Mechanisms of Synapse formation and Maintenance: Insights From the Developing and Diseased Nervous System

ABSTRACT MECHANISMS OF SYNAPSE FORMATION AND MAINTENANCE: INSIGHTS FROM THE DEVELOPING AND DISEASED NERVOUS SYSTEM Ethan G. Hughes Rita J. Balice-Gordon, Ph.D. The formation and maintenance of synapses is essential for the central nervous system (CNS) to function. In the developing nervous system, the assembly of synaptic circuits is a complex and dynamic process, requiring the coordinated exchange of signals between pre- and postsynaptic neurons and surrounding glia. The maintenance and modulation of synaptic connections is required for normal CNS function and ongoing plasticity. The structural and functional integrity of synaptic connections is often modified or lost in the diseased nervous system, resulting in profound cognitive and behavioral deficits. While some aspects of the mechanisms underlying the formation, maintenance and plasticity of CNS synapses in the developing and diseased nervous system have been elucidated, many more remain to be understood. In my thesis work, I have examined the role of astrocytes in the development of GABAergic hippocampal synapses in in vitro models. I have also examined the maintenance of glutamatergic synapses in in vitro and in vivo models of anti-NMDAR encephalitis, an immune-mediated disorder of memory and behavior. First, I demonstrate that secreted factors released from astrocytes specifically increase GABAergic axon length, branching, and synaptogenesis, that these effects are not mediated by several well-known candidates, and that the secreted factors from astrocytes are proteins. Second, I examined the identity of the proteins released from astrocytes that affect GABAergic neurons using size fractionation, mass spectroscopy, and computational analyses. Third, I examined the cellular and synaptic mechanisms underlying anti-NMDAR encephalitis and investigated the effects of autoantibodies from patients with this disorder on the maintenance and function of CNS excitatory synapses. Together, my work extends our understanding of how neuron-glial communication modulates the formation of synapses in the developing brain, and how the disruption of synapse maintenance may underlie cognitive deficits in the diseased nervous system

Dust Emission from Evolved and Unevolved HII Regions in the Large Magellanic Cloud

We present a study of the dust properties of 12 classical and superbubble HII regions in the Large Magellanic Cloud. We use infrared photometry from Spitzer (8, 24, 70, and 160 \mum bands), obtained as part of the Surveying the Agents of a Galaxy's Evolution (SAGE) program, along with archival spectroscopic classifications of the ionizing stars to examine the role of stellar sources on dust heating and processing. Our infrared observations show surprisingly little correlation between the emission properties of the dust and the effective temperatures or bolometric magnitudes of stars in the HII regions, suggesting that the HII region evolutionary timescale is not on the order of the dust processing timescale. We find that the infrared emission of superbubbles and classical HII regions shows little differentiation between the two classes, despite the significant differences in age and morphology. We do detect a correlation of the 24 \mum emission from hot dust with the ratio of 70 to 160 \mum flux. This correlation can be modeled as a trend in the temperature of a minority hot dust component, while a majority of the dust remains significantly cooler.Comment: 15 pages, 5 figures. Accepted to Ap

Universal heat conduction in the iron-arsenide superconductor KFe2As2 : Evidence of a d-wave state

The thermal conductivity of the iron-arsenide superconductor KFe2As2 was measured down to 50 mK for a heat current parallel and perpendicular to the tetragonal c-axis. A residual linear term (RLT) at T=0 is observed for both current directions, confirming the presence of nodes in the superconducting gap. Our value of the RLT in the plane is equal to that reported by Dong et al. [Phys. Rev. Lett. 104, 087005 (2010)] for a sample whose residual resistivity was ten times larger. This independence of the RLT on impurity scattering is the signature of universal heat transport, a property of superconducting states with symmetry-imposed line nodes. This argues against an s-wave state with accidental nodes. It favors instead a d-wave state, an assignment consistent with five additional properties: the magnitude of the critical scattering rate for suppressing Tc to zero; the magnitude of the RLT, and its dependence on current direction and on magnetic field; the temperature dependence of the thermal conductivity.Comment: To appear in Physical Review Letter

From d-wave to s-wave pairing in the iron-pnictide superconductor (Ba,K)Fe2As2

The nature of the pairing state in iron-based superconductors is the subject of much debate. Here we argue that in one material, the stoichiometric iron pnictide KFe2As2, there is overwhelming evidence for a d-wave pairing state, characterized by symmetry-imposed vertical line nodes in the superconducting gap. This evidence is reviewed, with a focus on thermal conductivity and the strong impact of impurity scattering on the critical temperature Tc. We then compare KFe2As2 to Ba0.6K0.4Fe2As2, obtained by Ba substitution, where the pairing symmetry is s-wave and the Tc is ten times higher. The transition from d-wave to s-wave within the same crystal structure provides a rare opportunity to investigate the connection between band structure and pairing mechanism. We also compare KFe2As2 to the nodal iron-based superconductor LaFePO, for which the pairing symmetry is probably not d-wave, but more likely s-wave with accidental line nodes

Kondo tunneling through real and artificial molecules

When a cerocene molecule is chemisorbed on metallic substrate, or when an asymmetric double dot is hybridized with itinerant electrons, its singlet ground state crosses its lowly excited triplet state, leading to a competition between the Zhang-Rice mechanism of singlet-triplet splitting in a confined cluster and the Kondo effect (which accompanies the tunneling through quantum dot under a Coulomb blockade restriction). The rich physics of an underscreened S=1 Kondo impurity in the presence of low-lying triplet/singlet excitations is exposed. Estimates of the magnetic susceptibility and the electric conductance are presented.Comment: 4 two-column revtex pages including 1 eps figur

Capacitance of a quantum dot from the channel-anisotropic two-channel Kondo model

We investigate the charge fluctuations of a large quantum dot coupled to a two-dimensional electron gas via a quantum point contact following the work of Matveev. We limit our discussion to the case where exactly two channels enter the dot and we discuss the role of an anisotropy between the transmission coefficients (for these two channels) at the constriction. Experimentally, a channel-anisotropy can be introduced applying a relatively weak in-plane magnetic field to the system when only one ``orbital'' channel is open. The magnetic field leads to different transmission amplitudes for spin-up and spin-down electrons. In a strong magnetic field the anisotropic two-channel limit corresponds to two (spin-polarized) orbital channels entering the dot. The physics of the charge fluctuations can be captured using a mapping on the channel-anisotropic two-channel Kondo model. For the case of weak reflection at the point contact this has already briefly been stressed by one of us in PRB {\bf 64}, 161302R (2001). This mapping is also appropriate to discuss the conductance behavior of a two-contact set-up in strong magnetic field. Here, we elaborate on this approach and also discuss an alternative solution using a mapping on a channel-isotropic Kondo model. In addition we consider the limit of weak transmission. We show that the Coulomb-staircase behavior of the charge in the dot as a function of the gate voltage, is already smeared out by a small channel-anisotropy both in the weak- and strong transmission limits.Comment: 17 pages, 4 figures, 1 Table; Expands cond-mat/0101126; Sec. VI on 2-contact setup added (Final version for PRB

On the photoproduction of jets at HERA

We discuss the inclusive jet production at HERA in the next-to-leading logarithm approximation. Theoretical uncertainties are considered in some details. We show the importance of the jet rapidity distribution to constrain the parton densities in the photon. A comparison is made with the recent H1 data.Comment: 10 + 7 figures included uuencoded tar-compressed ([email protected]) , ENSLAPP-A-484/94, LPTHE Orsay 94-8

Efficacy of topical cobalt chelate CTC-96 against adenovirus in a cell culture model and against adenovirus keratoconjunctivitis in a rabbit model

BACKGROUND: Adenovirus (Ad), associated with significant morbidity, has no topical treatment. A leading CTC compound (CTC-96), a Co(III )chelate, was found to have potent in vitro and in vivo antiviral efficacy against herpes viruses. In this study CTC-96 is being tested for possible anti-Adenovirus activity. METHODS: The biological anti-adenovirus activity of CTC-96 in concentrations from 5 to 250 ug/ml, was evaluated initially by viral inactivation (viral exposure to CTC-96 followed by dilution and inoculation of cells), virucidal (viral exposure to CTC-96 and inoculation of cells without dilution) and antiviral (effect of CTC-96 on previously adsorbed virus) plaque assays on HeLa (human cervical carcinoma), A549 (human lung carcinoma) and SIRC (rabbit corneal) cells. After verifying the antiviral activity, New Zealand White rabbits were infected with Ad-5 into: 1) the anterior cul-de-sac scarifying the conjunctiva (Group "C+"); 2) the anterior cul-de-sac scarifying the conjunctiva and cornea (Group "CC+"); 3) the stroma (Group "CI+"). Controls were sham-infected ("C-", "CC-", "CI-"). Other rabbits, after "CC", were treated for 21 days with: 1) placebo, 9x/day ("-"); 2) CTC-96, 50 ug/ml, 9x/day ("50/9"); CTC-96, 50 ug/ml, 6x/day ("50/6"); CTC-96, 25 ug/ml, 6x/day ("25/6"). All animals were monitored via examination and plaque assays. RESULTS: In vitro viral inactivation, virucidal and antiviral assays all demonstrated CTC-96 to be effective against Adenvirus type 5 (ad-5). The in vivo model of Ad keratoconjunctivitis most similar to human disease and producing highest viral yield was "CC". All eyes (6/6) developed acute conjunctivitis. "CI" yielded more stromal involvement (1/6) and iritis (5/6), but lower clinical scores (area × severity). Infection via "C" was inconsistent (4/6). Fifty (50) ug/ml was effective against Ad-5 at 6x, 9x dosings while 25 ug/ml (6x) was only marginally effective. CONCLUSION: CTC-96 demonstrated virucidal activity against Ad5 in tissue culture with HeLa, A549 and SIRC cell lines. Animal Model Development: 1) "CC" produced conjunctival infection with occasional keratitis similar to human disease; "CI" yielded primarily stromal involvement; 2) "C" consistently produced neither conjunctivitis nor keratitis. CTC Testing: 1) Conjunctivitis in all eyes; 2) Resolution fastest in "50/9" ("50/9". "50/6" > "25/6" > "-"); 3) Efficacy in "50/6" was not statistically different than "50/9"; 4) Conjunctival severity was lower in treatment groups then controls; 5) Little corneal or intra-ocular changes were noted