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1.  Inhibitory networks of the amygdala for emotional memory 
The amygdala is important for emotional memory, including learned fear. A number of studies for amygdala neural circuits that underlie fear conditioning have elucidated specific cellular and molecular mechanisms of emotional memory. Recent technical advances such as optogenetic approaches have not only confirmed the importance of excitatory circuits in fear conditioning, but have also shed new light for a direct role of inhibitory circuits in both the acquisition and extinction of fear memory in addition to their role in fine tuning of excitatory neural circuitry. As a result, the circuits in amygdala could be drawn more elaborately, and it led us to understand how fear or extinction memories are formed in the detailed circuit level, and various neuromodulators affect these circuit activities, inducing subtle behavioral changes.
PMCID: PMC3729980  PMID: 23914157
neural circuits; inhibitory neurons; amygdala; fear; extinction
2.  Neuritin Attenuates Cognitive Function Impairments in Tg2576 Mouse Model of Alzheimer's Disease 
PLoS ONE  2014;9(8):e104121.
Neuritin, also known as CPG15, is a neurotrophic factor that was initially discovered in a screen to identify genes involved in activity-dependent synaptic plasticity. Neuritin plays multiple roles in the process of neural development and synaptic plasticity, although its binding receptor(s) and downstream signaling effectors remain unclear. In this study, we found that the cortical and hippocampal expression of neuritin is reduced in the brains of Alzheimer's disease (AD) patients and demonstrated that viral-mediated expression of neuritin in the dentate gyrus of 13-month-old Tg2576 mice, an AD animal model, attenuated a deficit in learning and memory as assessed by a Morris water maze test. We also found that neuritin restored the reduction in dendritic spine density and the maturity of individual spines in primary hippocampal neuron cultures prepared from Tg2576 mice. It was also shown that viral-mediated expression of neuritin in the dentate gyrus of 7-week-old Sprague-Dawley rats increased neurogenesis in the hippocampus. Taken together, our results demonstrate that neuritin restores the reduction in dendritic spine density and the maturity of individual spines in primary hippocampal neurons from Tg2576 neurons, and also attenuates cognitive function deficits in Tg2576 mouse model of AD, suggesting that neuritin possesses a therapeutic potential for AD.
PMCID: PMC4125179  PMID: 25101829
3.  Exosomes neutralize synaptic-plasticity-disrupting activity of Aβ assemblies in vivo 
Molecular Brain  2013;6:47.
Exosomes, small extracellular vesicles of endosomal origin, have been suggested to be involved in both the metabolism and aggregation of Alzheimer’s disease (AD)-associated amyloid β-protein (Aβ). Despite their ubiquitous presence and the inclusion of components which can potentially interact with Aβ, the role of exosomes in regulating synaptic dysfunction induced by Aβ has not been explored.
We here provide in vivo evidence that exosomes derived from N2a cells or human cerebrospinal fluid can abrogate the synaptic-plasticity-disrupting activity of both synthetic and AD brain-derived Aβ. Mechanistically, this effect involves sequestration of synaptotoxic Aβ assemblies by exosomal surface proteins such as PrPC rather than Aβ proteolysis.
These data suggest that exosomes can counteract the inhibitory action of Aβ, which contributes to perpetual capability for synaptic plasticity.
PMCID: PMC4222117  PMID: 24284042
Alzheimer’s disease; Aβ; Exosomes; Synaptic plasticity; PrPC
4.  Mind bomb-1 is an essential modulator of long-term memory and synaptic plasticity via the Notch signaling pathway 
Molecular Brain  2012;5:40.
Notch signaling is well recognized as a key regulator of the neuronal fate during embryonic development, but its function in the adult brain is still largely unknown. Mind bomb-1 (Mib1) is an essential positive regulator in the Notch pathway, acting non-autonomously in the signal-sending cells. Therefore, genetic ablation of Mib1 in mature neuron would give valuable insight to understand the cell-to-cell interaction between neurons via Notch signaling for their proper function.
Here we show that the inactivation of Mib1 in mature neurons in forebrain results in impaired hippocampal dependent spatial memory and contextual fear memory. Consistently, hippocampal slices from Mib1-deficient mice show impaired late-phase, but not early-phase, long-term potentiation and long-term depression without change in basal synaptic transmission at SC-CA1 synapses.
These data suggest that Mib1-mediated Notch signaling is essential for long-lasting synaptic plasticity and memory formation in the rodent hippocampus.
PMCID: PMC3541076  PMID: 23111145
Mind bomb-1; Notch; Synaptic plasticity; Memory; Hippocampus
5.  Several Days of CPEB-Dependent Local Protein Synthesis Are Required to Stabilize Synaptic Growth for Persistence of Long-Term Facilitation in Aplysia 
Neuron  2008;59(6):1024-1036.
The time course of the requirement for local protein synthesis in the stabilization of learning-related synaptic growth and the persistence of long-term memory was examined using Aplysia bifurcated sensory neuron-motor neuron cultures. We find that following repeated pulses of serotonin (5-HT) the local perfusion of emetine, an inhibitor of protein synthesis, or a TAT-AS oligonucleotide directed against ApCPEB blocks long-term facilitation (LTF) at either 24 hr or 48 hr and leads to a selective retraction of newly formed sensory neuron varicosities induced by 5-HT. By contrast, later inhibition of local protein synthesis, at 72 hr after 5-HT, has no effect on either synaptic growth or LTF. These results define a specific stabilization phase for the storage of long-term memory during which newly formed varicosities are labile and require sustained CPEB-dependent local protein synthesis to acquire the more stable properties of mature varicosities required for the persistence of LTF.
PMCID: PMC3442368  PMID: 18817739
6.  Pathway-Specific Alteration of Synaptic Plasticity in Tg2576 Mice 
Molecules and Cells  2011;32(2):197-201.
Various animal models of Alzheimer disease (AD) are characterized by deficits in spatial memory that are causally related to altered synaptic function and impairment of long-term potentiation (LTP) in the hippocampus. In Tg2576 AD mice, we compared LTP in 2 major hippocampal pathways, Schaffer collateral (SC) and mossy fiber (MF) pathways. Whereas LTP was completely abolished in the SC pathway of Tg2576 mice, we found no decrease in LTP induced by stimulation of the MF pathway. In fact, we found that in the MF pathway, LTP was slightly, but significantly, enhanced compared with that in the MF pathway of WT littermates. This pathway-specific impairment of LTP is not attributable to alterations in transmitter release, as indicated by an unaltered paired-pulse ratio. These results suggest that the spatial memory deficits normally seen in AD models arise primarily from LTP impairment at the SC pathway.
PMCID: PMC3887667  PMID: 21638202
Alzheimer’s disease; long-term potentiation; mossy fiber pathway; schaffer collateral pathway; Tg2576
7.  Neurexin-Neuroligin Trans-Synaptic Interaction Mediates Learning-Related Synaptic Remodeling and Long-Term Facilitation in Aplysia 
Neuron  2011;70(3):468-481.
Neurexin and neuroligin, which undergo heterophilic interactions with each other at the synapse, are mutated in some patients with autism spectrum disorder, a set of disorders characterized by deficits in social and emotional learning. We have explored the role of neurexin and neuroligin at sensory-to-motor neuron synapses of the gill-withdrawal reflex in Aplysia that undergoes sensitization, a simple form of learned fear. We find that depleting neurexin in the presynaptic sensory neuron or neuroligin in the postsynaptic motor neuron abolishes both long-term facilitation and the associated presynaptic growth induced by repeated pulses of serotonin. Moreover, introduction into the motor neuron of the R451C mutation of neuroligin-3 linked to autism spectrum disorder blocks both intermediate-term and long-term facilitation. Our results suggest that activity-dependent regulation of the neurexin-neuroligin interaction may govern trans-synaptic signaling required for the storage of long-term memory, including emotional memory that may be impaired in autism spectrum disorder.
PMCID: PMC3136118  PMID: 21555073
8.  Comparative Study of Clinical Outcomes of Anterior Cervical Discectomy and Fusion Using Autobone Graft or Cage with Bone Substitute 
Asian Spine Journal  2011;5(3):169-175.
Study Design
A retrospective study.
To compare the clinical and radiological outcomes of autogenous bone graft and cage with bone substitute for anterior cervical discectomy and fusion.
Overview of Literature
The clinical outcomes of cage with bone substitute for anterior cervical discectomy and fusion is satisfactory.
Eighty four patients who underwent cervical spine surgery between February 2004 and April 2009 were included. Fifty-nine patients were approached anteriorly and underwent anterior cervical discectomy and fusion by the Smith-Robinson method (Group A), and 25 patients underwent fusion by decompression of the cervical spine and cage with bone substitute (Group B). We measured and evaluated the postoperative period until patients were able to ambulate, for pre- and postoperative symptomatic improvement, postoperative complications, pre- and postoperative change of lordosis, degree of endplate collapse or subsidence, and fusion rate and period of union.
By Robinson's criteria, respectively 45, 10 and 4 patients in Group A experienced excellent, good and fair symptomatic improvement, and respectively 19, 5 and 1 patients in Group B experienced excellent, good and fair symptomatic improvement. The postoperative period in which patients became ambulant and the period of hospital stay was significantly shorter in Group B. Increase of lordosis at final follow up after surgery was significantly larger in Group A, as was the fusion period. Significantly more endplate collapse occurred in Group B.
Of patients who had anterior cervical discectomy and fusion, results of both groups were both satisfactory.
PMCID: PMC3159065  PMID: 21892389
Cervical vertbrae; Anterior cervical discectomy and fusion; Autobone graft; Cage; Bone substitutes
9.  Amyloid Precursor Protein Binding Protein-1 Modulates Cell Cycle Progression in Fetal Neural Stem Cells 
PLoS ONE  2010;5(12):e14203.
Amyloid precursor protein binding protein-1 (APP-BP1) binds to the carboxyl terminus of the amyloid precursor protein (APP) and serves as the bipartite activation enzyme for the ubiquitin-like protein, NEDD8. In the present study, we explored the physiological role of APP-BP1 in the cell cycle progression of fetal neural stem cells. Our results show that cell cycle progression of the cells is arrested at the G1 phase by depletion of APP-BP1, which results in a marked decrease in the proliferation of the cells. This action of APP-BP1 is antagonistically regulated by the interaction with APP. Consistent with the evidence that APP-BP1 function is critical for cell cycle progression, the amount of APP-BP1 varies depending upon cell cycle phase, with culminating expression at S-phase. Furthermore, our FRET experiment revealed that phosphorylation of APP at threonine 668, known to occur during the G2/M phase, is required for the interaction between APP and APP-BP1. We also found a moderate ubiquitous level of APP-BP1 mRNA in developing embryonic and early postnatal brains; however, APP-BP1 expression is reduced by P12, and only low levels of APP-BP1 were found in the adult brain. In the cerebral cortex of E16 rats, substantial expression of both APP-BP1 and APP mRNAs was observed in the ventricular zone. Collectively, these results indicate that APP-BP1 plays an important role in the cell cycle progression of fetal neural stem cells, through the interaction with APP, which is fostered by phopshorylation of threonine 668.
PMCID: PMC2996309  PMID: 21151996

Results 1-9 (9)