Cell death was examined by studying the spinal cords of rats subjected to traumatic insults of mild to moderate severity. Within minutes after mild weight drop impact (a 10 gm weight falling 6.25 mm), neurons in the immediate impact area showed a loss of cytoplasmic Nissl substances. Over the next 7 d, this lesion area expanded and cavitated. Terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL)-positive neurons were noted primarily restricted to the gross lesion area 4-24 hr after injury, with a maximum presence at 8 hr after injury. TUNEL-positive glia were present at all stages studied between 4 hr and 14 d, with a maximum presence within the lesion area 24 hr after injury. However 7 d after injury, a second wave of TUNEL-positive glial cells was noted in the white matter peripheral to the lesion and extending at least several millimeters away from the lesion center. The suggestion of apoptosis was supported by electron microscopy, as well as by nuclear staining with Hoechst 33342 dye, and by examination of DNA prepared from the lesion site. Furthermore, repeated intraperitoneal injections of cycloheximide, beginning immediately after a 12.5 mm weight drop insult, produced a substantial reduction in histological evidence of cord damage and in motor dysfunction assessed 4 weeks later. Present data support the hypothesis that apoptosis dependent on active protein synthesis contributes to the neuronal and glial cell death, as well as to the neurological dysfunction, induced by mild-to-moderate severity traumatic insults to the rat spinal cord.
Programmed cell death (apoptosis) is a normal process in the developing nervous system. Recent data suggest that certain features seen in the process of programmed cell death may be favored in the developing versus the adult brain in response to different brain injuries. In a well characterized model of neonatal hypoxia-ischemia, we demonstrate marked but delayed cell death in which there is prominent DNA laddering, TUNEL-labeling, and nuclei with condensed chromatin. Caspase activation, which is required in many cases of apoptotic cell death, also followed a delayed time course after hypoxia-ischemia. Administration of boc-aspartyl(OMe)-fluoromethylketone, a pan-caspase inhibitor, was significantly neuroprotective when given by intracerebroventricular injection 3 h after cerebral hypoxia-ischemia. In addition, systemic injections of boc-aspartyl(OMe)-fluoromethylketone also given in a delayed fashion, resulted in significant neuroprotection. These findings suggest that caspase inhibitors may be able to provide benefit over a prolonged therapeutic window after hypoxic-ischemic events in the developing brain, a major contributor to static encephalopathy and cerebral palsy.
The low-density lipoprotein (LDL) receptor-related protein (LRP) is a multifunctional endocytic receptor that is expressed abundantly in neurons of the CNS. Both LRP and several of its ligands, including tissue plasminogen activator (tPA), apolipoprotein E/lipoproteins, alpha(2)-macroglobulin, and the beta-amyloid precursor protein, have been implicated in various neuronal functions and in the pathogenesis of Alzheimer's disease. It has been reported that induction of tPA expression may contribute to activity-dependent synaptic plasticity in the hippocampus and cerebellum. In addition, long-term potentiation (LTP) is significantly decreased in mice lacking tPA. Here we demonstrate that tPA receptor LRP is abundantly expressed in hippocampal neurons and participates in hippocampal LTP. Perfusion of hippocampal slices with receptor-associated protein (RAP), an antagonist for ligand interactions with LRP, significantly reduced late-phase LTP (L-LTP). In addition, RAP also blocked the enhancing effect of synaptic potentiation by exogenous tPA in hippocampal slices prepared from tPA knock-out mice. Metabolic labeling and ligand binding analyses showed that both tPA and LRP are synthesized by hippocampal neurons and that LRP is the major cell surface receptor that binds tPA. Finally, we found that tPA binding to LRP in hippocampal neurons enhances the activity of cyclic AMP-dependent protein kinase, a key molecule that is known to be involved in L-LTP. Taken together, our results demonstrate that interactions between tPA and cell surface LRP are important for hippocampal L-LTP.
The thalamus is known to receive single-whisker 'lemniscal' inputs from the trigeminal nucleus principalis (PrV) and multiwhisker 'paralemniscal' inputs from the spinal trigeminal nucleus (SpV), yet the responses of cells in the thalamic ventroposteromedial nucleus (VPM) are most similar to and contingent upon inputs from PrV. This may reflect a differential termination pattern, density and/or synaptic organization of PrV and SpV projections. This hypothesis was tested in adult rats using anterograde double-labelling with fluorescent dextrans, horseradish peroxidase (HRP) and choleragenoid, referenced against parvalbumin and calbindin immunoreactivity. The results indicated that PrV's most robust thalamic projection is to the whisker-related barreloids of VPM. The SpV had robust projections to non-barreloid thalamic regions, including the VPM 'shell' encapsulating the barreloid area, a caudal and ventral region of VPM that lacks barreloids and PrV inputs, the posterior thalamic nucleus, nucleus submedius and zona incerta. Within the barreloid portion of VPM, SpV projections were sparse relative to those from PrV, and most terminal labelling occurred in the peripheral fringes of whisker-related patches and in interbarreloid septae. Thus, PrV and SpV have largely complementary projection foci in the thalamus. Intra-axonal staining of a small sample of trigeminothalamic axons with whisker or guard hair receptive fields revealed highly localized and somatotopic terminal aggregates in VPM that spanned areas no larger than that of a single barreloid. In the electron microscopic component of this study, HRP transport to the barreloid region of VPM from left SpV and right PrV in the same cases revealed PrV terminals contacting dendrites with a broad range of minor axis diameters (mean +/- SD: 1.51 +/- 0.10 microns). SpV terminals were indistinguishable from those of PrV, but they had a disproportionate number of contacts on narrow dendrites (1.27 +/- 0.07 microns, P < 0.01). PrV endings were also more likely to contact VPM somata (11.0 +/- 4.2% of all labelled terminals) than those from SpV (3.0 +/- 1.0%, P < 0.01). Insofar as primary dendrites are thicker than distal dendrites in VPM, these data suggest a differential distribution of PrV and SpV inputs onto VPM cells that may account for their relative efficacies in dictating the responses of VPM cells to whisker stimulation. Multiwhisker receptive fields in VPM may also reflect direct transmission of convergent inputs from PrV.
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