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Titolo:
Focal inhibitory interneuron loss and principal cell hyperexcitability in the rat hippocampus after microinjection of a neurotoxic conjugate of saporin and a peptidase-resistant analog of Substance P
Autore:
Martin, JL; Sloviter, RS;
Indirizzi:
Univ Arizona, Coll Med, Dept Pharmacol, Tucson, AZ 85724 USA Univ ArizonaTucson AZ USA 85724 ed, Dept Pharmacol, Tucson, AZ 85724 USA Univ Arizona, Coll Med, Dept Neurol, Tucson, AZ 85724 USA Univ Arizona Tucson AZ USA 85724 l Med, Dept Neurol, Tucson, AZ 85724 USA
Titolo Testata:
JOURNAL OF COMPARATIVE NEUROLOGY
fascicolo: 2, volume: 436, anno: 2001,
pagine: 127 - 152
SICI:
0021-9967(20010723)436:2<127:FIILAP>2.0.ZU;2-0
Fonte:
ISI
Lingua:
ENG
Soggetto:
SUSTAINED ELECTRICAL-STIMULATION; KAINIC ACID; DENTATE GYRUS; IMMUNOCYTOCHEMICAL LOCALIZATION; SELECTIVE VULNERABILITY; FUNCTIONAL-ORGANIZATION; NEURONAL DEGENERATION; CHANDELIER CELLS; FASCIA-DENTATA; PERFORANT PATH;
Keywords:
epilepsy; GABA; Substance P receptor; neurokinin-1 receptor; parvalbumin; calbindin; calretinin; somatostatin; neurotoxin; neurotoxicity;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
84
Recensione:
Indirizzi per estratti:
Indirizzo: Sloviter, RS Univ Arizona, Coll Med, Dept Pharmacol, 1501 N Campbell Ave, Tucson, AZ 85724 USA Univ Arizona 1501 N Campbell Ave Tucson AZ USA 85724 5724 USA
Citazione:
J.L. Martin e R.S. Sloviter, "Focal inhibitory interneuron loss and principal cell hyperexcitability in the rat hippocampus after microinjection of a neurotoxic conjugate of saporin and a peptidase-resistant analog of Substance P", J COMP NEUR, 436(2), 2001, pp. 127-152

Abstract

Episodes of prolonged seizures or head trauma produce chronic hippocampal network hyperexcitability hypothesized to result primarily from inhibitory interneuron loss or dysfunction. The possibly causal role of inhibitory neuron failure in the development of epileptiform pathophysiology remains unclear because global neurologic injuries produce such a multitude of effects. The recent finding that Substance P receptors (SPRs) are expressed exclusively in the rat hippocampus by inhibitory interneurons provided the rationale for attempting to ablate interneurons selectively by using neurotoxic conjugates of SPR ligands and the ribosome inactivating protein saporin that specifically target Substance P receptor-expressing cells. Whereas intrahippocampal microinjection of a conjugate of native SP and saporin produced significant nonspecific damage at concentrations needed to produce even limited selective loss of SPR-positive cells, a conjugate of saporin and the more potent and peptidase-resistant SP analog [Sar(9), Met(O-2)(11)] SubstanceP (SSP-saporin) caused negligible nonspecific damage at the injection site, and a virtually complete loss of SPR-like immunoreactivity (LI) up to 1 mm from the injection site. Within the SPR depletion zone, immunoreactivities for most GABA-, parvalbumin-, somatostatin-, and cholecystokinin-immunoreactive cells and fibers were eliminated. The few interneurons detectable within the affected zone were devoid of SPR-LI. The apparent loss of interneurons was selective in that calbindin- and glutamate receptor subunit 2 (GLuR2) -positive principal cells survived within the affected zone, as did myelinated fibers and the extrinsic calretinin- and tyrosine hydroxylase-immunoreactive terminals of subcortical afferents. An apparent lack of reactive synaptic reorganization in response to interneuron loss was indicated by zinc transporter-3 (ZnT3)- and beta -synuclein-LI, as well as by Timm staining, all of which revealed relatively normal patterns of excitatory terminal distribution. Control injections produced minor damage at the injection site, but no apparent specific loss of SPR-LI. One to 12 weeks after injectionof SSP-saporin, extracellular electrophysiological field responses recorded in the CA1 pyramidal and dentate granule cell layers in response to afferent stimulation were blindly evaluated simultaneously in two sites 1-2 mm apart along the longitudinal hippocampal axis. SSP-saporin-treated rats exhibited relatively normal responses in some sites, whereas disinhibition and hyperexcitability indistinguishable from the pathophysiology produced by experimental status epilepticus were simultaneously recorded at adjacent sites. Anatomic analysis of the recording sites in each animal revealed that epileptiform pathophysiology was consistently observed only within areas of SPR ablation, whereas relatively normal evoked responses were recorded from immediately adjacent and relatively unaffected regions. These data establish the efficacy of [Sar(9), Met(O-2)(11)] Substance P-saporin for producing a selective and spatially extensive ablation of hippocampal inhibitory interneurons in vivo and a highly focal disinhibition that was restricted to the site of interneuron loss. These results also demonstrate that the "epileptic" pathophysiology produced by experimental status epilepticus or head trauma can be replicated by focal interneuron loss per se, without involving principal cell loss and other interpretive confounds inherent in the use ofglobal neurologic injury models. J. Comp. Neurol. 436:127-152, 2001. (C) 2001 Wiley-Liss, Inc.

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Documento generato il 31/03/20 alle ore 05:00:21