Increased Excitatory Synaptic Transmission Associated with Adult Seizure Vulnerability Induced by Early-Life Inflammation in Mice

Abstract

Early-life inflammatory stress increases seizure susceptibility later in life. However, possible sex-and age-specific differences and the associated mechanisms are largely unknown. C57BL/6 mice were bred in house, and female and male pups were injected with lipopolysaccharide (LPS; 100 lg/kg, i.p.) or vehicle control (saline solution) at postnatal day 14 (P14). Seizure threshold was assessed in response to pentylenetetrazol (1% solution, i.v.) in adolescence (;P40) and adulthood (;P60). We found that adult, but not adolescent, mice treated with LPS displayed ;34% lower seizure threshold compared with controls. Females and males showed similar increased seizure susceptibility, suggesting that altered brain excitability was age dependent, but not sex dependent. Whole-cell recordings revealed no differences in excitatory synaptic activity onto CA1 pyramidal neurons from control or neonatally inflamed adolescent mice of either sex. However, adult mice of both sexes previously exposed to LPS displayed spontaneous EPSC frequency approximately twice that of controls, but amplitude was unchanged. Although these changes were not associated with alterations in dendritic spines or in the NMDA/AMPA receptor ratio, they were linked to an increased glutamate release probability from Schaffer collateral, but not temporoammonic pathway. This glutamate increase was associated with reduced activity of presynaptic GABA B receptors and was independent of the endocannabinoid-mediated suppression of excitation. Our new findings demonstrate that early-life inflammation leads to long-term increased hippocampal excitability in adult female and male mice associated with changes in glutamatergic synaptic transmission. These alterations may contribute to enhanced vulnerability of the brain to subsequent pathologic challenges such as epileptic seizures.

Vasopressin and central control of the cardiovascular system: A 40‐year retrospective

“…[80][81][82] Of particular interest is the fact that this very modest early-life intervention caused not only altered innate immune responses, 83,84 but also significant changes in brain excitability, 85 revealed as changes in intrinsic neuronal properties, altered GABAergic function and increased excitatory transmission. 86,87 Although these neuronal and synaptic changes were found in areas outside of the hypothalamus, it is entirely possible that similar changes would occur in the hypothalamus, including the PVN. To the best of my knowledge, this has not been explored.…”

Severe inflammation in new-borns induces long-term cognitive impairment by activation of IL-1β/KCC2 signaling during early development

“…Therefore, any abnormity in either above-mentioned functions may contribute to the neonatal inflammation-induced long-term cognitive defects. For example, it is possible that early-life inflammation and/or GABAergic shift influences the development of excitatory glutamatergic transmission [ 20 , 48 ], thus leading to an impaired glutamatergic function in adolescence. Future studies are required to investigate why upregulation of KCC2 in early development period cause long-term cognitive impairment in adolescence or even adult.…”

Delayed effects of neonatal immune activation on brain neurochemistry and hypothalamic–pituitary–adrenal axis functioning

“…In addition, in adolescent animals on PND42, there is downregulation of vesicular GABA transporter (vGAT) and of the main enzyme for GABA synthesis: glutamate decarboxylase (GAD67) (Wu et al, 2021), but in adults, concentrations of these molecules do not differ from those in a control (Liang et al, 2019). In this context, the amounts of glutamate and the vesicular glutamate transporter (vGLUT1) (its main transporter) do not change in adolescent mice (Wu et al, 2021) but increase in adult rodents (Gomez et al, 2021; Kubesova et al, 2015). On Day 14 after the administration of LPS in adult mice, a similar shift in the balance towards glutamatergic activity is observed in CA1 pyramidal neurons of the hippocampus: The amount of glutamate goes up, whereas the activity of presynaptic GABA B receptor, which regulates the reuptake of GABA from the synaptic cleft, declines (Gomez et al, 2021).…”

“…In this context, the amounts of glutamate and the vesicular glutamate transporter (vGLUT1) (its main transporter) do not change in adolescent mice (Wu et al, 2021) but increase in adult rodents (Gomez et al, 2021; Kubesova et al, 2015). On Day 14 after the administration of LPS in adult mice, a similar shift in the balance towards glutamatergic activity is observed in CA1 pyramidal neurons of the hippocampus: The amount of glutamate goes up, whereas the activity of presynaptic GABA B receptor, which regulates the reuptake of GABA from the synaptic cleft, declines (Gomez et al, 2021). It has been demonstrated that a lack of the GAD67 enzyme or an increase in the vGLUT1/vGAT ratio reduces the extent of GABAergic inhibitory control over glutamatergic neurons.…”