Abstract
Maternal inflammation during pregnancy is associated with the later development of cognitive and behavioral impairment in the offspring, reminiscent of the traits of schizophrenia or autism spectrum disorders. Hippocampal long-term potentiation and long-term depression of glutamatergic synapses are respectively involved in memory formation and consolidation. In male rats, maternal inflammation with lipopolysaccharide (LPS) led to a premature loss of long-term depression, occurring between 12 and 25 postnatal days instead of after the first postnatal month, and aberrant occurrence of long-term potentiation. We hypothesized this would be related to GABAergic system impairment. Sprague Dawley rats received either LPS or isotonic saline ip on gestational day 19. Male offspring's hippocampus was studied between 12 and 25 postnatal days. Morphological and functional analyses demonstrated that prenatal LPS triggered a deficit of hippocampal GABAergic interneurons, associated with presynaptic GABAergic transmission deficiency in male offspring. Increasing ambient GABA by impairing GABA reuptake with tiagabine did not interact with the low frequency-induced long-term depression in control animals but fully prevented its impairment in male offspring of LPS-challenged dams. Tiagabine furthermore prevented the aberrant occurrence of paired-pulse triggered long-term potentiation in these rats. Deficiency in GABA seems to be central to the dysregulation of synaptic plasticity observed in juvenile in utero LPS-challenged rats. Modulating GABAergic tone may be a possible therapeutic strategy at this developmental stage.
Highlights
Epidemiological studies have repeatedly demonstrated that prenatal infection is associated with an increased risk for adverse neurological outcome and neuropsychiatric diseases, most schizophrenia and autism spectrum disorders [1,2,3]
There was a main effect of prenatal LPS treatment on hippocampal GAD67+ neuronal density of male offspring (F1,24 = 15; p,0.001), irrespective of the hippocampal area considered (F3,24 = 0.39; p = 0.760)
We confirmed that the decrease in GABAergic input onto pyramidal neurons contributed to the abnormal synaptic plasticity observed in LPS young offspring
Summary
Epidemiological studies have repeatedly demonstrated that prenatal infection is associated with an increased risk for adverse neurological outcome and neuropsychiatric diseases, most schizophrenia and autism spectrum disorders [1,2,3]. Consistent with reduced learning abilities in the Morris watermaze, prenatally LPS-challenged males displayed a deficit in long-term potentiation (LTP) [11,12]. These deficits, whether electrophysiological or behavioral, resulted from a post LPSchallenge-induced oxidative stress in the fetal hippocampus (as determined by tocopherol oxidation, protein carbonylation and GSH oxidation) that could be prevented by treatment with the antioxidant N-acetylcysteine given before [12] or after [11] the LPS challenge. Prenatal LPS was associated with a reduced expression of GluN1 NMDA receptor (NMDAr) subunit and a rapid decline in NMDAr-associated synaptic signals, together with a premature loss of long-term depression (LTD) and the transient occurrence of an aberrant form of LTP [15] in young male offspring
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
