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The circuitry of the hippocampal CA3 region has long been hypothesized to be well suited to the storage of memories. Mulle and colleagues provide an update on the known types and mechanisms of synaptic plasticity in CA3 and describe evidence for their roles in memory formation and retrieval.

Although they contain NMDA receptors, hippocampal mossy fiber synapses onto CA3 pyramidal cells have been reported to lack conventional NMDA receptor–dependent LTP of AMPA EPSCs. Here, the authors find that LTP of NMDA receptors serves as a metaplastic switch, making mossy fiber synapses competent to express NMDA receptor–dependent LTP of AMPA EPSCs.

Glutamate-induced kainate receptor activation can inhibit or facilitate inhibitory synaptic transmission. This study demonstrates that it is the concerted activity of presynaptic CB1 receptors and kainate receptors that together mediate short-term depression of inhibitory synaptic transmission.

Hippocampal synaptic dysfunctions are an early symptom of Alzheimer’s disease. Here, the authors find adenosine A2A receptors are up-regulated in APP/PS1 model mice and that deleting or blocking receptor activity helps alleviate plasticity and memory impairments.

Our understanding of the functional roles of presynaptic glutamate receptors continues to grow. Pinheiro and Mulle capture the current state of this knowledge, describing the modes and mechanisms of action of these receptors and the evidence for their contributions to synaptic transmission.

Mutations in presenilin, which cleaves amyloid precursor protein, cause familial Alzheimer’s Disease. Here, the authors show that loss of presenilin leads to loss of synaptotagmin 7, leading to impaired presynaptic release.

Kainate receptors are selectively found at CA3-mossy fibre synapses, although the mechanisms regulating this compartmentalisation have yet to be determined. Here, the authors find KAR segregation is dependent on the amount of GluK2a protein and an interaction between the GluK2 C-terminal domain and N-cadherin.

Loss-of-function mutations in the PARK2gene are implicated in autosomal recessive juvenile parkinsonism, but the mechanisms are unclear. Here, the authors show that these mutations cause accumulation of the kainate receptor subunit GluK2 in the plasma membrane of neurons, which facilitates neuronal death.

Rabphilin 3A is a synaptic vesicle-associated protein involved in membrane trafficking at presynaptic sites. Here Stanic et al.show that Rabphilin 3A binds to the NMDA receptor GluN2A and stabilises its surface localisation at postsynaptic sites in dendritic spines.

Caged signalling intermediates are powerful cell biological tools, however it can be challenging to precisely control where activation occurs. Nadler et al. develop a caging group that specifically targets the plasma membrane, and demonstrate spatially controlled activation of arachidonic acid signalling.

The authors show that activation of GluK2-containing kainate receptors on hippocampal neurons, by either agonist application or high-frequency synaptic stimulation, leads to a new form of NMDA-receptor-independent LTP. Induction of this form of plasticity requires the metabotropic action of postsynaptic kainate receptors, which triggers spine growth and potentiation of AMPA-receptor-mediated transmission.

Dysfunction of mGluR5 has been implicated in Fragile X syndrome. Here, using a single-molecule tracking technique, the authors found an increased lateral mobility of mGluR5 at the synaptic site in Fmr1 KO hippocampal neurons, leading to abnormal NMDAR-mediated synaptic plasticity and cognitive deficits.

The authors show that the type-1 cannabinoid receptor (CB₁) is present in mouse neuronal mitochondrial membranes. They show that mitochondrial CB₁ receptors regulate cellular respiration and energy production in the brain and may contribute to synaptic plasticity in the hippocampus.