Abstract
Reproductive endocrine disorders are prominent comorbidities of temporal lobe epilepsy (TLE) in both men and women. The neural mechanisms underlying these comorbidities remain unclear, but hypothalamic gonadotropin-releasing hormone (GnRH) neurons may be involved. Here, we report the first direct demonstrations of aberrant GnRH neuron function in an animal model of epilepsy. Recordings of GnRH neuron firing and excitability were made in acute mouse brain slices prepared two months after intrahippocampal injection of kainate (KA) or control saline, a well-established TLE model in which most females develop comorbid estrous cycle disruption. GnRH neurons from control females showed elevated firing and excitability on estrus compared with diestrus. By contrast, cells from KA-injected females that developed prolonged, disrupted estrous cycles (KA-long) showed the reverse pattern. Firing rates of cells from KA-injected females that maintained regular cycles (KA-regular) were not different from controls on diestrus, but were reduced on estrus. In KA-injected males, only GnRH neurons in the medial septum displayed elevated firing. In contrast to the diestrus versus estrus and sex-specific changes in firing, GnRH neuron intrinsic excitability was elevated in all KA-injected groups, indicating a role for afferent synaptic and neuromodulatory inputs in shaping overall changes in firing activity. Furthermore, KA-injected females showed cycle-stage-specific changes in circulating sex steroids on diestrus and estrus that also differed between KA-long and KA-regular groups. Together, these findings reveal that the effects of epilepsy on the neural control of reproduction are dynamic across the estrous cycle, distinct in association with comorbid estrous cycle disruption severity, and sex-specific.
Highlights
Reproductive endocrine disorders are prominent comorbidities of epilepsy (Herzog et al, 1986a,b; Bilo et al, 2001; Klein et al, 2001; Löfgren et al, 2007; Bauer and Cooper᎑Mahkorn, 2008)
Our results indicate that the effects of intrahippocampal KA injection on gonadotropin-releasing hormone (GnRH) neuron activity and excitability are different on diestrus compared with estrus, varied according to the severity of comorbid estrous cycle disruption, and sex-specific
Confirmation of hippocampal KA injection targeting Mice treated with intrahippocampal KA exhibit acute non-convulsive or mild clonic status epilepticus followed by spontaneous focal seizures that rarely generalize to tonic-clonic seizures, along with histopathological features including hippocampal sclerosis and gliosis, recapitulating cardinal hallmarks of human temporal lobe epilepsy (TLE) (Bouilleret et al, 1999; Riban et al, 2002; Blümcke et al, 2013)
Summary
Reproductive endocrine disorders are prominent comorbidities of epilepsy (Herzog et al, 1986a,b; Bilo et al, 2001; Klein et al, 2001; Löfgren et al, 2007; Bauer and Cooper᎑Mahkorn, 2008). 60% of women with TLE not taking antiepileptic drugs exhibit menstrual disorders, indicating that there is a strong association between TLE seizures and reproductive endocrine dysfunction (Herzog et al, 1986a). Seizures are exacerbated at certain phases of the menstrual cycle in ϳ40% of women with epilepsy, a pattern termed catamenial epilepsy (Laidlaw, 1956; Herzog et al, 2004). Understanding the mechanisms underlying epilepsy-induced reproductive endocrine disorders is crucial for the development of new strategies for both reproductive cycle maintenance and seizure management
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