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Hippocampal cholinergic alterations and related behavioral deficits after early exposure to phenobarbital
Y Rogel-Fuchs1, M E Newman, D Trombka
1Melvin A. and Eleanor Ross Laboratory for Studies in Neural Birth Defects, Department of Anatomy and Embryology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Insights
Early exposure to phenobarbital (PhB) alters brain chemistry and behavior in mice. This study shows PhB affects cholinergic receptors and impairs hippocampus-dependent learning, suggesting long-term neurodevelopmental impacts.
Area of Science:
- Neuroscience
- Developmental Toxicology
- Pharmacology
Background:
- Phenobarbital (PhB) is a widely used sedative and anticonvulsant.
- Early-life exposure to certain medications can lead to long-term neurodevelopmental consequences.
- The septohippocampal system is crucial for learning and memory.
Purpose of the Study:
- To investigate the long-term biochemical and behavioral effects of prenatal and neonatal phenobarbital (PhB) exposure on the mouse septohippocampal system.
- To assess alterations in cholinergic receptor binding and signaling.
- To evaluate hippocampus-related behavioral deficits following early PhB exposure.
Main Methods:
- Mice were exposed to phenobarbital (PhB) either prenatally via maternal diet or neonatally via direct injection.
- Biochemical assays measured muscarinic cholinergic receptor binding ([3H]QNB) and inositol phosphate (IP) formation.
- Choline acetyltransferase (ChAT) activity was assessed.
- Behavioral testing included the Morris water maze to evaluate spatial learning and memory.
Main Results:
- Both prenatal and neonatal PhB exposure significantly increased muscarinic cholinergic receptor binding (B(max)) in the septohippocampal system, without altering receptor affinity (Kd).
- Inositol phosphate (IP) formation in response to carbachol was significantly increased following both exposure routes.
- No changes in choline acetyltransferase (ChAT) activity were observed.
- Mice exposed to PhB early in life exhibited deficits in the Morris water maze task.
Conclusions:
- Early-life phenobarbital exposure induces significant alterations in the postsynaptic components of the hippocampal cholinergic system.
- These biochemical changes are associated with impairments in hippocampus-dependent behaviors, such as spatial learning and memory.
- The findings highlight potential long-term neurodevelopmental risks associated with early phenobarbital exposure.
Abstract:
Mice were exposed to phenobarbital (PhB) prenatally and neonatally. Prenatal exposure was accomplished by feeding the mother PhB (3 g/kg milled food) on gestation days 9-18. Neonatal exposure was accomplished by daily injections of 50 mg/kg sodium PhB directly to the pups on days 2-21. Long-term biochemical alterations in the pre- and postsynaptic septohippocampal system, as well as related behavioral deficits, were assessed in the treated animals. Significant increase in B(max) values for binding of [3H]QNB to muscarinic cholinergic receptors was obtained on both ages 22 and 50 in prenatally (40-90%, respectively, p less than 0.001) and neonatally exposed (58-89%, p less than 0.001) mice whereas Kd remained normal. Similarly, a significant increase of inositol phosphate (IP) formation in response to carbachol was found after both prenatal and neonatal exposure to PhB (p less than 0.05). No alterations in choline acetyltransferase (ChAT) activity were observed in the prenatally or neonatally treated animals. The early exposed mice showed deficits in the performance in Morris water maze, a behavior related to the septohippocampal pathway. The results suggest that early exposure to PhB induces alterations in postsynaptic components of the hippocampal cholinergic system and concomitantly to impairment in hippocampus-related behavior.