Plasticity and mTOR: Towards Restoration of Impaired Synaptic Plasticity in mTOR-Related Neurogenetic Disorders

Objective. To review the recent literature on the clinical features, genetic mutations, neurobiology associated with dysregulation of mTOR (mammalian target of rapamycin), and clinical trials for tuberous sclerosis complex (TSC), neurofibromatosis-1 (NF1) and fragile X syndrome (FXS), and phosphatase and tensin homolog hamartoma syndromes (PTHS), which are neurogenetic disorders associated with abnormalities in synaptic plasticity and mTOR signaling. Methods. Pubmed and Clinicaltrials.gov were searched using specific search strategies. Results/Conclusions. Although traditionally thought of as irreversible disorders, significant scientific progress has been made in both humans and preclinical models to understand how pathologic features of these neurogenetic disorders can be reduced or reversed. This paper revealed significant similarities among the conditions. Not only do they share features of impaired synaptic plasticity and dysregulation of mTOR, but they also share clinical features—autism, intellectual disability, cutaneous lesions, and tumors. Although scientific advances towards discovery of effective treatment in some disorders have outpaced others, progress in understanding the signaling pathways that connect the entire group indicates that the lesser known disorders will become treatable as well

Dark Matter Constraints from the Sagittarius Dwarf and Tail System

2MASS has provided a three-dimensional map of the >360 degree, wrapped tidal tails of the Sagittarius (Sgr) dwarf spheroidal galaxy, as traced by M giant stars. With the inclusion of radial velocity data for stars along these tails, strong constraints exist for dynamical models of the Milky Way-Sgr interaction. N-body simulations of Sgr disruption with model parameters spanning a range of initial conditions (e.g., Sgr mass and orbit, Galactic rotation curve, halo flattening) are used to find parameterizations that match almost every extant observational constraint of the Sgr system. We discuss the implications of the Sgr data and models for the orbit, mass and M/L of the Sgr bound core as well as the strength, flattening, and lumpiness of the Milky Way potential.Comment: 6 pages, 0 figures. Contribution to proceedings of ``IAU Symposium 220: Dark Matter in Galaxies'', eds. S. Ryder, D.J. Pisano, M. Walker, and K. Freema

Fossil Signatures of Ancient Accretion Events in the Halo

The role that minor mergers have played in the formation and structure of the Milky Way is still an open question, about which there is much debate. We use numerical simulations to explore the evolution of debris from a tidally disrupted satellite, with the aim of developing a method that can be used to identify and quantify signatures of accretion in a survey of halo stars. For a Milky Way with a spherical halo, we find that debris from minor mergers can remain aligned along great circles throughout the lifetime of the Galaxy. We exploit this result to develop the method of Great Circle Cell Counts (GC3), which we test by applying it to artificially constructed halo distributions. Our results suggest that if as few as 1\% of the stars in a halo survey are accreted from the disruption of a single subsystem smaller than the Large Magellanic Cloud, GC3 can recover the great circle associated with this debris. The dispersion in GC3 can also be used to detect the presence of structure characteristic of accretion in distributions containing a much smaller percentage of material accreted from any single satellite.Comment: 26 pages, AAS TeX, including 11 postscript figures. Accepted for publication in the Astrophysical Journal (Vol 466

Hematological monitoring during therapy with carbamazepine in children

No Abstract.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50302/1/410130622_ftp.pd

N -Methyl-D-Aspartate-Mediated Injury Enhances Quisqualic Acid-Stimulated Phosphoinositide Turnover in Perinatal Rats

Previous work in our laboratory demonstrated that ischemic-hypoxic brain injury in postnatal day 7 rats causes a substantial increase in phosphoinositide (PPI) turnover stimulated by the glutamate analogue quisqualic acid (QUIS) in the hippocampus and striatum. To examine this phenomenon in more detail, we performed similar experiments after producing injury by unilateral intracerebral injections of the glutamate analogue N -methyl-D-aspartate (NMDA). The 7-day-old rodent brain is hypersensitive to NMDA neurotoxicity and NMDA injection causes histopathology that closely resembles that produced by ischemia-hypoxia. NMDA, 17 nmol in 0.5 Μl, was injected into the right posterior striatum of 7-day-old rat pups and they were killed 3 days later. Hippocampal or striatal tissue slices were prepared from ipsilateral and contralateral hemispheres from vehicle-injected control and from noninjected control rat pups. Slices were then incubated with myo -[ 3 H]inositol plus glutamate agonists or antagonists in the presence of lithium ions and [ 3 H]inositol monophosphate ([ 3 H]IP 1 ) accumulation was measured. The glutamate agonists, QUIS, L-glutamic acid, and ( RS )-Α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, stimulated greater [ 3 H]IP 1 release in tissue ipsilateral to the NMDA injection compared with that in the contralateral side and in control pups. The glutamate antagonists, D,L-2-amino-7-phosphonoheptanoic acid, 3-[(+)-2-carboxypiperazin-4-yl]-propyl-l-phosphoric acid, kynurenic acid, and 6,7-dinitroquinoxaline-2,3-dione did not inhibit QUIS-stimulated [ 3 H]IP 1 release. The enhanced PPI turnover in the lesioned tissue was specific to glutamate receptors because carbachol (CARB) failed to elicit preferential enhanced stimulation. To investigate the possibility that alterations in the release of endogenous neurotransmitters had a role in potentiating QUIS-stimulated PPI turnover after NMDA injection, we examined the effect of tetrodotoxin. Tetrodotoxin (0.5 Μ M ) did not alter QUIS-or CARB-stimulated PPI hydrolysis in the lesioned or unlesioned tissue. The influence of extracellular calcium concentration on QUIS-stimulated [ 3 H]IP 1 formation was also examined after the NMDA lesion. Moderate reduction of calcium in the buffer (1 Μ M ) enhanced the lesion effect. Low calcium buffer enhanced QUIS-stimulated PPI turnover in the lesioned hippocampal slices, but reduced QUIS stimulation in contralateral slices and controls. In contrast, CARB-stimulated PPI turnover was not enhanced in low Ca 2+ buffer. A similar pattern of Ca 2+ dependency was observed in striatal slices. Calcium-free (<10 n M ) buffer suppressed PPI turnover in all groups. These studies demonstrate that NMDA-induced excitotoxic injury in neonatal rats causes a selective enhancement of QUIS-stimulated PPI turnover that resembles the effects of ischemia-hypoxia. In addition, we found that agonist-stimulated PPI turnover is sensitive to the in vitro Ca 2+ concentration. These changes could reflect altered coupling of non-NMDA receptors to phospholipase C activity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65991/1/j.1471-4159.1992.tb08337.x.pd

High time-resolution observations of the Vela pulsar

We present high time resolution observations of single pulses from the Vela pulsar (PSR B0833-45) made with a baseband recording system at observing frequencies of 660 and 1413 MHz. We have discovered two startling features in the 1413 MHz single pulse data. The first is the presence of giant micro-pulses which are confined to the leading edge of the pulse profile. One of these pulses has a peak flux density in excess of 2500 Jy, more than 40 times the integrated pulse peak. The second new result is the presence of a large amplitude gaussian component on the trailing edge of the pulse profile. This component can exceed the main pulse in intensity but is switched on only relatively rarely. Fluctutation spectra reveal a possible periodicity in this feature of 140 pulse periods. Unlike the rest of the profile, this component has low net polarization and emits predominantly in the orthogonal mode. This feature appears to be unique to the Vela pulsar. We have also detected microstructure in the Vela pulsar for the first time. These same features are present in the 660 MHz data. We suggest that the full width of the Vela pulse profile might be as large as 10 ms but that the conal edges emit only rarely.Comment: 6 pages, 5 figures, In Press with ApJ Letter

Effects of postnatal hypoxia-ischemia on cholinergic neurons in the developing rat forebrain: choline acetyltransferase immunocytochemistry

We studied the effect of early postnatal hypoxia-ischemia on cholinergic neurons in the developing rat forebrain using immunohistochemistry for choline acetyltransferase (ChAT). In 7-day-old rat pups, hypoxia-ischemia was induced in one cerebral hemisphere by combining unilateral carotid ligation with exposure to 8% oxygen for 2.5 h. This procedure caused brain injury in the hemisphere ipsilateral to ligation, most prominent in the corpus striatum, hippocampus and overlying cortex. In animals sacrificed 2-3 weeks after the insult, at approximately 3 weeks of age, the density of cholinergic cell bodies was slightly higher in the lesioned rostral caudate-putamen than the opposite side (+12%, P &lt; 0.05). In the more caudal portion of caudate-putamen, this effect was greater. In contrast, the size of the cholinergic perikarya in the injured striatum was significantly reduced. Cholinergic neurons in the septum (Ch1, Ch2), globus pallidus and nucleus basalis (Ch4) were relatively unaffected. Considered together with previously reported neurochemical data, these observations suggest that the immature cholinergic neurons are less vulnerable to death from hypoxia-ischemia than other components of the striatum. However, differentiation of surviving cholinergic perikarya and possibly their axonodendritic processes may be disrupted by the early insult.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26647/1/0000190.pd

Perinatal Hypoxic-Ischemic Brain Injury Enhances Quisqualic Acid-Stimulated Phosphoinositide Turnover

In an experimental model of perinatal hypoxic-ischemic brain injury, we examined quisqualic acid (Quis)-stimulated phosphoinositide (PPI) turnover in hippocampus and striatum. To produce a unilateral forebrain lesion in 7-day-old rat pups, the right carotid artery was ligated and animals were then exposed to moderate hypoxia (8% oxygen) for 2.5 h. Pups were killed 24 h later and Quis-stimulated PPI turnover was assayed in tissue slices obtained from hippocampus and striatum, target regions for hypoxic-ischemic injury. The glutamate agonist Quis (10 -4 M ) preferentially stimulated PPI hydrolysis in injured brain. In hippocampal slices of tissue derived from the right cerebral hemisphere, the addition of Quis stimulated accumulation of inositol phosphates by more than ninefold (1,053 ± 237% of basal, mean ± SEM, n = 9). In contrast, the addition of Quis stimulated accumulation of inositol phosphates by about fivefold in the contralateral hemisphere (588 ± 134%) and by about sixfold in controls (631 ± 177%, p < 0.005, comparison of ischemic tissue with control). In striatal tissue, the corresponding values were 801 ± 157%, 474 ± 89%, and 506 ± 115% (p < 0.05). In contrast, stimulation of PPI turnover elicited by the cho-linergic agonist carbamoylcholine, (10 -4 or 10 -2 M ) was unaffected by hypoxia-ischemia. The results suggest that prior exposure to hypoxia-ischemia enhances coupling of excitatory amino acid receptors to phospholipase C activity. This activation may contribute to the pathogenesis of irreversible brain injury and/or to mechanisms of recovery.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66017/1/j.1471-4159.1988.tb01046.x.pd