AMPA Receptor Properties are Modulated in the Early Stages Following Pilocarpine-induced Status Epilepticus

Glutamate over-activation and the consequent neuronal excitotoxicity have been identified as crucial players in brain dysfunctions such as status epilepticus (SE). Owing to the central function of 2-amino-3-(hydroxyl-5- methylisoxazole-4-yl) propionic acid receptors (AMPARs) in fast excitatory neurotransmission, these receptors have been recognized to play a prominent role in the development and generation of epileptic seizure. This study was undertaken to investigate both the early changes that affect glutamatergic neurons in the rat cerebral cortex and hippocampus and the level and channel properties of AMPARs in response to SE. The results obtained after 3 h of pilocarpine (PILO)-induced SE showed a disorganization of glutamatergic neurons in the CA3 and a thinner neuronal cell layer in the dentate gyrus (DG) region as compared with controls. A significant increase in AMPAR GluA2 protein expression, a decrease in GluA1, GluA3, and GluA4 expression, and a reduction in the phosphorylation of Ser831-GluA1 and Ser880-GluA2 were also observed. In addition, we report a downregulation of R/G editing levels and of Flip splicing isoforms, with a prominent effect on the hippocampus of PILO-treated rats. Our results suggest the presence of an attenuation of AMPARs' post-synaptic excitatory response to glutamate after PILO treatment, thus conferring neuronal protection from the excitotoxic conditions observed in the SE. This study suggests a role for AMPARs in alterations of the glutamatergic pathway during the onset and early progression of epilepsy, thus indicating additional targets for potential therapeutic interventions

Survey of Selective Neurotoxins

There has been an awareness of nerve poisons from ancient times. At the dawn of the twentieth century, the actions and mechanisms of these poisons were uncovered by modern physiological and biochemical experimentation. However, the era of selective neurotoxins began with the pioneering studies of R. Levi-Montalcini through her studies of the neurotrophin nerve growth factor (NGF), a protein promoting growth and development of sensory and sympathetic noradrenergic nerves. An antibody to NGF, namely, anti-NGF - developed in the 1950s in a collaboration with S. Cohen - was shown to produce an immunosympathectomy and virtual lifelong sympathetic denervation. These Nobel Laureates thus developed and characterized the first identifiable selective neurotoxin. Other selective neurotoxins were soon discovered, and the compendium of selective neurotoxins continues to grow, so that today there are numerous selective neurotoxins, with the potential to destroy or produce dysfunction of a variety of phenotypic nerves. Selective neurotoxins are of value because of their ability to selectively destroy or disable a common group of nerves possessing (1) a particular neural transporter, (2) a unique set of enzymes or vesicular transporter, (3) a specific type of receptor or (4) membranous protein, or (5) other uniqueness. The era of selective neurotoxins has developed to such an extent that the very definition of a selective neurotoxin has warped. For example, (1) N-methyl-D- aspartate receptor (NMDA-R) antagonists, considered to be neuroprotectants by virtue of their prevention of excitotoxicity from glutamate receptor agonists, actually lead to the demise of populations of neurons with NMDA receptors, when administered during ontogenetic development. The mere lack of natural excitation of this nerve population, consequent to NMDA-R block, sends a message that these nerves are redundant - and an apoptotic cascade is set in motion to eliminate these nerves. (2) The rodenticide rotenone, a global cytotoxin that acts mainly to inhibit complex I in the respiratory transport chain, is now used in low dose over a period of weeks to months to produce relatively selective destruction of substantia nigra dopaminergic nerves and promote alpha-synuclein deposition in brain to thus model Parkinson\u27s disease. Similarly, (3) glial toxins, affecting oligodendrocytes or other satellite cells, can lead to the damage or dysfunction of identifiable groups of neurons. Consequently, these toxins might also be considered as selective neurotoxins, despite the fact that the targeted cell is nonneuronal. Likewise, (4) the dopamine D2-receptor agonist quinpirole, administered daily for a week or more, leads to development of D2-receptor supersensitivity - exaggerated responses to the D2-receptor agonist, an effect persisting lifelong. Thus, neuroprotectants can become selective neurotoxins; nonspecific cytotoxins can become classified as selective neurotoxins; and receptor agonists, under defined dosing conditions, can supersensitize and thus be classified as selective neurotoxins. More examples will be uncovered as the area of selective neurotoxins expands. The description and characterization of selective neurotoxins, with unmasking of their mechanisms of action, have led to a level of understanding of neuronal activity and reactivity that could not be understood by conventional physiological observations. This chapter will be useful as an introduction to the scope of the field of selective neurotoxins and provide insight for in-depth analysis in later chapters with full descriptions of selective neurotoxins

Search for Gravitational-lensing Signatures in the Full Third Observing Run of the LIGO–Virgo Network

Abstract Gravitational lensing by massive objects along the line of sight to the source causes distortions to gravitational wave (GW) signals; such distortions may reveal information about fundamental physics, cosmology, and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO-Virgo network. We search for repeated signals from strong lensing by (1) performing targeted searches for subthreshold signals, (2) calculating the degree of overlap among the intrinsic parameters and sky location of pairs of signals, (3) comparing the similarities of the spectrograms among pairs of signals, and (4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by (1) frequency-independent phase shifts in strongly lensed images, and (2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the nondetection of GW lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects.</jats:p

Search for Gravitational-lensing Signatures in the Full Third Observing Run of the LIGO–Virgo Network

Abstract Gravitational lensing by massive objects along the line of sight to the source causes distortions to gravitational wave (GW) signals; such distortions may reveal information about fundamental physics, cosmology, and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO-Virgo network. We search for repeated signals from strong lensing by (1) performing targeted searches for subthreshold signals, (2) calculating the degree of overlap among the intrinsic parameters and sky location of pairs of signals, (3) comparing the similarities of the spectrograms among pairs of signals, and (4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by (1) frequency-independent phase shifts in strongly lensed images, and (2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the nondetection of GW lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects.</jats:p