Immune Challenges and Seizures: How Do Early Life Insults Influence Epileptogenesis?

Abstract

The development of epilepsy, a process known as epileptogenesis, often occurs later in life following a prenatal or early postnatal insult such as cerebral ischemia, stroke, brain trauma, or infection. These insults share common pathophysiological pathways involving innate immune activation including neuroinflammation, which is proposed to play a critical role in epileptogenesis. This review provides a comprehensive overview of the latest preclinical evidence demonstrating that early life immune challenges influence neuronal hyperexcitability and predispose an individual to later life epilepsy. Here, we consider the range of brain insults that may promote the onset of chronic recurrent spontaneous seizures at adulthood, spanning intrauterine insults (e.g. maternal immune activation), perinatal injuries (e.g. hypoxic-ischemic injury, perinatal stroke), and insults sustained during early postnatal life-such as fever-induced febrile seizures, traumatic brain injuries, infections, and environmental stressors. Importantly, all of these insults represent, to some extent, an immune challenge, triggering innate immune activation and implicating both central and systemic inflammation as drivers of epileptogenesis. Increasing evidence suggests that pro-inflammatory cytokines such as interleukin-1 and subsequent signaling pathways are important mediators of seizure onset and recurrence, as well as neuronal network plasticity changes in this context. Our current understanding of how early life immune challenges prime microglia and astrocytes will be explored, as well as how developmental age is a critical determinant of seizure susceptibility. Finally, we will consider the paradoxical phenomenon of preconditioning, whereby these same insults may conversely provide neuroprotection. Together, an improved appreciation of the neuroinflammatory mechanisms underlying the long-term epilepsy risk following early life insults may provide insight into opportunities to develop novel immunological anti-epileptogenic therapeutic strategies.

Keywords: brain injury; cytokines; development; epilepsy; immune response; interleukin-1; neuroinflammation; seizure.

Figure 1

Schematic summary of prenatal, perinatal, and postnatal insults to the developing human brain that initiate an inflammatory immune response, including the release of pro-inflammatory cytokines interleukin (IL)-1β, tumor necrosis factor alpha (TNFα), IL-6 and others. Experimental models have revealed that these cytokines promote astrocyte and microglial reactivity, and contribute to neuronal dysfunction by several mechanisms including alterations in neurotransmitter receptor subunit expression. These changes may lead to hyperexcitability or a reduced seizure threshold, resulting in an increased vulnerability to epilepsy. Epilepsy may develop over time and can be accelerated or triggered by a second-hit insult, such as a later life immune challenge.

Figure 2

Schematic timeline illustrating key neurodevelopmental processes ongoing through gestational and postnatal periods in the mammalian brain. A wide range of prenatal, perinatal, and postnatal insults influence the developing brain both acutely but also chronically, driving an increased propensity for neuronal hyperexcitability and seizure susceptibility during later life. Age-dependent vulnerability to these chronic consequences is thought to be determined, at least in part, by the state of microglial development (changes in number, phenotype, and activity), as well as maturation of neuronal circuits (a product of synaptogenesis and synaptic pruning over time). Adapted from Semple et al. (2013) and Lenz and Nelson (2018).