Neuropeptide-mediated excitability: a key triggering mechanism for seizure generation in the developing brain

Abstract

Most human seizures occur early in life, consistent with established excitability-promoting features of the developing brain. Surprisingly, the majority of developmental seizures are not spontaneous but are provoked by injurious or stressful stimuli. What mechanisms mediate 'triggering' of seizures and limit such reactive seizures to early postnatal life? Recent evidence implicates the excitatory neuropeptide, corticotropin-releasing hormone (CRH). Stress activates expression of the CRH gene in several limbic regions, and CRH-expressing neurons are strategically localized in the immature rat hippocampus, in which this neuropeptide increases the excitability of pyramidal cells in vitro. Indeed, in vivo, activation of CRH receptors -maximally expressed in hippocampus and amygdala during the developmental period which is characterized by peak susceptibility to 'provoked' convulsions -induces severe, age-dependent seizures. Thus, converging data indicate that activation of expression of CRH constitutes an important mechanism for generating developmentally regulated, triggered seizures, with considerable clinical relevance.The majority of seizures occurring in the developing human are not spontaneous, that is, they are not related to inherent abnormalities in the balance of neuronal excitation and inhibition 1 . Rather, most seizures during infancy and childhood are provoked or triggered by alterations in the normal milieu of excitable neurons 2 . Thus, rapid triggering by fever, hypoxia or trauma provokes the majority of seizures in the infant and young child. These seizures -a manifestation of rapid and transient enhancement of neuronal excitability in response to adverse and potentially injurious agents -demonstrate an exquisite age specificity (Table 1): febrile seizures are exclusive to infancy and early childhood 1,2 , immediate traumatic seizures (as opposed to posttraumatic epilepsy) are far more common in the young human compared with the adult, and anoxia-related seizures occur primarily in the full-term neonate 5,7 . Other seizures that are not genetic in origin, such as infantile spasms, which have been linked to a large number of injuries of the CNS and stressors that include infections and malformations, are highly age specific and primarily restricted to the first year of life 6 .In the present review, we focus on novel and evolving concepts regarding potential mechanisms for the rapid transduction of stressful alterations of neuronal milieu into enhanced excitability and resulting seizures. We discuss the cascade of molecular events triggered by 'stress', with an emphasis on the excitatory neuropeptide, corticotropinreleasing hormone (CRH). Established and novel in vivo and in vitro evidence for the role of CRH in enhancing excitation in key limbic circuits, particularly in the tri-synaptic hippocampal pathway, are discussed. Finally, we describe recent data regarding the receptors that mediate CRH-induced excitation, and provide the probable mechanisms underlying the remarkable age specificit...

Neuronal activity and stress differentially regulate hippocampal and hypothalamic corticotropin-releasing hormone expression in the immature rat

“…Using specific probes directed against heteronuclear (unedited) CRH RNA, our 6 and other 17 groups have shown a rapid activation of the CRH gene in the immature rat hypothalamus after appropriate challenges. The half-life of heteronuclear CRH RNA is short, permitting resolution of gene activation and inactivation in the range of minutes.…”

“…32 More recently, in vitro studies have shown that CRH modulates glutamatergic mechanisms to increase excitatory neurotransmission in the hippocampal circuit. 6,25 Thus, under physiological circumstances, release of CRH may modulate hippocampal neurotransmission, augmenting glutamate-mediated alterations of hippocampal function. This may influence both normal hippocampal processes such as longterm potentiation and, when excessive, may promote abnormal excitation 1,6,25 and excitotoxicity.…”

“…6,25 Thus, under physiological circumstances, release of CRH may modulate hippocampal neurotransmission, augmenting glutamate-mediated alterations of hippocampal function. This may influence both normal hippocampal processes such as longterm potentiation and, when excessive, may promote abnormal excitation 1,6,25 and excitotoxicity. 9,36,37 The neuroanatomical basis for the influence of CRH on hippocampal neurotransmission has been explored.…”

“…7,39 It has been suggested that excessive elevation of hippocampal CRH levels may contribute to abnormal neuronal excitation (seizures). 6 Thus, regulation of CRH levels in peptidergic hippocampal neurons may be important for both normal and pathological activation of the hippocampal circuit, 6,25,50 predicting that these levels may be subject to tight physiological control. However, the regulation of CRH expression in the hippocampus has not been elucidated.…”

Chronic Low-Dose Corticosterone Supplementation Enhances Acquired Epileptogenesis in the Rat Amygdala Kindling Model of TLE

“…This raises the possibility that the HPA axis may be dysfunctional in hippocampal sclerosis and MTLE. The stress mediator, corticotrophin-releasing hormone (CRH), is present in these structures; although its functions there are not yet well understood, considerable evidence exists for a pivotal role for CRH in epileptogenesis in infancy and childhood (Baram and Hatalski, 1998). In a range of animal models, laboratory stressors and exposure to exogenous glucocorticoids result in structural and functional alterations in brain regions critically involved in MTLE, especially the hippocampus and amygdala (Gould et al, 2000;McEwen and Magarinos, 2001;Vyas et al, 2003).…”