Nitric oxide and synaptic function

The free radical gas nitric oxide (NO) is a recently identified neuronal messenger that carries out diverse signaling tasks in both the central and peripheral nervous systems. Whereas most neurotransmitters are packaged in synaptic vesicles and secreted in a Ca2+-dependent manner from specialized nerve endings, NO is an unconventional transmitter which is not packaged in vesicles, but rather diffuses from its site of production in the absence of any specialized release machinery. The lack of a requirement for release apparatus raises the possibility that NO can be released from both pre- and postsynaptic neuronal elements. In addition, because NO is gaseous and extremely membrane permeant, it can bypass normal signal transduction routes involving interactions with synaptic membrane receptors. Although the targets of NO have not yet been completely described, it is known that NO can bind to the iron contained in heine groups, leading to conformational changes in associated proteins, such as guanylyl cyclase

Multifaceted Changes in Synaptic Composition and Astrocytic Involvement in a Mouse Model of Fragile X Syndrome.

Fragile X Syndrome (FXS), a common inheritable form of intellectual disability, is known to alter neocortical circuits. However, its impact on the diverse synapse types comprising these circuits, or on the involvement of astrocytes, is not well known. We used immunofluorescent array tomography to quantify different synaptic populations and their association with astrocytes in layers 1 through 4 of the adult somatosensory cortex of a FXS mouse model, the FMR1 knockout mouse. The collected multi-channel data contained approximately 1.6 million synapses which were analyzed using a probabilistic synapse detector. Our study reveals complex, synapse-type and layer specific changes in the neocortical circuitry of FMR1 knockout mice. We report an increase of small glutamatergic VGluT1 synapses in layer 4 accompanied by a decrease in large VGluT1 synapses in layers 1 and 4. VGluT2 synapses show a rather consistent decrease in density in layers 1 and 2/3. In all layers, we observe the loss of large inhibitory synapses. Lastly, astrocytic association of excitatory synapses decreases. The ability to dissect the circuit deficits by synapse type and astrocytic involvement will be crucial for understanding how these changes affect circuit function, and ultimately defining targets for therapeutic intervention

Dynamin-dependent NMDAR endocytosis during LTD and its dependence on synaptic state

BACKGROUND: The N-methyl-D-aspartate (NMDA)-type glutamate receptor expressed at excitatory glutamatergic synapses is required for learning and memory and is critical for normal brain function. At a cellular level, this receptor plays a pivotal role in triggering and controlling synaptic plasticity. While it has been long recognized that this receptor plays a regulatory role, it was considered by many to be itself immune to synaptic activity-induced plasticity. More recently, we and others have shown that NMDA receptor-mediated synaptic responses can be subject to activity-dependent depression. RESULTS: Here we show that depression of synaptic transmission mediated by NMDA receptors displays a state-dependence in its plasticity; NMDA receptors are resistant to activity-induced changes at silent and recently-silent synapses. Once synapses transition to the active state however, NMDA receptors become fully 'plastic'. This state-dependence is identical to that shown by the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor. Furthermore, the down-regulation of NMDAR-mediated responses during synaptic depression is prevented by disruption of dynamin-dependent endocytosis. CONCLUSION: NMDA receptor-mediated synaptic responses are plastic in a state-dependent manner. Depending on the plasticity state in which a synapse currently resides, NMDA receptors will either be available or unavailable for down-regulation. The mechanism underlying the down-regulation of NMDA receptor-mediated synaptic responses is endocytosis of the NMDA receptor. Other potential mechanisms, such as receptor diffusion along the plane of the membrane, or changes in the activity of the channel are not supported. The mechanisms of AMPA receptor and NMDA receptor endocytosis appear to be tightly coupled, as both are either available or unavailable for endocytosis in the same synaptic states. Endocytosis of NMDA receptors would serve as a potent mechanism for metaplasticity. Such state-dependent regulation of NMDAR endocytosis will provide fundamental control over downstream NMDA receptor-dependent plasticity of neuronal circuitry

Distinctive Structural and Molecular Features of Myelinated Inhibitory Axons in Human Neocortex.

Numerous types of inhibitory neurons sculpt the performance of human neocortical circuits, with each type exhibiting a constellation of subcellular phenotypic features in support of its specialized functions. Axonal myelination has been absent among the characteristics used to distinguish inhibitory neuron types; in fact, very little is known about myelinated inhibitory axons in human neocortex. Here, using array tomography to analyze samples of neurosurgically excised human neocortex, we show that inhibitory myelinated axons originate predominantly from parvalbumin-containing interneurons. Compared to myelinated excitatory axons, they have higher neurofilament and lower microtubule content, shorter nodes of Ranvier, and more myelin basic protein (MBP) in their myelin sheath. Furthermore, these inhibitory axons have more mitochondria, likely to sustain the high energy demands of parvalbumin interneurons, as well as more 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), a protein enriched in the myelin cytoplasmic channels that are thought to facilitate the delivery of nutrients from ensheathing oligodendrocytes. Our results demonstrate that myelinated axons of parvalbumin inhibitory interneurons exhibit distinctive features that may support the specialized functions of this neuron type in human neocortical circuits

Tribute to Professor Doug Rendleman

A tribute to Professor Doug Rendleman, who served on the faculty of the Washington and Lee University School of Law from 1988 to 2020. Rendleman became Professor of Law, Emeritus in 2020

Peculiar Type II Supernovae from Blue Supergiants

The vast majority of Type II supernovae (SNe) are produced by red supergiants (RSGs), but SN 1987A revealed that blue supergiants (BSGs) can produce members of this class as well, albeit with some peculiar properties. This best studied event revolutionized our understanding of SNe, and linking it to the bulk of Type II events is essential. We present here optical photometry and spectroscopy gathered for SN 2000cb, which is clearly not a standard Type II SN and yet is not a SN 1987A analog. The light curve of SN 2000cb is reminiscent of that of SN 1987A in shape, with a slow rise to a late optical peak, but on substantially different time scales. Spectroscopically, SN 2000cb resembles a normal SN II but with ejecta velocities that far exceed those measured for SN 1987A or normal SNe II, above 18000 km/s for H-alpha at early times. The red colours, high velocities, late photometric peak, and our modeling of this object all point toward a scenario involving the high-energy explosion of a small-radius star, most likely a BSG, producing 0.1 solar masses of Ni-56. Adding a similar object to the sample, SN 2005ci, we derive a rate of about 2% of the core-collapse rate for this loosely defined class of BSG explosions.Comment: Accepted to MNRAS on March 14, 201

Who Commits to the Rule of Law? Constrained Government and Foreign Direct Investment in Postcommunist States

Research linking credible commitments to the rule of law in terms of property rights and contract enforcement is a hallmark of recent efforts to explain economic growth and development. However, many postcommunist states have had difficulty making such commitments and spurring growth. Many argue political polarization prevents states from reforming laws and protecting property rights in some countries whereas single-party governance renders state promises incredible in others. I analyze pooled cross-sectional time-series data for twenty-four postcommunist countries and provide evidence effective constraints among elected officials act as democratic commitment mechanisms rendering government policies credible

The NANOGrav Nine-year Data Set:Observations, Arrival Time Measurements, and Analysis of 37 Millisecond Pulsars

We present high-precision timing observations spanning up to nine years for 37 millisecond pulsars monitored with the Green Bank and Arecibo radio telescopes as part of the North American Nanohertz Observatory for Gravitational Waves (NANOGrav) project. We describe the observational and instrumental setups used to collect the data, and methodology applied for calculating pulse times of arrival; these include novel methods for measuring instrumental offsets and characterizing low signal-to-noise ratio timing results. The time of arrival data are fit to a physical timing model for each source, including terms that characterize time-variable dispersion measure and frequency-dependent pulse shape evolution. In conjunction with the timing model fit, we have performed a Bayesian analysis of a parameterized timing noise model for each source, and detect evidence for excess low-frequency, or "red," timing noise in 10 of the pulsars. For 5 of these cases this is likely due to interstellar medium propagation effects rather than intrisic spin variations. Subsequent papers in this series will present further analysis of this data set aimed at detecting or limiting the presence of nanohertz-frequency gravitational wave signals