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1.  The organization of two novel cortical interneuronal circuits 
Nature neuroscience  2013;16(2):210-218.
Deciphering interneuronal circuitry is central to understanding brain functions yet remains as a challenging task in neurobiology. Using simultaneous quadruple-octuple in vitro and dual in vivo whole-cell recordings, we found two previously unknown interneuronal circuits that link cortical layer 1–3 (L1-3) interneurons and L5 pyramidal neurons in the rat neocortex. L1 single-bouquet cells (SBCs) preferentially form unidirectional inhibitory connections on L2/3 interneurons that inhibit the entire dendritic-somato-axonal axis of ~1% of L5 pyramidal neurons located within the same column. In contrast, L1 elongated neurogliaform cells (ENGCs) frequently form mutual inhibitory and electric connections with L2/3 interneurons, and these L1-3 interneurons inhibit the distal apical dendrite of >60% of L5 pyramidal neurons across multiple columns. Functionally, SBC→L2/3 interneuron→L5 pyramidal neuronal circuits disinhibit and ENGC↔L2/3 interneuron→L5 pyramidal neuronal circuits inhibit the initiation of dendritic complex spikes in L5 pyramidal neurons. As dendritic complex spikes can serve coincidence detection, these cortical interneuronal circuits may be essential for salience selection.
PMCID: PMC3589105  PMID: 23313910
2.  Activity Level-Dependent Synapse-Specific AMPA Receptor Trafficking Regulates Transmission Kinetics 
Central glutamatergic synapses may express AMPA-sensitive glutamate receptors (AMPA-Rs) with distinct gating properties and exhibit different transmission dynamics, which are important for computing various synaptic inputs received at different populations of synapses. However, how glutamatergic synapses acquire AMPA-Rs with distinct kinetics to influence synaptic integration remains poorly understood. Here I report synapse-specific trafficking of distinct AMPA-Rs in rat cortical layer 4 stellate and layer 5 pyramidal neurons. The analysis indicates that in single layer 4 stellate neurons thalamocortical synapses generate faster synaptic responses than intracortical synapses. Moreover, GluR1-containing AMPA-Rs traffic selectively into intracortical synapses, and this process requires sensory experience-dependent activity and slows down transmission kinetics. GluR4-containing AMPA-Rs traffic more heavily into thalamocortical synapses than intracortical synapses, and this process requires spontaneous synaptic activity and speeds up transmission kinetics. GluR2-containing AMPA-Rs traffic equally into both thalamocortical and intracortical synapses, and this process requires no synaptic activity and resets transmission kinetics. Notably, synaptic trafficking of distinct AMPA-Rs differentially regulates synaptic integration. Thus, synapse-specific AMPA-R trafficking coarsely sets and synaptic activity finely tunes transmission kinetics and integration properties at different synapses in central neurons.
PMCID: PMC2734326  PMID: 19439609
3.  Single-molecule force measurement via optical tweezers reveals different kinetic features of two BRaf mutants responsible for cardio-facial-cutaneous (CFC) syndrome: errata 
Biomedical Optics Express  2014;6(1):244.
We correct the omission of the construct and protein purification method in our recent paper [Biomed. Opt. Express 4(12), 2835–2845 (2013)].
PMCID: PMC4317112  PMID: 25656083
(170.0170) Medical optics and biotechnology; (170.1420) Biology; (170.4520) Optical confinement and manipulation; (350.4855) Optical tweezers or optical manipulation
4.  Ras Signaling Mechanisms Underlying Impaired GluR1-dependent Plasticity Associated with Fragile X Syndrome 
Fragile X syndrome, caused by the loss of FMR1 gene function and loss of fragile X mental retardation protein (FMRP), is the most commonly inherited form of mental retardation. The syndrome is characterized by associative learning deficits, reduced risk of cancer, dendritic spine dysmorphogenesis and facial dysmorphism. However, the molecular mechanism that links loss of function of FMR1 to the learning disability remains unclear. Here we report an examination of small GTPase Ras signaling and synaptic AMPA receptor (-Rs) trafficking in cultured slices and intact brains of wild type and FMR1 knockout mice. In FMR1 knockout mice, synaptic delivery of GluR1-, but not GluR2L- and GluR4-containing AMPA-Rs is impaired, resulting in a selective loss of GluR1-dependent long-term synaptic potentiation (LTP). Although Ras activity is up-regulated, its downstream extracellular signal-regulated kinase kinase (MEK)–extracellular signal-regulated kinase (ERK) signaling appears normal and phosphoinositide 3-kinase (PI3K)–protein kinase B (PKB or Akt) signaling is compromised in FMR1 knockout mice. Enhancing Ras–PI3K–PKB signaling restores synaptic delivery of GluR1-containing AMPA-Rs and normal LTP in FMR1 knockout mice. These results suggest aberrant Ras signaling as a novel mechanism for fragile X syndrome and indicate manipulating Ras–PI3K–PKB signaling to be a potentially effective approach for treating patients with fragile X syndrome.
PMCID: PMC2553221  PMID: 18667617
Autism; AMPA receptor trafficking; Ras-PI3K signaling; cancer risk; mental retardation; dendritic spine dysmorphogenesis; facial dysmorphism
5.  Arf6-GEF BRAG1 regulates JNK-mediated synaptic removal of GluA1-containing AMPA receptors: a new mechanism for nonsyndromic X-linked mental disorder 
Activity-dependent modifications of excitatory synapses contribute to synaptic maturation and plasticity, and are critical for learning and memory. Consequently, impairments in synapse formation or synaptic transmission are thought to be responsible for several types of mental disability. BRAG1 is a guanine nucleotide exchange factor (GEF) for the small GTP-binding protein Arf6 that localizes to the postsynaptic density of excitatory synapses. Mutations in BRAG1 have been identified in families with X-linked intellectual disability (XLID). These mutations mapped to either the catalytic domain or an IQ-like motif, however the pathophysiological basis of these mutations remains unknown. Here, we show that the BRAG1 IQ motif binds apo-calmodulin (CaM), and that calcium-induced CaM release triggers a reversible conformational change in human BRAG1. We demonstrate that BRAG1 activity, stimulated by activation of NMDA-sensitive glutamate receptors (-Rs), depresses AMPA-R-mediated transmission via JNK-mediated synaptic removal of GluA1-containing AMPA-Rs in rat hippocampal neurons. Importantly, a BRAG1 mutant that fails to activate Arf6 also fails to depress AMPA-R signaling, indicating that Arf6 activity is necessary for this process. Conversely, a mutation in the BRAG1 IQ-like motif that impairs CaM binding results in hyperactivation of Arf6 signaling and constitutive depression of AMPA transmission. Our findings reveal a role for BRAG1 in response to neuronal activity with possible clinical relevance to nonsyndromic X-linked intellectual disability.
PMCID: PMC3459061  PMID: 22915114
6.  Cdk5 Is Required for Memory Function and Hippocampal Plasticity via the cAMP Signaling Pathway 
PLoS ONE  2011;6(9):e25735.
Memory formation is modulated by pre- and post-synaptic signaling events in neurons. The neuronal protein kinase Cyclin-Dependent Kinase 5 (Cdk5) phosphorylates a variety of synaptic substrates and is implicated in memory formation. It has also been shown to play a role in homeostatic regulation of synaptic plasticity in cultured neurons. Surprisingly, we found that Cdk5 loss of function in hippocampal circuits results in severe impairments in memory formation and retrieval. Moreover, Cdk5 loss of function in the hippocampus disrupts cAMP signaling due to an aberrant increase in phosphodiesterase (PDE) proteins. Dysregulation of cAMP is associated with defective CREB phosphorylation and disrupted composition of synaptic proteins in Cdk5-deficient mice. Rolipram, a PDE4 inhibitor that prevents cAMP depletion, restores synaptic plasticity and memory formation in Cdk5-deficient mice. Collectively, our results demonstrate a critical role for Cdk5 in the regulation of cAMP-mediated hippocampal functions essential for synaptic plasticity and memory formation.
PMCID: PMC3184170  PMID: 21984943
7.  Ras and Rap Signaling in Synaptic Plasticity and Mental Disorders 
The Ras family GTPases (Ras, Rap1, and Rap2) and their downstream mitogen-activated protein kinases (ERK, JNK, and p38MAPK) and PI3K signaling cascades control various physiological processes. In neuronal cells, recent studies have shown that these parallel cascades signal distinct forms of AMPA-sensitive glutamate receptor trafficking during experience-dependent synaptic plasticity and adaptive behavior. Interestingly, both hypo- and hyper-activation of Ras/Rap signaling impair the capacity of synaptic plasticity, underscoring the importance of a “happy-medium” dynamic regulation of the signaling. Moreover, accumulating reports have linked various genetic defects that either up- or down-regulate Ras/Rap signaling with a number of mental disorders associated with learning disability (e.g., Alzheimer’s disease, Angelman syndrome, autism, cardio-facio-cutaneous syndrome, Coffin-Lowry syndrome, Costello syndrome, Cowden and Bannayan-Riley-Ruvalcaba syndromes, fragile X syndrome, neurofibromatosis type 1, Noonan syndrome, schizophrenia, tuberous sclerosis, and X-linked mental retardation), highlighting the necessity of happy-medium dynamic regulation of Ras/Rap signaling in learning behavior. Thus, the recent advances in understanding of neuronal Ras/Rap signaling provide a useful guide for developing novel treatments for mental diseases.
PMCID: PMC3119507  PMID: 20431046
AMPA receptors; MAPK; neuromodulator; NMDA receptors; plasticity; Ras; Rap1; Rap2; sensory experience; subcellular compartment; synaptic transmission; trafficking
8.  Activity patterns govern synapse-specific AMPA receptor trafficking between deliverable and synaptic pools 
Neuron  2009;62(1):84-101.
In single neurons, glutamatergic synapses receiving distinct afferent inputs may contain AMPA receptors (-Rs) with unique subunit compositions. However, the cellular mechanisms by which differential receptor transport achieves this synaptic diversity remain poorly understood. In lateral geniculate neurons, we show that retinogeniculate and corticogeniculate synapses have distinct AMPA-R subunit compositions. Under basal conditions at both synapses, GluR1-containing AMPA-Rs are transported from an anatomically defined reserve pool to a deliverable pool near the postsynaptic density (PSD), but further incorporate into the PSD or functional synaptic pool only at retinogeniculate synapses. Vision-dependent activity, stimulation mimicking retinal input, or activation of CaMKII or Ras signaling regulated forward GluR1 trafficking from the deliverable pool to the synaptic pool at both synapses, whereas Rap2 signals reverse GluR1 transport at retinogeniculate synapses. These findings suggest that synapse-specific AMPA-R delivery involves constitutive and activity-regulated transport steps between morphological pools, a mechanism that may extend to the site-specific delivery of other membrane protein complexes.
PMCID: PMC2682220  PMID: 19376069
9.  Amyotrophic Lateral Sclerosis 2-Deficiency Leads to Neuronal Degeneration in Amyotrophic Lateral Sclerosis through Altered AMPA Receptor Trafficking 
Amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disease is caused by a selective loss of motor neurons. One form of juvenile onset autosomal recessive ALS (ALS2) has been linked to the loss of function of the ALS2 gene. The pathogenic mechanism of ALS2-deficiency, however, remains unclear. To further understand the function of alsin that is encoded by the full-length ALS2 gene, we screened proteins interacting with alsin. Here, we report that alsin interacted with glutamate receptor interacting protein 1 (GRIP1) both in vitro and in vivo, and colocalized with GRIP1 in neurons. In support of the physiological interaction between alsin and GRIP1, the subcellular distribution of GRIP1 was altered in ALS2-/- spinal motor neurons, which correlates with a significant reduction of AMPA-type glutamate receptor subunit 2 (GluR2) at the synaptic/cell surface of ALS2-/- neurons. The decrease of calcium-impermeable GluR2-containing AMPA receptors at the cell/synaptic surface rendered ALS2-/- neurons more susceptible to glutamate receptor-mediated neurotoxicity. Our findings reveal a novel function of alsin in AMPA receptor trafficking and provide a novel pathogenic link between ALS2-deficiency and motor neuron degeneration, suggesting a protective role of alsin in maintaining the survival of motor neurons.
PMCID: PMC2556290  PMID: 17093100
ALS2; knock-out mouse; motor neuron; GRIP1; AMPA receptor; excitotoxicity

Results 1-9 (9)