Phenotypic differences based on lateralization of intrahippocampal kainic acid injection in female mice

Cutia, Cathryn A.; Leverton, Leanna K.; Ge, Xiyu; Youssef, Rana; Raetzman, Lori T.; Christian‐Hinman, Catherine A.

doi:10.1016/j.expneurol.2022.114118

Cited by 14 publications

(38 citation statements)

References 75 publications

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“…Therefore, all 32 KA-injected mice passed this screening procedure. It should be noted that we recently demonstrated that in a parallel cohort of mice injected identically to those described here, 100% developed spontaneous recurrent seizures by 1 month after injection, as recorded in hippocampal depth electroencephalography recordings (Cutia et al, 2022). This finding indicates a high rate of effective epilepsy induction in this model in our hands and provides strong confidence that the 32 KA-injected mice in the present work also developed chronic epilepsy by 2 months after injection.…”

Section: Verification Of Successful Intrahippocampal Kainic Acid Inje...supporting

confidence: 81%

“…To determine whether the epilepsy-associated changes in GnRH neuron firing activity in the IHKA model are associated with altered GABAergic transmission, we recorded GABA A R-mediated postsynaptic currents (PSCs) in GnRH neurons in slices of hypothalamus from IHKA mice and saline-injected controls. All recordings were performed at 2-3 months after injection, a time point by which a large majority of IHKA mice have been documented to display chronic spontaneous seizures (Cutia et al, 2022; Li et al, 2020; Lisgaras and Scharfman, 2022) and the majority of IHKA females exhibit disrupted estrous cycles (Cutia et al, 2022; Li et al, 2017). In light of the largely depolarizing effects of GABA A R activation in GnRH neurons, which could potentially promote increased firing activity, we recorded GABAergic transmission to GnRH neurons from males and diestrous females, as increased GnRH neuron firing was previously observed in IHKA mice from these groups (Li et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Increased GABA transmission to GnRH neurons after intrahippocampal kainic acid injection in mice is sex-specific and associated with estrous cycle disruption

Ingram

Leverton

Daniels

et al. 2022

Preprint

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Patients with epilepsy develop reproductive endocrine comorbidities at a rate higher than that of the general population. Clinical studies have identified disrupted luteinizing hormone (LH) release patterns in patients of both sexes, suggesting potential epilepsy-associated changes in hypothalamic gonadotropin-releasing hormone (GnRH) neuron function. In previous work, we found that GnRH neuron firing is increased in diestrous females and males in the intrahippocampal kainic acid (IHKA) mouse model of temporal lobe epilepsy. Notably, GABAA receptor activation is depolarizing in adult GnRH neurons. Therefore, here we tested the hypothesis that increased GnRH neuron firing in IHKA mice is associated with increased GABAergic drive to GnRH neurons. When ionotropic glutamate receptors (iGluRs) were blocked to isolate GABAergic postsynaptic currents (PSCs), no differences in PSC frequency were seen between GnRH neurons from control and IHKA diestrous females. In the absence of iGluR blockade, however, GABA PSC frequency was increased in GnRH neurons from IHKA females with disrupted estrous cycles, but not saline-injected controls nor IHKA females without estrous cycle disruption. GABA PSC amplitude was also increased in IHKA females with disrupted estrous cycles. These findings suggest the presence of an iGluR-dependent increase in feed-forward GABAergic transmission to GnRH neurons specific to IHKA females with comorbid cycle disruption. In males, GABA PSC frequency and amplitude were unchanged but PSC duration was reduced. Together, these findings suggest that increased GABA transmission helps drive elevated firing in IHKA females on diestrus and indicate the presence of a sex-specific hypothalamic mechanism underlying reproductive endocrine dysfunction in IHKA mice.HIGHLIGHTSIncreased GABA transmission to GnRH neurons in IHKA mouse model of epilepsyIncreased GABA transmission is dependent on upstream glutamate signalingIncreased GABA transmission only seen in females with disrupted estrous cyclesPotential sex-specific mechanism for reproductive endocrine dysfunction in epilepsy

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Section: Verification Of Successful Intrahippocampal Kainic Acid Inje...supporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Increased GABA transmission to GnRH neurons after intrahippocampal kainic acid injection in mice is sex-specific and associated with estrous cycle disruption

Ingram

Leverton

Daniels

et al. 2022

Preprint

Self Cite

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“…Although there were no differences observed in LH pulsatility or FSH levels, most IHKA females develop elongated estrous cycles (22)(23)(24)27). The present results suggest that altered gonadotropin levels may not contribute to the development of this phenotype.…”

Section: Discussioncontrasting

confidence: 59%

“…For example, female rats in the pilocarpine post-status epilepticus model of TLE often develop PCOS-like symptoms (18), including ovarian cysts and hyperandrogenism. Additionally, multiple rodent models of epilepsy exhibit disrupted estrous cycles (18)(19)(20)(21)(22). In the intrahippocampal kainic acid (IHKA) mouse model of TLE, hypothalamic GnRH neurons show disrupted firing and excitability in a manner that not only changes over the estrous cycle, but is also associated with the severity of estrous cycle disruption (23,24).…”

Section: Introductionmentioning

confidence: 99%

“…These effects are also reflected in changes in GABAergic transmission to GnRH neurons (25). IHKA females were also recently found to display differences in expression of gonadotropin hormone subunit and GnRH receptor genes in the pituitary (22). These pituitary gene expression changes depended on the side of hippocampus targeted for IHKA injection (22), thus further supporting a role for seizure activity itself in driving these downstream effects.…”

Section: Introductionmentioning

confidence: 99%

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Female-Specific Pituitary Hypersensitivity to Gonadotropin-Releasing Hormone in a Mouse Model of Chronic Temporal Lobe Epilepsy

Cutia

Leverton

Weis

et al. 2022

Preprint

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Gonadotropin hormone release from the anterior pituitary is critical to regulating reproductive endocrine function. Clinical evidence has documented that people with epilepsy display altered levels of gonadotropin hormones, both acutely following seizures and chronically. Despite this relationship, pituitary function remains a largely understudied avenue in preclinical epilepsy research. Recently, we showed that females in the intrahippocampal kainic acid (IHKA) mouse model of temporal lobe epilepsy were found to display changes in pituitary expression of gonadotropin hormone and GnRH receptor genes. Circulating gonadotropin hormone levels, however, have yet to be measured in an animal model of epilepsy. Here, we evaluated the circulating levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), GnRH receptor (Gnrhr) gene expression, and sensitivity to exogenous GnRH in IHKA males and females. Although no changes in overall dynamics of pulsatile patterns of LH release were found in IHKA mice of either sex, estrus vs. diestrus changes in basal and mean LH levels were larger in IHKA females with prolonged, disrupted estrous cycles. In addition, IHKA females displayed increased pituitary sensitivity to GnRH and higher Gnrhr expression. The hypersensitivity to GnRH was observed on diestrus, but not estrus. Chronic seizure severity was not found to be correlated with LH parameters, and FSH levels were unchanged in IHKA mice. These results indicate that although there are changes in pituitary gene expression and sensitivity to GnRH in IHKA females, there may also be compensatory mechanisms that aid in maintaining gonadotropin release in the state of chronic epilepsy in this model.

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Nucleus accumbens shell electrical lesion attenuates seizures and gliosis in chronic temporal lobe epilepsy rats

Xue,

Yi,

Mao

et al. 2024

Epileptic Disorders

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ObjectiveTemporal lobe epilepsy (TLE) is the most prevalent form of epilepsy. Prior research has indicated the involvement of the nucleus accumbens shell (NAcSh) in the process of epileptogenesis, thereby implying its potential as a therapeutic target for TLE. In the present study, we investigated the antiepileptic effect of the NAcSh electrical lesion.MethodsChronic TLE was induced by stereotactic injection of kainic acid (KA) into the hippocampus 3 weeks after KA administration, and NAcSh electrical lesions were performed. Seizures in rats were monitored by video electroencephalogram (EEG) 1 week following the NAcSh electrical lesion. Besides, the spatial memory function assessment in rats was conducted using the Morris water maze (MWM) test in the final week of the experiment. Later, hippocampal glial cell activation and neuron loss in rats were evaluated through immunohistochemistry.ResultsTLE rats subjected to NAcSh electrical lesion exhibited a significant reduction in the frequency of seizures compared to untreated TLE rats. Furthermore, NAcSh electrical lesion led to less activation of hippocampal glial cells and fewer neuronal loss in TLE rats. It is worth noting that the NAcSh electrical lesion did not cause additional memory impairment.SignificanceIn the present study, the NAcSh electrical lesion exhibited a definitive therapeutic effect on the chronic TLE rat model, potentially due to decreased hippocampal TLE‐induced activation of glial cells and neuron loss. In conclusion, our results indicated that the NAcSh is a promising therapeutic target for TLE and possesses high potential for clinical application.

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Phenotypic differences based on lateralization of intrahippocampal kainic acid injection in female mice

Cited by 14 publications

References 75 publications

Increased GABA transmission to GnRH neurons after intrahippocampal kainic acid injection in mice is sex-specific and associated with estrous cycle disruption

Increased GABA transmission to GnRH neurons after intrahippocampal kainic acid injection in mice is sex-specific and associated with estrous cycle disruption

Female-Specific Pituitary Hypersensitivity to Gonadotropin-Releasing Hormone in a Mouse Model of Chronic Temporal Lobe Epilepsy

Nucleus accumbens shell electrical lesion attenuates seizures and gliosis in chronic temporal lobe epilepsy rats

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