriens lacunosum-moleculare (OLM) cells with the Chrna2 promoter to demonstrate that these cells differentially modulate CA3 and entorhinal inputs to CA1 pyramidal cells. They also find that OLM cells receive fast cholinergic inputs, providing a plausible explanation for how nicotine affects hippocampal plasticity.

Understanding the brain’s diversity requires spatially resolved maps of transcripts and proteins. Here, the authors construct an integrated molecular atlas of the mouse hippocampus revealing local enrichment profiles and compartmental organization.

Calcium imaging has been used to visualize the activity of individual synapses, but cannot be scaled up to monitor thousands of synapses in tissue. Here, the authors present genetic tools that can be photoconverted from green to red to create a map of active synapses.

Impairments in memory flexibility are associated with neuropsychiatric disorders such as PTSD and autism. Here, the authors report that the transcriptional repressor Wilm's Tumor 1 regulates synaptic plasticity leading to weakening of memory strength and enabling memory flexibility.

Astrocytes provide essential support for and modulate synaptic transmission between neurons. Here the authors show that non-channel functions of connexin 30, a gap-junction subunit, control the synaptic coverage of astroglial processes and regulate glutamate clearance, synaptic strength and memory function.

Astrocytes monitor and regulate both excitatory and inhibitory synaptic activity. Here, the authors identify a novel form of neuronal-glia communication, by which astrocytes detect rises in GABA via the GABA transporter GAT-3; this results in adenosine release that acts presynaptically to inhibit neural glutamatergic signalling.

The authors find that serotonin, acting through 5-HT_1B receptors, potentiates temporoammonic pathway–to–CA1 cell excitatory synapses in the hippocampus. Chronic unpredictable stress increased the magnitude of this potentiation, and chronic treatment with fluoxetine restored normal levels of this potentiation, a process that was required for the behavioral effects of chronic fluoxetine.

β-amyloid (Aβ)-dependent neuronal hyperactivity is an early marker of Alzheimer’s Disease (AD). Here, the authors report that scavenging Aβ monomers by an Aβ-binding anticalin protein blocks the formation of Aβ oligomers and prevents hyperactivity in AD mice.

Actin is crucial for nervous system function yet the role of microexons in its modulation is unclear. Here, the authors show that a microexon in DAAM1 has a role in actin dynamics, neuronal function and memory formation in mice.

The molecular diversity of microglia has been described. Here the authors show that ARG1-expressing microglia are enriched in phagocytic inclusions and are involved in hippocampal innervation and spine maturation in mice. ARG1-expressing microglia also modulate cognition in a sex-dependent manner.

Male and female mice need to generate spatial maps that integrate vomeronasal signals of territory owners in the hippocampus-dependent memory. The authors show that vomeronasal information influences learning-related activity in the hippocampus via the amygdaloid PMCo, lateral entorhinal cortex, and dorsal CA1.

How seizures emerge in epileptic brain remains an enigma. The authors show that the transition to seizure follows a ubiquitous dynamical principle inherent to many processes in nature characterized by repeated transitions between contrasting regimes.

In this study, the authors show that PTEN alters synaptic function after PDZ-dependent recruitment into spines induced by amyloid-β. This mechanism is crucial for pathogenesis, as preventing PTEN-PDZ interactions renders neurons resistant to amyloid-β and rescues cognitive function in Alzheimer's disease models. This suggests that PTEN is a critical effector of the synaptic pathology associated with Alzheimer's disease.

Several kinases regulate spine morphology and plasticity. Here, the authors show that the tyrosine kinase Pyk2 regulates hippocampal plasticity and contributes to cognitive and hippocampal plasticity deficits in a mouse model of Huntington’s disease.

The authors find that the principal hippocampal neurons consist of distinct subpopulations that show distinct neurogenesis and synaptogenesis time windows and that these neurons interconnect selectively at dentate gyrus–to-CA3 and CA3-to-CA1 synapses.

Mice with myeloid-specific loss of the transcription factor, Stat4, exhibit stronger long-term synaptic plasticity than control animals when given a high-fat, high-cholesterol diet, suggesting that suppressing Stat4 activation may be a useful strategy for protecting against the inflammatory effects of a Western diet.

SK2-containing channels are expressed on dendritic spines of mouse CA1 pyramidal neurons and influence synaptic responses, plasticity and learning. Allen et al. find that the long isoform of SK2 directs synaptic SK2-containing channel expression, mediating synaptic and behavioral effects.

The authors report that the ultrastructure and plasticity of excitatory synapses connecting dentate gyrus and CA3 of the hippocampus are severely compromised in a transchromosomic mouse model of Down syndrome. These alterations are accompanied by unstable information coding by CA3 and CA1 place cells, which may contribute to aspects of impaired cognition in the disease.

The authors show long-term potentiation at the hippocampal CA3–CA1 synapse is modulated by EphA4 in the postsynaptic CA1 neuron and by ephrin-A3, an EphA4 ligand, in astrocytes, through their regulation of glial glutamate transporters. These results suggest EphA4/ephrin-A3 signaling as a mechanism for astrocytic regulation of synaptic plasticity.

The metabolism of ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and the (2R,6R)-HNK enantiomer lacks ketamine-related side effects but exerts rapid and sustained antidepressant actions in mice; these antidepressant effects are independent of NMDAR inhibition but require AMPAR activity.

The authors report that a dose of BDNF elicits very different signaling, morphological and synaptic responses in hippocampal neurons or slices, depending on whether it is applied all at once or gradually.

Madar et al. report that behavioral timescale synaptic plasticity (BTSP), not spike-timing-dependent plasticity, explains heterogeneous place fields shifting in the hippocampus. The probability of BTSP induction follows patterned dynamics, is higher in new contexts and lower in CA3 than CA1.

The mutations that underlie the diseases tuberous sclerosis complex and fragile X syndrome produce abnormalities in synaptic plasticity and function that can be corrected by treatments that modulate metabotropic glutamate receptor 5 in opposite directions.

How intrinsic cell properties such as stiffness contribute to cell-cell junction stabilization is not well described. Here they show that higher levels of intrinsic cell mechanics at the cortex, cytoskeleton and nucleus of neighboring cells promote junctional maturation.

Novel experiences in mice lead to opposing effects on inhibition of Fos-activated hippocampal CA1 pyramidal neurons by parvalbumin- and cholecystokinin-expressing interneurons, revealing the roles of FOS and SCG2 in neural plasticity and consolidation of memories.