Effects of fimbria-fornix transection on calpain and choline acetyl transferase activities in the septohippocampal pathway.
The ability of fimbria-fornix bilateral axotomy to elicit calpain and caspase-3 activation in the rat septohippocampal pathway was determined using antibodies that selectively recognize either calpain- or caspase-cleaved products of the cytoskeletal protein alphaII-spectrin. Radioenzymatically determined choline acetyl transferase (ChAT) activity was elevated in the septum at day 5, but reduced in the dorsal hippocampus at days 3, 5 and 7, after axotomy. Prominent accumulation of calpain-, but not caspase-3-, cleaved spectrin proteolytic fragments was observed in both the septum and dorsal hippocampus 1-7 days after axotomy. ChAT-positive neuronal cell bodies in the septum also displayed calpain-cleaved spectrin indicating that calpain activation occurred in cholinergic septal neurons as a consequence of transection of the septohippocampal pathway. Calpain-cleaved alphaII-spectrin immunoreactivity was observed in cholinergic fibers coursing through the fimbria-fornix, but not in pyramidal neurons of the dorsal hippocampus, suggesting that degenerating cholinergic nerve terminals were the source of calpain activity in the dorsal hippocampus following axotomy. Accumulation of calpain-cleaved spectrin proteolytic fragments in the dorsal hippocampus and septum at day 5 after axotomy was reduced by i.c.v. administration of two calpain inhibitors. Calpain inhibition partially reduced the elevation of ChAT activity in the septum produced by transection but failed to decrease the loss of ChAT activity in the dorsal hippocampus following axotomy. These findings suggest that calpain activation contributes to the cholinergic cell body response and hippocampal axonal cytoskeletal degradation produced by transection of the septohippocampal pathway.
Ayala-Grosso
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C
Department of Pharmacology and Therapeutics, McGill University, McIntyre Medical Sciences Building, 3655 Promenade Sir-William-Osler, Montreal, Canada H3G 1Y6.
Tam
J
J
Xanthoudakis
S
S
Bureau
Y
Y
Roy
S
S
Nicholson
D W
DW
Robertson
G S
GS
D000818:Animals; D019771:Axotomy / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D002154:Calpain / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D020712:Fornix, Brain / Q000293:injuries / Q000502:physiology* / Q000601:surgery; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology*; D007150:Immunohistochemistry / Q000379:methods; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D009434:Neural Pathways / Q000187:drug effects / Q000201:enzymology*; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012688:Septum Pellucidum / Q000187:drug effects / Q000201:enzymology*; D013049:Spectrin / Q000378:metabolism; D013997:Time Factors
D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D007976:Leupeptins; D011480:Protease Inhibitors; D013049:Spectrin; D002795:Choline O-Acetyltransferase; D002154:Calpain; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; C058076:calpain inhibitor III