Early life stress in epilepsy: A seizure precipitant and risk factor for epileptogenesis

Early-life stress includes prenatal, postnatal, and adolescence stress. Early-life stress can affect the development of the hypothalamic-pituitary-adrenal (HPA) axis, and cause cellular and molecular changes in the developing hippocampus that can result in neurobehavioral changes later in life. Epidemiological data implicate stress as a cause of seizures in both children and adults. Emerging evidence indicates that both prenatal and postnatal stress can prime the developing brain for seizures and an increase in epileptogenesis. This article reviews the cellular and molecular changes encountered during prenatal and postnatal stress, and assesses the possible link between these changes and increases in seizure occurrence and epileptogenesis in the developing hippocampus. In addititon, the priming effect of prenatal and postnatal stress for seizures and epileptogenesis is discussed. Finally, the roles of epigenetic modifications in hippocampus and HPA axis programming, early-life stress, and epilepsy are discussed.

/pdf/early-life-stress-impacts-the-developing-hippocampus-and-vmet5oj2qs.pdf

Early-life stress impacts the developing hippocampus and primes seizure occurrence: cellular, molecular, and epigenetic mechanisms

The pathogenesis of mesial temporal lobe epilepsy (MTLE), the most prevalent form of refractory focal epilepsy in adults, is thought to begin in early life, even though seizures may not commence until adolescence or adulthood. Amongst the range of early life factors implicated in MTLE causation (febrile seizures, traumatic brain injury, etc.), stress may be one important contributor. Early life stress is an a priori agent deserving study because of the large amount of neuroscientific data showing enduring effects on structure and function in hippocampus and amygdala, the key structures involved in MTLE. An emerging body of evidence directly tests hypotheses concerning early life stress and limbic epilepsy: early life stressors, such as maternal separation, have been shown to aggravate epileptogenesis in both status epilepticus and kindling models of limbic epilepsy. In addition to elucidating its influence on limbic epileptogenesis itself, the study of early life stress has the potential to shed light on the psychiatric disorder that accompanies MTLE. For many years, psychiatric comorbidity was viewed as an effect of epilepsy, mediated psychologically and/or neurobiologically. An alternative – or complementary – perspective is that of shared causation. Early life stress, implicated in the pathogenesis of several psychiatric disorders, may be one such causal factor. This paper aims to critically review the body of experimental evidence linking early life stress and epilepsy; to discuss the direct studies examining early life stress effects in current models of limbic seizures/epilepsy; and to suggest priorities for future research.

/pdf/early-life-stress-as-an-influence-on-limbic-epilepsy-an-i19xnni1de.pdf

Early life stress as an influence on limbic epilepsy: an hypothesis whose time has come?

http://link.springer.com/content/pdf/10.1007/978-94-009-8576-6_13.pdf

A Critique of the Concepts of Heritability and Heredity in Behavioral Genetics

The effects of prenatal stress on the ability of the 5 alpha-reduced progesterone metabolite and neurosteroid 5 alpha-pregnan-3 alpha-ol-20-one (3 alpha,5 alpha-THP) to prevent seizures was examined. On gestational Day 18, pregnant rats were exposed to 20 min of restraint stress (prenatal stress condition) or no such stress (control condition). The adult, gonadectomized offspring exposed to the prenatal stress or control condition were administered 0.0, 4.0, or 8.0 mg/kg 3 alpha,5 alpha-THP 1 hr prior to testing for kainic-acid-induced (32 mg/kg SC) ictal activity. The rats exposed to prenatal stress tended to have more partial seizures and significantly more tonic clonic seizures that were of longer duration than the no prenatal stress rats. Four mg/kg 3 alpha,5 alpha-THP was sufficient to significantly reduce seizure duration of no prenatal stress females, compared to the 0.0 mg/kg dosage of 3 alpha,5 alpha-THP. Seizure duration was reduced in no prenatal stress females by a dose of 4 mg/kg 3 alpha,5 alpha-THP, whereas a dose of 8 mg/kg was required to obtain comparable seizure reduction in prenatally stressed females and males in both groups. There was attrition following kainic-acid testing; of the 18 animals in each group originally, 9 prenatally stressed males, 6 prenatally stressed females, 6 nonprenatally stressed males and 5 nonprenatally stressed females were able to be tested in the water maze and perfused. One week after seizures, there were no differences in the water maze performance of the remaining animals. There were fewer cresyl violet-stained neurons in the CA3 region of the hippocampus of prenatally stressed rats compared to the nonprenatally stressed rats. Basal plasma corticosterone was greater in prenatally stressed animals, but this was due to increases in females rather than males. Plasma 3 alpha,5 alpha-THP was not significantly different in prenatally stressed males and females compared to their no prenatal stress counterparts. These data suggest that the sensitivity to, or responsiveness of, 3 alpha,5 alpha-THP to prevent seizures is decreased after prenatal stress, particularly in females.

Prenatal stress reduces the effectiveness of the neurosteroid 3α,5α‐THP to block kainic‐acid‐induced seizures

Fetal mice treated on days 10, 11, and 12 of gestation by injecting the mothers with (i) 50 milligrams of beta-2-thienylalanine, (ii) solvent, or (iii) sham injection had identical frequencies of audiogenic seizures when tested 23 days after birth; these frequencies were significantly higher than those of an unhandled control group. Results of the sham treatment suggest that maternal stress induced by handling, rather than the nature of the substance injected, increased the susceptibility of the offspring to seizures.

Suceptibility of mice to audiogenic seizures is increased by handling their dams during gestation

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Suceptibility of mice to audiogenic seizures is increased by handling their dams during gestation