Search

The hippocampus is a temporal lobe structure critical for cognition, such as learning, memory, and attention, as well as emotional responses. Hippocampal dysfunction can lead to persistent anxiety and/or depression. However, how millions of neurons in the hippocampus are molecularly and structurally organized to engage their divergent functions remains unknown. Here, we genetically target a subset of neurons expressing the coagulation factor c homolog (COCH) gene. COCH-expressing neurons or COCH neurons are topographically segregated in the distal region of the ventral CA3 hippocampus and express Mtf1 and Cacna1h. MTF1 activation of Cacna1h transcription in COCH neurons encodes the ability of COCH neurons to burst action potentials and cause social-stress-induced anxiety-like behaviors by synapsing directly with a subset of GABAergic inhibitory neurons in the lateral septum. Together, this study provides a molecular and circuitry-based framework for understanding how COCH neurons in the hippocampus are assembled to engage social behavior.

SUMMARY Protein phosphatase 2A (PP2A) inhibition causes hy-perphosphorylation of tau and APP in Alzheimer’s disease (AD). However, the mechanisms underlying the downregulation of PP2A activity in AD brain remain unclear. We demonstrate that Cancerous Inhibitor of PP2A (CIP2A), an endogenous PP2A inhibitor, is overexpressed in AD brain. CIP2A-mediated PP2A inhibition drives tau/APP hyperphosphorylation and increases APP β-cleavage and Aβ production. Increase in CIP2A expression also leads to tau mislocalization to dendrites and spines and synaptic degeneration. In mice, injection of AAV-CIP2A to hippocampus induced AD-like cognitive deficits and impairments in long-term potentiation (LTP) and exacerbated AD pathologies in neurons. Indicative of disease exacerbating the feedback loop, we found that increased CIP2A expression and PP2A inhibition in AD brains result from increased Aβ production. In summary, we show that CIP2A overexpression causes PP2A inhibition and AD-related cellular pathology and cognitive deficits, pointing to CIP2A as a potential target for AD therapy., In Brief PP2A inactivation plays a key role in AD pathogenesis. Shentu et al. report that endogenous PP2A inhibitor CIP2A is upregulated in AD brains. CIP2A overexpression promotes β-cleavage of APP and tau hyperphosphorylation through PP2A inhibition, leading to impairments in synapse, hippocampal LTP, and memory., Graphical Abstract

The PSD-95/SAPAP/Shank complex functions as the major scaffold in orchestrating the formation and plasticity of the post-synaptic densities (PSDs). We previously demonstrated that the exquisitely specific SAPAP/Shank interaction is critical for Shank synaptic targeting and Shank-mediated synaptogenesis. Here, we show that the PSD-95/SAPAP interaction, SAPAP synaptic targeting, and SAPAP-mediated synaptogenesis require phosphorylation of the N-terminal repeat sequences of SAPAPs. The atomic structure of the PSD-95 guanylate kinase (GK) in complex with a phosphor-SAPAP repeat peptide, together with biochemical studies, reveals the molecular mechanism underlying the phosphorylation-dependent PSD-95/SAPAP interaction, and it also provides an explanation of a PSD-95 mutation found in patients with intellectual disabilities. Guided by the structural data, we developed potent non-phosphorylated GK inhibitory peptides capable of blocking the PSD-95/SAPAP interaction and interfering with PSD-95/SAPAP-mediated synaptic maturation and strength. These peptides are genetically encodable for investigating the functions of the PSD-95/SAPAP interaction in vivo.

Mossy cells (MCs) are a unique group of excitatory neurons in the hippocampus, a brain region important for emotion, learning, and memory. Due to the lack of a reliable method to isolate MCs from other cell types, how MCs integrate neural information and convey it to their synaptic targets for engaging a specific function are still unknown. Here, we report that MCs control the efficacy of spatial memory retrieval by synapsing directly onto local somatostatin-expressing (SST) cells. MC-SST synaptic transmission undergoes long-term potentiation (LTP), requiring Gria2-lacking Ca2+-permeable anti-α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor (Ca2+AR). A long noncoding RNA (Gria2I) is associated with Gria2 transcriptional repressors in SST cells. Silencing Gria2I induces Gria2 transcription, blocks LTP of MCs-SST synaptic transmission, and reduces the efficacy of memory retrieval. Thus, MCs directly and functionally innervate local SST neurons, and this innervation controls the efficacy of spatial memory retrieval by Gria2I inhibition of Gria2 transcription.

Summary: Kibra is a synaptic scaffold protein regulating learning and memory. Alterations of Kibra-encoding gene WWC1 cause various neuronal disorders, including Alzheimer’s disease and Tourette syndrome. However, the molecular mechanism underlying Kibra’s function in neurons is poorly understood. Here we discover that Kibra, via its N-terminal WW12 tandem domains, binds to a postsynaptic density enriched protein, Dendrin, with a nanomolar dissociation constant. On the basis of the structure of Kibra WW12 in complex with Dendrin PY motifs, we developed a potent peptide inhibitor capable of specifically blocking the binding between Kibra and Dendrin in neurons. Systematic administration of the inhibitory peptide attenuated excitatory synaptic transmission, completely blocked long-term potentiation induction, and impaired spatial learning and memory. A Kibra mutation found in Tourette syndrome patients causes defects in binding to Dendrin. Thus, Kibra can modulate spatial learning and memory via binding to Dendrin. : Ji et al. report that the memory-related molecule Kibra, via its WW tandem domains, specifically binds to the synaptic protein Dendrin with a low-nanomolar dissociation constant to modulate spatial learning and memory. Keywords: Kibra, Dendrin, WW domains, tandem repeats, scaffold protein, synaptic complex, synaptic transmission, learning and memory, psychiatric disorder, Tourette syndrome

Summary: Retroactive interference (RI) occurs when new incoming information impairs an existing memory, which is one of the primary sources of forgetting. Although long-term potentiation (LTP) reversal shows promise as the underlying neural correlate, the key molecules that control the sensitivity of memory circuits to RI are unknown, and the developmental trajectory of RI effects is unclear. Here we found that depotentiation in the hippocampal dentate gyrus (DG) depends on GluN2A-containing NMDA receptors (NMDARs). The susceptibility of LTP to disruption progressively increases with the rise in the GluN2A/GluN2B ratio during development. The vulnerability of hippocampus-dependent memory to interference from post-learning novelty exploration is subject to similar developmental regulation by NMDARs. Both GluN2A overexpression and GluN2B downregulation in the DG promote RI-induced forgetting. Altogether, our results suggest that a switch in GluN2 subunit predominance may confer age-related differences to depotentiation and underlie the developmental decline in memory resistance to RI. : Ge et al. report that the NMDA receptor GluN2A/GluN2B subunit ratio determines the sensitivity of strengthened neuronal connections to depotentiation. As the ratio rises during development, memories become more vulnerable to disruption by post-learning interference. These findings help to illuminate the mechanism by which forgetting rates may vary with age. Keywords: forgetting, retroactive interference, depotentiation, NMDA receptor