Functional changes in hippocampal synaptic signaling in offspring survivors of a mouse model of intrauterine inflammation

Abstract

BackgroundRecent evidence suggests that exposure to intrauterine inflammation causes acute fetal brain injury and is linked to a spectrum of neurobehavioral disorders. In a rodent model of intrauterine inflammation induced by lipopolysaccharide (LPS) exposure in utero, activated microglia can be detected in the hippocampus of offspring survivors, as late as 60 days postnatal (DPN). Given that the hippocampus is important for learning and memory, these results suggest that in utero inflammation underlies long-term cognitive deficits observed in children/survivors.MethodsAn established mouse model of LPS-induced intrauterine inflammation was used to study hippocampal function from offspring at 44–59 DPN. Microgliosis was examined at 45 DPN. Extracellular field recordings of synaptic transmission were performed on acute hippocampal slices.ResultsLPS offspring mice displayed persistent microglial activation and increased CA3–CA1 excitatory synaptic strength, which can be explained in part by an increase in the probability of glutamate release, and reduced long-term synaptic potentiation compared to control mice.ConclusionsThese results offer a mechanistic explanation for the cognitive and behavioral deficits observed in survivors of preterm birth caused by intrauterine inflammation.

Transcutaneous Auricular Vagus Nerve Stimulation-Paired Rehabilitation for Oromotor Feeding Problems in Newborns: An Open-Label Pilot Study

“…It is unclear why some participants did not respond. Systemic and neuro-inflammation or medications that inhibit synaptic plasticity and learning (e.g., mineralocorticoid receptor inhibitors) may impair learning this motor skill (Favrais et al, 2011;Kuban et al, 2014;Leviton et al, 2016;Kelley et al, 2017). Alternatively, other negative sensory inputs of reflux or esophagitis may counteract positive sensorimotor circuit stimulation (Wingenfeld and Otte, 2019).…”

Intrauterine inflammation reduces postnatal neurogenesis in the hippocampal subgranular zone and leads to accumulation of hilar ectopic granule cells

“…Interestingly, while extra hEGCs are present in the hilus area at P14, they are no longer detectable at the later time point, P28, which suggests that the hippocampus may, at least temporarily, recover from the prenatal insult. Although the accumulation of hEGCs takes place during a limited developmental window, their presence may still adversely affect hippocampal function and behavioral performance which have been shown to be altered in response to intrauterine inflammation Kelley et al, 2017 ; Makinson et al, 2017 . In particular, as shown in animal models of epilepsy, misplaced granule cells differ from other granule neurons in that they develop excessive excitatory innervation while being almost devoid of inhibitory inputs Pierce et al, 2005 ; Scharfman et al, 2007 ; Scharfman and Pierce, 2012 ; Zhan et al, 2010 .…”

Inflammatory molecules and neurotrophic factors as biomarkers of neuropsychomotor development in preterm neonates: A Systematic Review

“…The association between a pro-inflammatory profile and poor cognitive and motor development is not completely elucidated. One of the possible explanations is that inflammatory molecules, including cytokines, are able to cross the compromised blood-brain barrier and to activate the microglia (Kelley et al, 2017;Patra et al, 2017). This might induce neuronal and glial cell apoptosis, therefore interfering in axonal growth and myelin sheath formation (Burd et al, 2012;Guo et al, 2010;Jenster et al, 2014).…”

“…Fetus growth and development require time and may be affected by multiple conditions that jeopardize healthy development, during the gestation period (Kelley et al, 2017; Talati et al, 2017). At this stage, the placenta provides the fetus with growth factors needed for normal body and brain development (Leviton et al, 2017a).…”

“…As a consequence of prematurity, motor, sensory, cognitive and/or behavioral impairments may persistent throughout lifespan (Stewart et al, 2013;Molnár and Rutherford, 2013;Stephens and Vohr, 2009). Fetus growth and development require time and may be affected by multiple conditions that jeopardize healthy development, during the gestation period (Kelley et al, 2017;Talati et al, 2017). At this stage, the placenta provides the fetus with growth factors needed for normal body and brain development (Leviton et al, 2017a).…”