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1.  Synaptic Correlates of Binocular Convergence: Just a Coincidence? 
The Journal of Neuroscience  2014;34(27):8931-8933.
PMCID: PMC4078076  PMID: 24990913
2.  MeCP2: Making sense of missense in Rett syndrome 
Cell Research  2013;23(11):1244-1246.
Fine scale genomic regulation is critical for maintaining genomic integrity and is often disrupted in neurodevelopmental disorders. An intriguing new study reveals the intricate biochemical complexity of de novo post-translational modifications of MeCP2, including activity-dependent protein-protein interactions that 'bridge' the nuclear receptor co-repressor (NCoR) complex to chromatin and lead to alterations in gene expression that characterize Rett syndrome.
PMCID: PMC3817541  PMID: 23938294
3.  Distinct mechanisms of spike timing‐dependent LTD at vertical and horizontal inputs onto L2/3 pyramidal neurons in mouse barrel cortex 
Physiological Reports  2014;2(3):e00271.
Spike timing‐dependent plasticity (STDP) is an attractive candidate to mediate the synaptic changes that support circuit plasticity in sensory cortices during development. STDP is prevalent at excitatory synapses, but it is not known whether the underlying mechanisms are universal, or whether distinct mechanisms underpin STDP at different synapses. Here, we set out to compare and contrast STDP at vertical layer 4 and horizontal layer 2/3 inputs onto postsynaptic layer 2/3 neurons in the mouse barrel cortex. We find that both vertical and horizontal inputs show STDP, but that they display different time windows for induction of timing‐dependent long‐term depression (t‐LTD). Moreover, whereas t‐LTD at vertical inputs requires presynaptic NMDA receptors and is expressed presynaptically, using paired recordings we find that t‐LTD at horizontal inputs requires postsynaptic NMDA receptors and is expressed postsynaptically. These results demonstrate that similar forms of plasticity on the same postsynaptic neuron can be mediated by distinct mechanisms, and suggest that these forms of plasticity may enable these two types of cortical synapses to support different functions.
Timing‐dependent LTD (t‐LTD) at vertical inputs on layer 2/3 neurons (L4‐L2/3) requires presynaptic NMDA receptors and is expressed presynaptically, but little is known about these mechanisms at horizontal inputs (L2/3‐L2/3). Using paired recordings we demonstrate here that t‐LTD at L2/3‐L2/3 synapses also requires NMDA receptors but is induced and expressed postsynaptically. These results indicate that similar forms of plasticity on the same postsynaptic neuron may be mediated by distinct mechanisms and suggest that these forms of plasticity may support different developmental functions in the cortex.
PMCID: PMC4002250  PMID: 24760524
LTD; LTP; mouse; somatosensory cortex; STDP
4.  T2 measurement of J-coupled metabolites in the human brain at 3T 
NMR in biomedicine  2011;25(4):10.1002/nbm.1767.
The proton T2 relaxation times of metabolites in the human brain were measured using point-resolved spectroscopy at 3T in vivo. Four echo times (54, 112, 246 and 374 ms) were selected from numerical and phantom analyses for effective detection of the glutamate multiplet at ~2.35 ppm. In vivo data were obtained from medial occipital and left occipital cortices of five healthy volunteers, which contained predominantly gray and white matter, respectively. Spectra were analyzed with LCModel software using volume-localized calculated spectra of brain metabolites. The estimate of the signal strength vs. TE was fitted to a monoexponential function for estimation of apparent T2 (T2†). The T2† was estimated to be similar between the brain regions for creatine, choline, glutamate and myo-inositol, but significantly different for the N-acetylaspartate singlet and multiplet. The T2†s of glutamate and myo-inositol were measured as 181±16 and 197±14 ms (mean±SD, N = 5) for medial occipital, and 180±12 and 196±17 ms for left occipital, respectively.
PMCID: PMC3852663  PMID: 21845738
1H-MRS; Relaxation time (T2); J-coupled metabolites; 3T; Human brain; Gray matter; White matter
5.  Measurement of glycine in gray and white matter in the human brain in vivo by 1H-MRS at 7.0 T 
Magnetic Resonance in Medicine  2012;68(2):325-331.
The concentration of glycine (Gly) was measured in gray and white matter (GM and WM) in the human brain using single-voxel localized 1H-MRS at 7 T. A point-resolved spectroscopy (PRESS) sequence with TE = 150 ms was used for measuring Gly levels in various regions of the frontal and occipital lobes in eleven healthy volunteers and one subject with a glioblastoma. The PRESS spectra were analyzed with LCModel using basis functions generated from density matrix simulations that included the effects of volume localized radio-frequency and gradient pulses. The fraction of gray and white matter within the voxels was obtained from T1-weighted image segmentation. The metabolite concentrations within the voxels, estimated with respect to the GM+WM water concentrations, were fitted to a linear function of fractional GM content. The Gly concentrations in pure GM and WM were estimated to be 1.1 and 0.1 mM, with 95% confidence intervals 1.0 - 1.2 and 0.0 - 0.2, respectively.
PMCID: PMC3396723  PMID: 22693073
6.  Presynaptic Self-Depression at Developing Neocortical Synapses 
Neuron  2013;77(1):35-42.
A central tenet of most theories of synaptic modification during cortical development is that correlated activity drives plasticity in synaptically connected neurons. Unexpectedly, however, using sensory-evoked activity patterns recorded from the developing mouse cortex in vivo, the synaptic learning rule that we uncover here relies solely on the presynaptic neuron. A burst of three presynaptic spikes followed, within a restricted time window, by a single presynaptic spike induces robust long-term depression (LTD) at developing layer 4 to layer 2/3 synapses. This presynaptic spike pattern-dependent LTD (p-LTD) can be induced by individual presynaptic layer 4 cells, requires presynaptic NMDA receptors and calcineurin, and is expressed presynaptically. However, in contrast to spike timing-dependent LTD, p-LTD is independent of postsynaptic and astroglial signaling. This spike pattern-dependent learning rule complements timing-based rules and is likely to play a role in the pruning of synaptic input during cortical development.
► Natural spike patterns in layer 4 neurons induce LTD at downstream synapses ► Spike pattern-dependent LTD can be induced in individual presynaptic neurons ► Spike pattern-dependent LTD requires presynaptic NMDA receptors and calcineurin ► Spike pattern-dependent LTD is independent of postsynaptic and astroglial signaling
Using natural spike patterns recorded from cortical layer 4 neurons in vivo, Rodríguez-Moreno et al. uncover a new spike pattern-dependent synaptic learning rule. They find that individual presynaptic neurons can drive NMDA receptor-dependent synaptic depression without a requirement for postsynaptic activity.
PMCID: PMC3542421  PMID: 23312514
7.  Rett Syndrome: Genes, Synapses, Circuits, and Therapeutics 
Development of the nervous system proceeds through a set of complex checkpoints which arise from a combination of sequential gene expression and early neural activity sculpted by the environment. Genetic and environmental insults lead to neurodevelopmental disorders which encompass a large group of diseases that result from anatomical and physiological abnormalities during maturation and development of brain circuits. Rett syndrome (RTT) is a neurological disorder of genetic origin, caused by mutations in the X-linked gene methyl-CpG binding protein 2 (MeCP2). It features a range of neuropsychiatric abnormalities including motor dysfunctions and mild to severe cognitive impairment. Here, we discuss key questions and recent studies describing animal models, cell-type specific functions of methyl-CpG binding protein 2 (MeCP2), defects in neural circuit plasticity, and attempts to evaluate possible therapeutic strategies for RTT. We also discuss how genes, proteins, and overlapping signaling pathways affect the molecular etiology of apparently unrelated neuropsychiatric disorders, an understanding of which can offer novel therapeutic strategies for a range of autism spectrum disorders (ASDs).
PMCID: PMC3346964  PMID: 22586411
RTT; visual cortex; synapse; plasticity; development
8.  miR-132, an experience-dependent microRNA, is essential for visual cortex plasticity 
Nature neuroscience  2011;14(10):1240-1242.
Using multiple quantitative analyses, we discovered microRNAs (miRNAs) abundantly expressed in visual cortex that respond to dark-rearing (DR) and/or monocular deprivation (MD). The most significantly altered miRNA, miR-132, was rapidly upregulated after eye-opening and delayed by DR. In vivo inhibition of miR-132 prevented ocular dominance plasticity in identified neurons following MD, and affected maturation of dendritic spines, demonstrating its critical role in the plasticity of visual cortex circuits.
PMCID: PMC3183341  PMID: 21892155
9.  Presynaptic NMDA Receptors and Spike Timing-Dependent Depression at Cortical Synapses 
It has recently been discovered that some forms of timing-dependent long-term depression (t-LTD) require presynaptic N-methyl-d-aspartate (NMDA) receptors. In this review, we discuss the evidence for the presence of presynaptic NMDA receptors at cortical synapses and their possible role in the induction of t-LTD. Two basic models emerge for the induction of t-LTD at cortical synapses. In one model, coincident activation of presynaptic NMDA receptors and CB1 receptors mediates t-LTD. In a second model, CB1 receptors are not necessary, and the activation of presynaptic NMDA receptors alone appears to be sufficient for the induction of t-LTD.
PMCID: PMC3059699  PMID: 21423504
plasticity; STDP; t-LTD; NMDA; presynaptic mechanisms
10.  Double Dissociation of Spike Timing–Dependent Potentiation and Depression by Subunit-Preferring NMDA Receptor Antagonists in Mouse Barrel Cortex 
Cerebral Cortex (New York, NY)  2009;19(12):2959-2969.
Spike timing–dependent plasticity (STDP) is a strong candidate for an N-methyl-D-aspartate (NMDA) receptor-dependent form of synaptic plasticity that could underlie the development of receptive field properties in sensory neocortices. Whilst induction of timing-dependent long-term potentiation (t-LTP) requires postsynaptic NMDA receptors, timing-dependent long-term depression (t-LTD) requires the activation of presynaptic NMDA receptors at layer 4-to-layer 2/3 synapses in barrel cortex. Here we investigated the developmental profile of t-LTD at layer 4-to-layer 2/3 synapses of mouse barrel cortex and studied their NMDA receptor subunit dependence. Timing-dependent LTD emerged in the first postnatal week, was present during the second week and disappeared in the adult, whereas t-LTP persisted in adulthood. An antagonist at GluN2C/D subunit–containing NMDA receptors blocked t-LTD but not t-LTP. Conversely, a GluN2A subunit–preferring antagonist blocked t-LTP but not t-LTD. The GluN2C/D subunit requirement for t-LTD appears to be synapse specific, as GluN2C/D antagonists did not block t-LTD at horizontal cross-columnar layer 2/3-to-layer 2/3 synapses, which was blocked by a GluN2B antagonist instead. These data demonstrate an NMDA receptor subunit-dependent double dissociation of t-LTD and t-LTP mechanisms at layer 4-to-layer 2/3 synapses, and suggest that t-LTD is mediated by distinct molecular mechanisms at different synapses on the same postsynaptic neuron.
PMCID: PMC2774397  PMID: 19363149
development; LTD; LTP; rodent; synaptic plasticity

Results 1-10 (10)