Susceptibility to seizure-induced injury and acquired microencephaly following intraventricular injection of saporin-conjugated 192 IgG in developing rat brain.
To study the role of neurotrophin-responsive neurons in brain growth and developmental resistance to seizure-induced injury, we infused saporin-conjugated 192-IgG (192 IgG-saporin), a monoclonal antibody directed at the P75 neurotrophin receptors (p75(NTR)), into the ventricles of postnatal day 8 (P8) rat pups. 7-10 days after immunotoxin treatment, loss of p75(NTR) immunoreactivity was associated with depletion of basal forebrain cholinergic projection to the neocortex and hippocampus. Kainic acid (KA)-induced seizures on P15 resulted in hippocampal neuronal injury in the majority of toxin-treated animals (13/16), but only rarely in saline-injected controls (2/25) (P < 0.001). In addition, widespread cerebral atrophy and a significant decrease in brain weight with preserved body weight were observed. Volumetric analysis of the hippocampal hilar region revealed a 2-fold reduction in perikaryal size and a 1.7-fold increase in cell packing density after 192 IgG-saporin injection. These observations indicate that neurotrophin-responsive neurons including basal forebrain magnocellular cholinergic neurons may be critical for normal brain growth and play a protective role in preventing excitotoxic neuronal injury during development.
Koh
Sookyong
S
MGH Epilepsy Service, Epilepsy Research Laboratory, Massachusetts General Hospital and Harvard Medical School, VBK 830, 55 Fruit Street, Boston, MA 02114, USA.
Santos
Tatiane C
TC
Cole
Andrew J
AJ
D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001284:Atrophy / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D020532:Basal Nucleus of Meynert / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001925:Brain Damage, Chronic / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D018678:Cholinergic Agents / Q000494:pharmacology; D003292:Convulsants / Q000494:pharmacology; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000503:physiopathology; D004827:Epilepsy / Q000139:chemically induced / Q000150:complications* / Q000503:physiopathology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005260:Female; D000922:Immunotoxins / Q000494:pharmacology; D007276:Injections, Intraventricular; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D009699:N-Glycosyl Hydrolases; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D009414:Nerve Growth Factors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020800:Receptor, Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins
C085696:192 IgG-saporin; D000911:Antibodies, Monoclonal; D018678:Cholinergic Agents; D003292:Convulsants; D018690:Excitatory Amino Acid Agonists; D000922:Immunotoxins; D009414:Nerve Growth Factors; D020800:Receptor, Nerve Growth Factor; D054789:Ribosome Inactivating Proteins, Type 1; D009699:N-Glycosyl Hydrolases; D000076985:Saporins; D007608:Kainic Acid