Dendritic distribution of autophagosomes underlies pathway-selective induction of LTD.

The mechanism of long-term depression (LTD), a cellular substrate for learning, memory, and behavioral flexibility, is extensively studied in Schaffer collateral (SC) synapses, with inhibition of autophagy identified as a key factor. SC inputs terminate at basal and proximal apical dendrites, whereas distal apical dendrites receive inputs from the temporoammonic pathway (TAP). Here, we demonstrate that TAP and SC synapses have a shared LTD mechanism reliant on NMDA receptors, caspase-3, and autophagy inhibition. Despite this shared LTD mechanism, proximal apical dendrites contain more autophagosomes than distal apical dendrites. Additionally, unlike SC LTD, which diminishes with age, TAP LTD persists into adulthood. Our previous study shows that the high autophagy in adulthood disallows SC LTD induction. The reduction of autophagosomes from proximal to distal dendrites, combined with distinct LTD inducibility at SC and TAP synapses, suggests a model where the differential distribution of autophagosomes in dendrites gates LTD inducibility at specific circuits.

Enucleation combined with guided bone regeneration in small and medium-sized odontogenic jaw cysts.

BACKGROUND: The odontogenic jaw cyst is a cavity containing liquid, semifluid or gaseous components, with the development of the disease. In recent years, with the rapid development of oral materials and the transformation of treatment of jaw cysts, more options are available for treatment of postoperative bone defect of jaw cysts. Guided bone regeneration (GBR) places biomaterials in the bone defect, and then uses biofilm to separate the proliferative soft tissue and the slow-growing bone tissue to maintain the space for bone regeneration, which is widely used in the field of implantology. AIM: To observe the clinical effect of GBR in repairing bone defect after enucleation of small and medium-sized odontogenic jaw cysts. METHODS: From June 2018 to September 2020, 13 patients (7 male, 6 female) with odontogenic jaw cysts were treated in the Department of Oral Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. Adults without hypertension, heart disease, diabetes or other systemic diseases were selected. The diagnosis was based on the final pathological results: 11 cases were diagnosed as apical cysts, one as primordial cyst, and one as dentigerous cyst. The lesions were located in the maxilla in seven cases, and in the mandible in six cases. All cases were treated with the same method of enucleation combined with GBR. RESULTS: Three to four months after the operation, the boundary between the implant site and the surrounding normal stroma was not obvious in patients with small-sized odontogenic jaw cysts. The patients with tooth defects were treated with implant after 6 mo. For the patients with medium-sized odontogenic jaw cysts, the density of the center of the implant area was close to the normal mass at 6 mo after surgery, and there was a clear boundary between the periphery of the implant area and the normal mass. The boundary between the periphery of the implant area and the normal mass was blurred at 8-9 mo after surgery. Patients with tooth defects were treated with implants at > 6 mo after the operation. CONCLUSION: Enucleation combined with guided bone regeneration in small and medium-sized odontogenic jaw cysts can shorten the time of osteogenesis, increase the amount of new bone formation, reduce complications, and improve quality of life.

miR-26a and miR-384-5p are required for LTP maintenance and spine enlargement.

Long-term potentiation (LTP) is a form of synaptic plasticity that results in enhanced synaptic strength. It is associated with the formation and enlargement of dendritic spines-tiny protrusions accommodating excitatory synapses. Both LTP and spine remodelling are crucial for brain development, cognition and the pathophysiology of neurological disorders. The role of microRNAs (miRNAs) in the maintenance of LTP, however, is not well understood. Using next-generation sequencing to profile miRNA transcriptomes, we demonstrate that miR-26a and miR-384-5p specifically affect the maintenance, but not induction, of LTP and different stages of spine enlargement by regulating the expression of RSK3. Using bioinformatics, we also examine the global effects of miRNA transcriptome changes during LTP on gene expression and cellular activities. This study reveals a novel miRNA-mediated mechanism for gene-specific regulation of translation in LTP, identifies two miRNAs required for long-lasting synaptic and spine plasticity and presents a catalogue of candidate 'LTP miRNAs'.

NMDA receptor-dependent LTD is required for consolidation but not acquisition of fear memory.

NMDA receptor-dependent long-term depression (NMDAR-LTD) is a form of synaptic plasticity leading to long-lasting decreases in synaptic strength. NMDAR-LTD is essential for spatial and working memory, but its role in hippocampus-dependent fear memory has yet to be determined. Induction of NMDAR-LTD requires the activation of caspase-3 by cytochrome c. Cytochrome c normally resides in mitochondria and during NMDAR-LTD is released from mitochondria, a process promoted by Bax (Bcl-2-associated X protein). Bax induces cell death in apoptosis, but it plays a nonapoptotic role in NMDAR-LTD. Here, we investigated the role of NMDAR-LTD in fear memory in CA1-specific Bax knock-out mice. In hippocampal slices from these knock-out mice, while long-term potentiation of synaptic transmission, basal synaptic transmission, and paired-pulse ratio are intact, LTD in both young and fear-conditioned adult mice is obliterated. Interestingly, in CA1-specific Bax knock-out mice, long-term contextual fear memory is impaired, but the acquisition of fear memory and innate fear are normal. Moreover, these conditional Bax knock-out mice exhibit less behavioral despair. These findings indicate that NMDAR-LTD is required for consolidation, but not the acquisition of fear memory. Our study also shows that Bax plays an important role in depressive behavior.

miR-191 and miR-135 are required for long-lasting spine remodelling associated with synaptic long-term depression.

Activity-dependent modification of dendritic spines, subcellular compartments accommodating postsynaptic specializations in the brain, is an important cellular mechanism for brain development, cognition and synaptic pathology of brain disorders. NMDA receptor-dependent long-term depression (NMDAR-LTD), a prototypic form of synaptic plasticity, is accompanied by prolonged remodelling of spines. The mechanisms underlying long-lasting spine remodelling in NMDAR-LTD, however, are largely unclear. Here we show that LTD induction causes global changes in miRNA transcriptomes affecting many cellular activities. Specifically, we show that expression changes of miR-191 and miR-135 are required for maintenance but not induction of spine restructuring. Moreover, we find that actin depolymerization and AMPA receptor exocytosis are regulated for extended periods of time by miRNAs to support long-lasting spine plasticity. These findings reveal a miRNA-mediated mechanism and a role for AMPA receptor exocytosis in long-lasting spine plasticity, and identify a number of candidate miRNAs involved in LTD.

Distinct trafficking and expression mechanisms underlie LTP and LTD of NMDA receptor-mediated synaptic responses.

Although an increasing number of studies have demonstrated the plasticity of NMDA receptor-mediated synaptic transmission, little is known about the molecular mechanisms that underlie this neurologically important process. In a study of NMDAR-mediated synaptic responses in hippocampal Schaffer-CA1 synapses whose AMPA receptor (AMPAR) activity is totally blocked, we uncovered differences between the trafficking mechanisms that underlie the long-term potentiation (LTP) and long-term depression (LTD) that can be induced in these cells under these conditions. The LTP-producing protocol failed to induce a change in the amplitude of NMDAR-mediated postsynaptic currents (NMDAR EPSCs) in the first 5-10 min, but induced gradual enhancement of NMDAR EPSCs thereafter that soon reached a stable magnitude. This "slow" LTP of NMDAR EPSCs (LTP(NMDA)) was blocked by inhibiting exocytosis or actin polymerization in postsynaptic cells. By contrast, LTD of NMDAR EPSCs (LTD(NMDA)) was immediately inducible, and, although it was blocked by the actin stabilizer, it was unaffected by exocytosis or endocytosis inhibitors. Furthermore, concomitant changes in the decay time of NMDAR EPSCs suggested that differential switches in NR2 subunit composition accompanied LTP(NMDA) and LTD(NMDA), and these changes were blocked by the calcium buffer BAPTA or an mGluR antagonist. Our results suggest that LTP(NMDA) and LTD(NMDA) utilize different NMDAR trafficking pathways and express different ratios of NMDAR subunits on the postsynaptic surface.

Metaplastic regulation of long-term potentiation/long-term depression threshold by activity-dependent changes of NR2A/NR2B ratio.

In vivo experience induces changes in synaptic NMDA receptor (NMDAR) subunit components, which are correlated with subsequent modifications of synaptic plasticity. However, little is known about how these subunit changes regulate the induction threshold of subsequent plasticity. At hippocampal Schaffer collateral-CA1 synapses, we first examined whether a recent history of neuronal activity could affect subsequent synaptic plasticity through its actions on NMDAR subunit components. We found that prior activity history produced by priming stimulations (PSs) across a wide range of frequencies (1-100 Hz) could induce bidirectional changes in the NR2A/NR2B ratio, which governs the threshold for subsequent long-term potentiation/long-term depression (LTP/LTD). Manipulating the NR2A/NR2B ratio through partial NR2 subunit blockade mimicked the PS regulation of the LTP/LTD threshold. Our results demonstrate that activity-dependent changes in the NR2A/NR2B ratio can be critical factors in metaplastic regulation of the LTP/LTD threshold.

Synaptic metaplasticity through NMDA receptor lateral diffusion.

Lateral diffusion of glutamate receptors was proposed as a mechanism for regulating receptor numbers at synapses and affecting synaptic functions, especially the efficiency of synaptic transmission. However, a direct link between receptor lateral diffusion and change in synaptic function has not yet been established. In the present study, we demonstrated NMDA receptor (NMDAR) lateral diffusion in CA1 neurons in hippocampal slices by detecting considerable recovery of spontaneous or evoked EPSCs from the block of (+)-MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate], an irreversible NMDAR open-channel blocker. We observed changes on both the number and the composition of synaptic NMDAR on recovery. More importantly, after the recovery, long-term potentiation (LTP)-producing protocol induced only LTD (long-term depression) instead of LTP. In contrast, a complete recovery from competitive NMDAR blocker D,L-AP-5 was observed without subsequent changes on synaptic plasticity. Our data suggest a revised model of NMDAR trafficking wherein extrasynaptic NMDARs, mostly NR1/NR2B receptors, move laterally into synaptic sites, resulting in altered rule of synaptic modification. Thus, CA1 synapses exhibit a novel form of metaplasticity in which the direction of synaptic modification can be reverted through subtype-specific lateral diffusion of NMDA receptors.