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Excitotoxicity may be a contributing factor to the neuropathological dopamine cell loss in the substantia nigra seen in Parkinson's disease. We recently reported that dopaminergic neurons in CD-1 mouse mesencephalic cell cultures expressed NMDA receptors as a function of cell culture age and that activation of these receptors was not required for, but could contribute to MPP+- induced DA cell death1. The current study repeats these experiments using cell cultures from C57BL/6 mouse embryos, a strain that is more susceptible to MPP+ toxicity. C57BL/6 mouse mesencephalic cells were grown in culture for 7 (DIV 7) or 11 (DIV 11) days and the number of dopaminergic neurons (tyrosine hydroxylase immunoreactive cells [TH-IR cells]) expressing the NMDA R1(NR1) subunit were determined using double-label immunofluorescence microscopy. Over 80% of TH-IR cells co-stained for NR1 at both time points. Cultures were treated with various concentrations of MPP+ for 48 hours. Similar dose-dependent MPP+ toxicity was seen in both DIV 7 and DIV 11 cultures. MK-801 pretreatment was ineffective at antagonizing MPP+ toxicity in the C57BL/6 cultures at DIV 7 but significantly blocked MPP+ toxicity at all doses in DIV 11 cultures. This antagonism was not seen in CD-1 cultures. The DIV 11 C57BL/6 cultures were also more vulnerable to MPP+ toxicity than DIV11 CD-1 cultures. These results indicate that NMDA receptor activation contributes to MPP+-induced neurotoxicity in DIV 11 cultures but not in DIV 7 cultures grown from C57BL/6 mouse mesencephalon. The difference in susceptibility to MPTP-induced neurotoxicity in vivo between C57BL/6 and CD-1 mice may be a result of NMDA receptor-mediated processes.

1 Church and Hewett, J Neurosci Res 73:811-817(2003)
Support Contributed By: Trinity College Research Student Grants

Citation: D.A. Cuzzone, R. McGovern, W.H. Church. NMDA RECEPTOR EXPRESSION AND INVOLVEMENT IN MPP+ TOXICITY IN C57BL/6 MURINE CELL CULTURES Program No. 563.18. 2004 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, 2004. Online.

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We recently identified an arginine in the ß2 subunit of the GABAA receptor (ß2R207) that, when mutated, slowed GABA binding and sped unbinding (1). Homology modeling suggests that this arginine and two others (a 1R67, a 1R132) appear to be located at the GABA binding interface between a 1 and ß2 subunits, at approximately the same distance from the plasma membrane. Mutation of each of these arginines to cysteine causes a 70-120 fold increase in the EC50 for GABA. We therefore proposed that these three residues form a "crown of arginines" that contacts and stabilizes the GABA molecule in the binding site. This hypothesis predicts that mutation of each arginine should produce a similar slowing of binding and speeding of unbinding, but that none should alter gating. As an initial test, we used rapid GABA applications to outside-out patches of HEK-293 cells transfected with human a 1 and ß2 subunits (-60 mV, room temp). We examined wild type a 1ß2 receptors and alanine mutants a 1R67A and ß2R207A. Neither the rate nor extent of macroscopic desensitization during 500 ms pulses of saturating (10 mM) GABA was altered by either mutation, suggesting that no changes in gating had occurred (weighted time constant, mean ± SD, wt = 38±16 ms, n = 9; a 1ß2R207A = 58±37 ms, n = 7; a 1R67A ß2 = 79±82 ms, n = 3, p > 0.05, ANOVA). In contrast, deactivation following a brief (2 ms) pulse was greatly accelerated, to a similar degree, by both mutants (wt = 103±42 ms, n = 9; a 1ß2R207A = 7.9±1.5 ms, n = 4; a 1R67Aß2 = 19±4 ms, n = 2). The simplest explanation for these results is that a 1R67 and ß2R207 play roughly equivalent roles in stabilizing the GABA-bound state, whereas neither participates in channel gating. These effects are consistent with the idea that these two residues collaborate to form a region of contact with the GABA molecule.

Refs: 1) J Neurosci 24:2733.
Support Contributed By: Epilepsy Foundation (DAW)

Citation: K.A. Gniotczynski, M.P. Goldschen, M.V. Jones, D.A. Wagner. MULTIPLE ARGININES ON THE GABAA RECEPTOR COLLABORATE TO HOLD GABA Program No. 51.12. 2004 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, 2004. Online.

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The contributions of primary auditory cortex (AI) to sound localization have been extensively studied. However, little is known of the contributions of non-primary auditory cortex to sound localization. In this study we examined the contributions of both primary and all the recognized regions of acoustically-responsive non-primary auditory cortex to sound localization during unilateral or bilateral reversible deactivation. After attending to a central visual stimulus, cats learned to approach a 100ms broad-band, white noise stimulus emitted from one of 13 speakers (at 15 deg intervals) along the horizontal plane. Following training, cats had one or two bilateral pairs of cryoloops implanted over regions of auditory cortex. We examined AI (including the dorsal zone (DZ)), the three other tonotopic fields (anterior auditory field-AAF, posterior auditory field-PAF, ventroposterior auditory field-VPAF), as well as six non-tonotopic regions: second auditory cortex (AII), the anterior ectosylvian sulcus (AES), the insular (IN) region, the temporal (T) region (including the ventral auditory field (VAF)), the dorsal posterior ectosylvian (dPE) gyrus (including the intermediate posterior ectosylvian (iPE) gyrus), and the ventral posterior ectosylvian (vPE) gyrus. Unilateral deactivation of AI caused sound localization deficits in the contralateral field. Bilateral deactivation of AI resulted in bilateral sound localization deficits throughout the 180 deg field examined. Of the three other tonotopically organized fields, only deactivation of PAF resulted in sound localization deficits. These deficits were virtually identical to the unilateral and bilateral deactivation results during AI deactivation. Of the six non-tonotopic regions examined, only deactivation of AES resulted in sound localization deficits. Therefore, we identified one non-tonotopic (AES) and two tonotopic (AI and PAF) areas critical for sound localization.

Support Contributed By: NIDCD

Citation: A.J. Hall, S. Malhotra, S.G. Lomber. CEREBRAL CONTROL OF SOUND LOCALIZATION IN THE CAT: UNILATERAL AND BILATERAL DEACTIVATION OF 10 AUDITORY AREAS Program No. 529.8. 2004 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, 2004. Online.

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Alterations of attentional processing are thought to contribute to the positive symptoms in schizophrenia. Sensitization of the mesolimbic dopaminergic system has been hypothesized to underlie many of the cognitive deficits in schizophrenia. The present study tested the effects of administration of an escalating amphetamine regimen (1.0-5.0 mg/kg) in a sustained attention task. Rats were trained to perform a two-lever sustained attention task involving discrimination of brief visual signals and nonsignals. Attentional performance was assessed following administration of an escalating amphetamine regimen, following "challenge" amphetamine administration (1.0 mg/kg), and for three days after the challenge session. Finally, a dose-response experiment was conducted to test the appropriateness of the drug dose for the challenge session. Amphetamine-pretreatment increased errors on nonsignal trials (an increase in the false alarm rate) following escalating amphetamine administration. Administration of a challenge amphetamine dose did not differentially affect accuracy compared with sessions immediately prior the challenge administration. The latency to press a lever was decreased during and after challenge amphetamine administration. During the final three days of behavioral testing, there were no differences in accuracy between amphetamine-pretreated and saline-pretreated animals. The dose-response study revealed no differences between saline and 1.0 mg/kg amphetamine on any measures of task performance. Doses higher than 1.0 mg/kg amphetamine increased the omission rate. In summary, prior escalating amphetamine administration transiently disrupted attention, increasing incorrect "claims" for a signal on trials when no signal was presented. The present data support the use of escalating amphetamine regimens to model the attentional deficits in schizophrenia.

Support Contributed By: a Young Investigator Award from NARSAD to JAB and a summer grant from the Howard Hughes Medical Institute to RLK.

Citation: R.L. Kondrad, J.A. Burk. ESCALATING AMPHETAMINE TRANSIENTLY INCREASES FALSE ALARMS IN A SUSTAINED ATTENTION TASK IN RATS Program No. 779.5. 2004 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, 2004. Online.

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The cAMP signaling pathway appears to be essential in rodents for triggering sustained enhancement of synaptic transmission and for consolidation of spatial information into long-term storage. We and others have observed changes with aging in forms of hippocampal long term potentiation (LTP) that are mediated by the cAMP signal transduction pathway. These include age-related changes in L-LTP (Bach et al., PNAS 96:5280-5) and "chemLTP" induced by ß-adrenergic receptor stimulation followed immediately by application of Mg++ -free aCSF (Raskin et al., SFN Abstracts 2002). In this study we examined whether such changes in LTP are related to changes in basal and/or stimulated cAMP levels. Cyclic AMP production was assayed in hippocampal slices from young (6-week-old) and aged (22-month-old) F344 rats after exposure to isoproterenol (1 µM) paired with 10 mM Ca2+ /0 Mg2+ /30 mM K+ (ISO-chemLTP), or following direct stimulation of adenylate cyclase with forskolin (10 µM) paired with the Mg++ -free depolarizing solution (FSK-chemLTP). Cyclic AMP production in response to the ISO-chemLTP protocol was similar in hippocampal slices from young and aged Fischer 344 rats. However, cAMP production following the FSK-chemLTP protocol was significantly lower in aged vs young rats. Interestingly, we observed higher basal levels of cAMP in aged tissue as compared to young. These findings suggest that the molecular defects responsible for age-related deficits in the ß-adrenergic receptor-mediated form of chemLTP lie downstream of adenylate cyclase activation. Aged neurons appear to compensate for these downstream changes by up-regulating basal levels of cAMP. This elevation in basal [cAMP] could be due to decreases in cAMP phosphodiesterase activity, or increases in constitutive activity of adenylate cyclase. The ability to stimulate isoforms of adenylate cyclase that are not activated by ß-adrenergic receptors, however, was diminished in aged hippocampus.

Support Contributed By: Hirsch Foundation

Citation: S.P. Kuo, K.D. Parfitt. CHANGES WITH AGING IN FORSKOLIN-STIMULATED AND BASAL CYCLIC AMP IN THE HIPPOCAMPUS Program No. 905.5. 2004 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, 2004. Online.

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Historically, the insular cortex has attracted only minimal research interest, perhaps due to its inconspicuous position in the brain. Although its cytoarchitectural organization and circuitry have recently been documented, no quantitative data on the dendritic characteristics of the insula have yet been reported. The present study quantified the dendritic and spine extent of layer III pyramidal neurons across three regions of human insular cortex. The dendritic properties of the insula were also compared with those of previously quantified human neocortex. Tissue was removed from the left insula of five adult males (M.age = 43±6 years), specifically from the secondary gyrus breves, the precentral insular gyrus, and the postcentral insular gyrus. Sampled tissue was then stained with a modified rapid Golgi technique. Ten neurons from each gyrus (N = 150) were quantified. A nested ANOVA revealed significant differences across the three regions of the insula for total dendritic length and dendritic spine number. As predicted, both measures significantly increased from the postcentral gyrus to secondary gyrus breves, which is consistent with the general caudal to rostral dendritic progression observed in the neocortex. Moreover, comparison of dendritic morphology between the insula and the neocortex demonstrated that insular pyramidal neurons have longer but less branchy dendrites than those of the neocortex. The results suggest potential differences in dendritic systems between insular and neocortical neurons that may provide clues for understanding the functional characteristics of insular cortex.

Citation: H.W. Lee, K.E. Travis, C.A. Dufault, C.A. Hass, B. Jacobs. REGIONAL DENDRITIC VARIATION IN HUMAN INSULAR CORTEX: A QUANTITATIVE GOLGI STUDY Program No. 384.1. 2004 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, 2004. Online.

 

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Previous studies have established that the P13 midlatency auditory evoked potential (MAEP) is generated, at least in part, by cholinergic PPN neurons. It is sleep state-dependent, rapidly habituating, blocked by the muscarinic antagonist scopolamine and is the rodent equivalent of the human P50 potential. That is, the P13 MAEP may be a measure of reticular activating system (RAS) output to the thalamus. While the effects of several neuroactive agents on the amplitude and habituation of this potential in male rats have been reported, the vertex-recorded P13 MAEP has not been characterized in female rats. In this investigation the P13 MAEP of adult (age 4-6 months) Sprague-Dawley rats was recorded from intact and ovariectomized females and intact males prepared as described by Miyazato, et al, 1996. Recordings were made daily for 60-90 days. Vaginal smears were taken daily from females so that changes in P13 MAEP amplitude and habituation could be correlated with reproductive cycle phase. The amplitude of the P13 MAEP was significantly greater during diestrus than during metestrus (p<0.01) or proestrus (p<0.05). When compared to male animals, females showed significantly reduced responses during metestrus (p<0.001) and proestrus (p<0.01), but responses during diestrus and estrus were indistinguishable from males. Habituation was measured as the ratio of the P13 MAEP amplitude in response to the 2nd stimulus of a pair of identical stimuli (interstimulus interval 500 ms) to the amplitude of P13 elicited by the 1st stimulus of the pair. In intact females habituation was significantly greater during diestrus than in any other phase of the cycle.

Support Contributed By: Arkansas Biosciences Institute, NIH NCRR grants P20 RR-16460 from the BRIN PRogram and P20 COBRE RR-020146

Citation: M. Pate, R.D. Skinner, E. Garcia-Rill, R.A. Buchanan. CHANGES IN P13 AMPLITUDE AND HABITUATION DURING THE REPRODUCTIVE CYCLE OF FEMALE RATS Program No. 546.9. 2004 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, 2004. Online.

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Entorhinal cortex degeneration begins very early in Alzheimer's disease (AD), a disorder characterized by severe memory disruption. Indeed, loss of entorhinal volume is predictive of AD and two of the hallmark neuroanatomical markers of AD, amyloid plaques and neurofibrillary tangles (NFTs), are particularly prevalent in the entorhinal area of AD-afflicted brains. Gene transfer techniques were used to create an Alzheimer's model by injecting a recombinant adeno-associated viral vector with a mutated human tau gene (P301L) into the entorhinal cortex of adult rats. The objective of the present investigation was to determine whether localized expression of human mutated tau would produce either behavioral or anatomical pathology. Spatial memory on a Y-maze was tested for approximately four months post-surgery. Upon completion of behavioral testing the brains were assessed for expression of human tau and evidence of tauopathy. Rats injected with the tau vector became persistently impaired on the task after about 30 days of postoperative testing, whereas the control rats injected with a green fluorescent protein control vector performed at criterion levels during that period. Histological analysis confirmed the presence of hyperphosphorylated tau and NFTs in the entorhinal cortex and neighboring retrohippocampal areas as well as degeneration of the perforant path. Thus, vector-induced tauopathy in retrohippocampal areas significantly impaired mnemonic functioning in rats.

Support Contributed By: NIH Grant No. MH60608 to JJR and NIH Grant No. AG10485 to MAK

Citation: W.E. Poulton, M.A. King, E.M. Meyer, R. Wang, R.L. Klein, J.J. Ramirez. MODELING ALZHEIMER'S TAUOPATHY: ADENO-ASSOCIATED VIRUS VECTOR EXPRESSING MUTATED TAU IN THE ENTORHINAL CORTEX OF RATS IMPAIRS SPATIAL WORKING MEMORY Program No. 787.1. 2004 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, 2004. Online.

 

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Nestin is a class IV intermediate filament protein that is widely accepted as a marker for uncommitted neural progenitor cells in the developing and adult mammalian brain. Here we show for the first time that many terminally differentiated neurons in the adult male Sprague-Dawley rat brain also express nestin. These nestin-expressing neurons (NENs) are found in regions of the cholinergic basal forebrain, such as the nucleus of the diagonal band, medial septal nucleus, and nucleus basalis; and in associated areas, such as the preoptic areas of the hypothalamus, piriform cortex, corpus striatum, and hippocampus. Cytologically, NENs are characterized by medium to large cell somas supporting one or more primary processes, frequently with extensive ramification, and by the expression of the neuron-specific markers NeuN and ß-III tubulin. NENs in the cholinergic basal forebrain and corpus striatum express choline acetyl transferase, and NENs in the hippocampus express the neuronal glutamate transporter EAAC1, indicating cholinergic and glutamatergic phenotypes, respectively. To determine whether NENs are newly born, three adult rats were given daily injections of bromodeoxyuridine (BrdU) for four weeks and then sacrificed two hours after the last injection. In none of these animals did we observe BrdU-labeled NENs, demonstrating that these cells are not newly born. Nestin expression by terminally differentiated neurons in the adult brain may indicate that these cells are undergoing plasticity-related remodeling of their cytoskeletons or are dedifferentiating, but further work will be required to clarify the role played by the expression of nestin in NENs. Nevertheless, the present results demonstrate that nestin expression by a cell of neural lineage in the adult brain does not by itself identify the cell as an uncommitted neural progenitor cell.

Support Contributed By: Retina Research Foundation

Citation: A.J. Rao, O.N. Demerdash, M.L. Hendrickson, R.E. Kalil. NESTIN EXPRESSION BY TERMINALLY DIFFERENTIATED NEURONS IN THE ADULT RAT BRAIN Program No. 719.17. 2004 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, 2004. Online.

 

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The abuse of methamphetamine (MA) has increased in recent years and women of childbearing age who abuse MA are of particular interest since MA readily crosses the placenta and reaches the developing brain. MA causes spatial learning and memory deficits in the Morris Water Maze when administered to rats from P11-15, a period analogous to human third trimester dentate gyrus granule cell development. It also increases plasmatic CORT concentrations and decreases hippocampal serotonin levels following P11 administration. Changes in CORT and 5-HT can affect neurogenesis. In the current experiment, we investigated the effects of MA administration on cell proliferation (BrdU) and apoptosis (TUNEL) during the period when MA affects CORT and 5-HT and induces later learning deficits. Two different dosing regimens were investigated. One male and one female per litter were placed in one of 4 groups and administered MA (10mg/kg) or SAL subcutaneously 4X/day at 2 h intervals on P11 or P11-15. BrdU was administered immediately following the last dose on P11 or P15 and animals were perfused 18 hours later. Paraffin embedded sections were labeled for BrdU or TUNEL. Cells were counted in the anterior dentate gyrus. MA produced a significant decrease in BrdU labeled cells on P12. At P16, fewer cells were BrdU labeled overall and no group differences were seen. TUNEL staining at either age was too low to be reliable. The decrease in BrdU labeled cells observed following P11 administration of MA may indicate changes in neuronal cytoarchitecture that contribute to later MA-induced spatial learning and memory deficits.

Support Contributed By: DA06733, DA14269

Citation: T.L. Schaefer, K.A. Burns, C.Y. Kuan, C.V. Vorhees, M.T. Williams. EFFECTS OF METHAMPHETAMINE ADMINISTRATION ON CELL PROLIFERATION IN THE DEVELOPING RAT BRAIN Program No. 915.2. 2004 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, 2004. Online.

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| BUSHA | CUZZONE | HALL | GNIOTCZYNSKI | KONDRAD |
| KUO | LEE | PATE | POULTON | RAO | SCHAEFER |

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