RESUMEN
First-in-line benzodiazepine treatment fails to terminate seizures in about 30% of epilepsy patients, highlighting a need for novel anti-seizure strategies. It is emerging that impaired K+/Cl- cotransporter 2 (KCC2) activity leads to deficits in GABAergic inhibition and increased seizure vulnerability in patients. In neurons, the with-no-lysine (WNK) kinase-STE20/SPS1-related proline/alanine-rich (SPAK) kinase signalling pathway inhibits KCC2 activity via T1007 phosphorylation. Here, we exploit the selective WNK kinase inhibitor WNK463 to test the effects of pharmacological WNK inhibition on KCC2 function, GABAergic inhibition, and epileptiform activity. Immunoprecipitation and western blotting analysis revealed that WNK463 reduces KCC2-T1007 phosphorylation in vitro and in vivo. Using patch-clamp recordings in primary rat neurons, we further observed that WNK463 hyperpolarized the Cl- reversal potential, and enhanced KCC2-mediated Cl- extrusion. In the 4-aminopyridine slice model of acute seizures, WNK463 administration reduced the frequency and number of seizure-like events. In vivo, C57BL/6 mice that received intrahippocampal WNK463 experienced delayed onset of kainic acid-induced status epilepticus, less epileptiform EEG activity, and did not develop pharmaco-resistance to diazepam. Our findings demonstrate that acute WNK463 treatment potentiates KCC2 activity in neurons and limits seizure burden in two well-established models of seizures and epilepsy. In summary, our work suggests that agents which act to increase KCC2 activity may be useful adjunct therapeutics to alleviate diazepam-resistant status epilepticus.
Asunto(s)
Epilepsia , Estado Epiléptico , Simportadores , Animales , Diazepam/metabolismo , Diazepam/farmacología , Hipocampo/metabolismo , Humanos , Lisina/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratas , Estado Epiléptico/inducido químicamente , Estado Epiléptico/tratamiento farmacológico , Estado Epiléptico/metabolismo , Simportadores/metabolismoRESUMEN
The ventromedial hypothalamus (VMH) plays chief roles regulating energy and glucose homeostasis and is sexually dimorphic. We discovered that expression of metabotropic glutamate receptor subtype 5 (mGluR5) in the VMH is regulated by caloric status in normal mice and reduced in brain-derived neurotrophic factor (BDNF) mutants, which are severely obese and have diminished glucose balance control. These findings led us to investigate whether mGluR5 might act downstream of BDNF to critically regulate VMH neuronal activity and metabolic function. We found that mGluR5 depletion in VMH SF1 neurons did not affect energy balance regulation. However, it significantly impaired insulin sensitivity, glycemic control, lipid metabolism, and sympathetic output in females but not in males. These sex-specific deficits are linked to reductions in intrinsic excitability and firing rate of SF1 neurons. Abnormal excitatory and inhibitory synapse assembly and elevated expression of the GABAergic synthetic enzyme GAD67 also cooperate to decrease and potentiate the synaptic excitatory and inhibitory tone onto mutant SF1 neurons, respectively. Notably, these alterations arise from disrupted functional interactions of mGluR5 with estrogen receptors that switch the normally positive effects of estrogen on SF1 neuronal activity and glucose balance control to paradoxical and detrimental. The collective data inform an essential central mechanism regulating metabolic function in females and underlying the protective effects of estrogen against metabolic disease.
Asunto(s)
Glucemia/metabolismo , Estrógenos/metabolismo , Receptor del Glutamato Metabotropico 5/metabolismo , Núcleo Hipotalámico Ventromedial/fisiología , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Metabolismo Energético , Femenino , Glutamato Descarboxilasa/metabolismo , Homeostasis , Metabolismo de los Lípidos , Masculino , Ratones , Ratones Mutantes , Red Nerviosa , Inhibición Neural , Neuronas/metabolismo , Neuronas/fisiología , Receptor del Glutamato Metabotropico 5/genética , Receptores de Estrógenos/metabolismo , Factores Sexuales , Transducción de Señal , Factor Esteroidogénico 1/metabolismo , Sistema Nervioso Simpático/metabolismo , Transmisión Sináptica , Núcleo Hipotalámico Ventromedial/citología , Núcleo Hipotalámico Ventromedial/metabolismoRESUMEN
The epilepsies are common neurologic disorders characterized by spontaneous recurrent seizures. Boys, girls, men, and women of all ages are affected by epilepsy and, in many cases, by associated comorbidities as well. The primary courses of treatment are pharmacological, dietary, and/or surgical, depending on several factors, including the areas of the brain affected and the severity of the epilepsy. There is a growing appreciation that sex differences in underlying brain function and in the neurobiology of epilepsy are important factors that should be accounted for in the design and development of new therapies. In this review, we discuss the current knowledge on sex differences in epilepsy and associated comorbidities, with emphasis on those aspects most informative for the development of new pharmacotherapies. Particular focus is placed on sex differences in the prevalence and presentation of various focal and generalized epilepsies; psychiatric, cognitive, and physiologic comorbidities; catamenial epilepsy in women; sex differences in brain development; the neural actions of sex and stress hormones and their metabolites; and cellular mechanisms, including brain-derived neurotrophic factor signaling and neuronal-glial interactions. Further attention placed on potential sex differences in epilepsies, comorbidities, and drug effects will enhance therapeutic options and efficacy for all patients with epilepsy. SIGNIFICANCE STATEMENT: Epilepsy is a common neurological disorder that often presents together with various comorbidities. The features of epilepsy and seizure activity as well as comorbid afflictions can vary between men and women. In this review, we discuss sex differences in types of epilepsies, associated comorbidities, pathophysiological mechanisms, and antiepileptic drug efficacy in both clinical patient populations and preclinical animal models.
Asunto(s)
Anticonvulsivantes/farmacología , Epilepsia/tratamiento farmacológico , Animales , Anticonvulsivantes/uso terapéutico , Comorbilidad , Modelos Animales de Enfermedad , Epilepsia/fisiopatología , Femenino , Humanos , Masculino , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores SexualesRESUMEN
This review aims to summarize the diverse proposed pathophysiological mechanisms contributing to postpartum depression, highlighting both clinical and basic science research findings. The risk factors for developing postpartum depression are discussed, which may provide insight into potential neurobiological underpinnings. The evidence supporting a role for neuroendocrine changes, neuroinflammation, neurotransmitter alterations, circuit dysfunction, and the involvement of genetics and epigenetics in the pathophysiology of postpartum depression are discussed. This review integrates clinical and preclinical findings and highlights the diversity in the patient population, in which numerous pathophysiological changes may contribute to this disorder. Finally, we attempt to integrate these findings to understand how diverse neurobiological changes may contribute to a common pathological phenotype. This review is meant to serve as a comprehensive resource reviewing the proposed pathophysiological mechanisms underlying postpartum depression.
Asunto(s)
Depresión Posparto , Epigénesis Genética/genética , Sistema Hipotálamo-Hipofisario/metabolismo , Inflamación , Sistema Hipófiso-Suprarrenal/metabolismo , Animales , Depresión Posparto/etiología , Depresión Posparto/genética , Depresión Posparto/inmunología , Depresión Posparto/metabolismo , Femenino , Humanos , Inflamación/complicaciones , Inflamación/inmunología , Inflamación/metabolismoRESUMEN
Estrogen plays a critical role in many physiological processes and exerts profound effects on behavior by regulating neuronal excitability. While estrogen has been established to exert effects on dendritic morphology and excitatory neurotransmission its role in regulating neuronal inhibition is poorly understood. Fast synaptic inhibition in the adult brain is mediated by specialized populations of γ-c aA receptors (GABAARs) that are selectively enriched at synapses, a process dependent upon their interaction with the inhibitory scaffold protein gephyrin. Here we have assessed the role that estradiol (E2) plays in regulating the dynamics of GABAARs and stability of inhibitory synapses. Treatment of cultured cortical neurons with E2 reduced the accumulation of GABAARs and gephyrin at inhibitory synapses. However, E2 exposure did not modify the expression of either the total or the plasma membrane GABAARs or gephyrin. Mechanistically, single-particle tracking revealed that E2 treatment selectively reduced the dwell time and thereby decreased the confinement of GABAARs at inhibitory synapses. Consistent with our cell biology measurements, we observed a significant reduction in amplitude of inhibitory synaptic currents in both cultured neurons and hippocampal slices exposed to E2, while their frequency was unaffected. Collectively, our results suggest that acute exposure of neurons to E2 leads to destabilization of GABAARs and gephyrin at inhibitory synapses, leading to reductions in the efficacy of GABAergic inhibition via a postsynaptic mechanism.
Asunto(s)
Estradiol/farmacología , Inhibición Neural/efectos de los fármacos , Receptores de GABA-A/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Animales , Proteínas Portadoras/farmacología , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Células Cultivadas , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Proteínas de la Membrana/farmacología , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratas , Transmisión Sináptica/efectos de los fármacosRESUMEN
Our laboratory recently demonstrated that seizures activate the hypothalamic-pituitary-adrenal (HPA) axis, increasing circulating levels of corticosterone (O'Toole et al., 2013). Given the well-established proconvulsant actions of corticosterone, we hypothesized that seizure-induced activation of the HPA axis may contribute to future seizure susceptibility. Further, since hypercortisolism is associated with depression, we propose that seizure-induced activation of the HPA axis may contribute to comorbid depression and epilepsy. To test this hypothesis, we generated mice lacking the GABAA receptor (GABAAR) δ subunit specifically in corticotropin-releasing hormone (CRH) neurons (Gabrd/Crh mice), which exhibit hyporeactivity of the HPA axis (Lee et al., 2014). Gabrd/Crh mice exhibit blunted seizure-induced elevations in corticosterone, establishing a useful tool to investigate the contribution of HPA axis dysfunction on epilepsy and associated comorbidities. Interestingly, Gabrd/Crh mice exhibit decreased acute seizure susceptibility following kainic acid (KA) administration. Furthermore, chronically epileptic Gabrd/Crh mice exhibit a decrease in both spontaneous seizure frequency and depression-like behaviors compared with chronically epileptic Cre-/- littermates. Seizure susceptibility and associated depression-like behaviors can be restored to wild type levels by treating Gabrd/Crh mice with exogenous corticosterone. Similarly, chemogenetic activation of CRH neurons in the paraventricular nucleus (PVN) is sufficient to increase seizure susceptibility; whereas, chemogenetic inhibition of CRH neurons in the PVN of the hypothalamus is sufficient to decrease seizure susceptibility and depression-like behaviors in chronically epileptic mice. These data suggest that seizure-induced activation of the HPA axis promotes seizure susceptibility and comorbid depression-like behaviors, suggesting that the HPA axis may be a novel target for seizure control.
Asunto(s)
Corticosterona/farmacología , Depresión/epidemiología , Trastorno Depresivo/epidemiología , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Receptores de GABA-A/metabolismo , Convulsiones/epidemiología , Animales , Hormona Liberadora de Corticotropina/sangre , Hormona Liberadora de Corticotropina/metabolismo , Trastorno Depresivo/fisiopatología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/fisiopatología , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , Ratones , Neuronas/metabolismo , Núcleo Hipotalámico Paraventricular , Sistema Hipófiso-Suprarrenal/fisiopatología , Convulsiones/sangre , Convulsiones/fisiopatologíaRESUMEN
Alterations in the efficacy of neuronal inhibition mediated by GABAA receptors (GABAARs) containing ß3 subunits are continually implicated in autism spectrum disorders (ASDs). In vitro, the plasma membrane stability of GABAARs is potentiated via phosphorylation of serine residues 408 and 409 (S408/9) in the ß3 subunit, an effect that is mimicked by their mutation to alanines. To assess if modifications in ß3 subunit expression contribute to ASDs, we have created a mouse in which S408/9 have been mutated to alanines (S408/9A). S408/9A homozygotes exhibited increased phasic, but decreased tonic, inhibition, events that correlated with alterations in the membrane stability and synaptic accumulation of the receptor subtypes that mediate these distinct forms of inhibition. S408/9A mice exhibited alterations in dendritic spine structure, increased repetitive behavior, and decreased social interaction, hallmarks of ASDs. ASDs are frequently comorbid with epilepsy, and consistent with this comorbidity, S408/9A mice exhibited a marked increase in sensitivity to seizures induced by the convulsant kainic acid. To assess the relevance of our studies using S408/9A mice for the pathophysiology of ASDs, we measured S408/9 phosphorylation in Fmr1 KO mice, a model of fragile X syndrome, the most common monogenetic cause of ASDs. Phosphorylation of S408/9 was selectively and significantly enhanced in Fmr1 KO mice. Collectively, our results suggest that alterations in phosphorylation and/or activity of ß3-containing GABAARs may directly contribute to the pathophysiology of ASDs.
Asunto(s)
Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Regulación de la Expresión Génica , Receptores de GABA-A/genética , Alanina/genética , Animales , Conducta Animal , Biotinilación , Membrana Celular/metabolismo , Espinas Dendríticas/metabolismo , Modelos Animales de Enfermedad , Electroencefalografía , Fenómenos Electrofisiológicos , Epilepsia/complicaciones , Miedo , Técnicas de Sustitución del Gen , Hipocampo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Mutación , Fenotipo , Fosforilación , Serina/genética , Conducta Social , Sinapsis/metabolismo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Neurosteroids are synthesized within the brain and act as endogenous anxiolytic, anticonvulsant, hypnotic, and sedative agents, actions that are principally mediated via their ability to potentiate phasic and tonic inhibitory neurotransmission mediated by γ-aminobutyric acid type A receptors (GABAARs). Although neurosteroids are accepted allosteric modulators of GABAARs, here we reveal they exert sustained effects on GABAergic inhibition by selectively enhancing the trafficking of GABAARs that mediate tonic inhibition. We demonstrate that neurosteroids potentiate the protein kinase C-dependent phosphorylation of S443 within α4 subunits, a component of GABAAR subtypes that mediate tonic inhibition in many brain regions. This process enhances insertion of α4 subunit-containing GABAAR subtypes into the membrane, resulting in a selective and sustained elevation in the efficacy of tonic inhibition. Therefore, the ability of neurosteroids to modulate the phosphorylation and membrane insertion of α4 subunit-containing GABAARs may underlie the profound effects these endogenous signaling molecules have on neuronal excitability and behavior.
Asunto(s)
Neuronas/metabolismo , Neurotransmisores/metabolismo , Receptores de GABA-A/metabolismo , Filtrado Sensorial/fisiología , Sinapsis/metabolismo , Animales , Células COS , Células Cultivadas , Chlorocebus aethiops , Células HEK293 , Hipocampo/citología , Hipocampo/fisiología , Humanos , Neurotransmisores/farmacología , Técnicas de Placa-Clamp , Fosforilación/efectos de los fármacos , Fosforilación/fisiología , Proteína Quinasa C/metabolismo , Receptores de Superficie Celular/metabolismo , Receptores de GABA-A/fisiología , Filtrado Sensorial/efectos de los fármacosRESUMEN
GABA(A) receptors form Cl(-) permeable channels that mediate the majority of fast synaptic inhibition in the brain. The K(+)/Cl(-) cotransporter KCC2 is the main mechanism by which neurons establish low intracellular Cl(-) levels, which is thought to enable GABAergic inhibitory control of neuronal activity. However, the widely used KCC2 inhibitor furosemide is nonselective with antiseizure efficacy in slices and in vivo, leading to a conflicting scheme of how KCC2 influences GABAergic control of neuronal synchronization. Here we used the selective KCC2 inhibitor VU0463271 [N-cyclopropyl-N-(4-methyl-2-thiazolyl)-2-[(6-phenyl-3-pyridazinyl)thio]acetamide] to investigate the influence of KCC2 function. Application of VU0463271 caused a reversible depolarizing shift in E(GABA) values and increased spiking of cultured hippocampal neurons. Application of VU0463271 to mouse hippocampal slices under low-Mg(2+) conditions induced unremitting recurrent epileptiform discharges. Finally, microinfusion of VU0463271 alone directly into the mouse dorsal hippocampus rapidly caused epileptiform discharges. Our findings indicated that KCC2 function was a critical inhibitory factor ex vivo and in vivo.
Asunto(s)
Hipocampo/fisiología , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/farmacología , Simportadores/antagonistas & inhibidores , Simportadores/fisiología , Animales , Animales Recién Nacidos , Células Cultivadas , Células HEK293 , Hipocampo/efectos de los fármacos , Humanos , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Ratones , Ratones Endogámicos C57BL , Técnicas de Cultivo de Órganos , Ratas , Ratas Sprague-Dawley , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Cotransportadores de K ClRESUMEN
A subset of corticotropin-releasing hormone (CRH) neurons was previously identified in the hippocampus with unknown function. Here we demonstrate that hippocampal CRH neurons represent a novel subtype of interneurons in the hippocampus, exhibiting unique morphology, electrophysiological properties, molecular markers, and connectivity. This subset of hippocampal CRH neurons in the mouse reside in the CA1 pyramidal cell layer and tract tracing studies using AAV-Flex-ChR2-tdTomato reveal dense back-projections of these neurons onto principal neurons in the CA3 region of the hippocampus. These hippocampal CRH neurons express both GABA and GAD67 and using in vitro optogenetic techniques, we demonstrate that these neurons make functional connections and release GABA onto CA3 principal neurons. The location, morphology, and importantly the functional connectivity of these neurons demonstrate that hippocampal CRH neurons represent a unique subtype of hippocampal interneurons. The connectivity of these neurons has significant implications for hippocampal function.
Asunto(s)
Hormona Liberadora de Corticotropina/metabolismo , Hipocampo/citología , Hipocampo/fisiología , Interneuronas/citología , Interneuronas/fisiología , Animales , Hormona Liberadora de Corticotropina/genética , Glutamato Descarboxilasa/metabolismo , Inmunohistoquímica , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Potenciales de la Membrana , Ratones Transgénicos , Inhibición Neural/fisiología , Vías Nerviosas/citología , Vías Nerviosas/fisiología , Técnicas de Trazados de Vías Neuroanatómicas , Optogenética , Técnicas de Placa-Clamp , Reacción en Cadena de la Polimerasa , Análisis de la Célula Individual , Técnicas de Cultivo de Tejidos , Ácido gamma-Aminobutírico/metabolismoRESUMEN
It is well established that stress impacts the underlying processes of learning and memory. The effects of stress on memory are thought to involve, at least in part, effects on the hippocampus, which is particularly vulnerable to stress. Chronic stress induces hippocampal alterations, including but not limited to dendritic atrophy and decreased neurogenesis, which are thought to contribute to chronic stress-induced hippocampal dysfunction and deficits in learning and memory. Changes in synaptic transmission, including changes in GABAergic inhibition, have been documented following chronic stress. Recently, our laboratory demonstrated shifts in EGABA in CA1 pyramidal neurons following chronic stress, compromising GABAergic transmission and increasing excitability of these neurons. Interestingly, here we demonstrate that these alterations are unique to CA1 pyramidal neurons, since we do not observe shifts in EGABA following chronic stress in dentate gyrus granule cells. Following chronic stress, there is a decrease in the expression of the GABAA receptor (GABAA R) δ subunit and tonic GABAergic inhibition in dentate gyrus granule cells, whereas there is an increase in the phasic component of GABAergic inhibition, evident by an increase in the peak amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs). Given the numerous changes observed in the hippocampus following stress, it is difficult to pinpoint the pertinent contributing pathophysiological factors. Here we directly assess the impact of a reduction in tonic GABAergic inhibition of dentate gyrus granule cells on learning and memory using a mouse model with a decrease in GABAA R δ subunit expression specifically in dentate gyrus granule cells (Gabrd/Pomc mice). Reduced GABAA R δ subunit expression and function in dentate gyrus granule cells is sufficient to induce deficits in learning and memory. Collectively, these findings suggest that the reduction in GABAA R δ subunit-mediated tonic inhibition in dentate gyrus granule cells contributes, at least in part, to deficits in learning and memory associated with chronic stress. These findings have significant implications regarding the pathophysiological mechanisms underlying impairments in learning and memory associated with stress and suggest a role for GABAA R δ subunit containing receptors in dentate gyrus granule cells. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Giro Dentado/metabolismo , Discapacidades para el Aprendizaje/metabolismo , Trastornos de la Memoria/metabolismo , Inhibición Neural/fisiología , Estrés Psicológico/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Animales , Enfermedad Crónica , Femenino , Aprendizaje/fisiología , Discapacidades para el Aprendizaje/etiología , Masculino , Memoria/fisiología , Trastornos de la Memoria/etiología , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de GABA-A/deficiencia , Receptores de GABA-A/genética , Restricción Física , Estrés Psicológico/complicaciones , Técnicas de Cultivo de TejidosRESUMEN
OBJECTIVE: We investigated the role of chloride homeostasis in seizure progression and development of pharmacoresistant status epilepticus (SE) by pharmacologically targeting the Na-K-Cl cotransporter (NKCC1) with bumetanide. We also investigated the ability of bumetanide to restore the efficacy of diazepam following SE. METHODS: Kainic acid (KA)-induced SE in vivo and 0-Mg(2+) -induced seizure-like events (SLEs) in vitro were monitored using electroencephalography (EEG) recordings in freely moving adult male mice and extracellular field potential recordings in acute entorhinal cortex-hippocampus slices, respectively. The ability of bumetanide to decrease epileptiform activity and prevent the development of pharmacoresistance to diazepam following SE was evaluated. RESULTS: Bumetanide treatment significantly reduced KA-induced ictal activity in vivo and SLEs in vitro. In addition, bumetanide restored the efficacy of diazepam in decreasing ictal activity following SE in both the in vivo and in vitro models. SIGNIFICANCE: Our data demonstrate an anticonvulsant effect of bumetanide on KA-induced seizures in adult mice, suggesting a role for chloride plasticity in seizure progression. These data also demonstrate that the erosion of inhibition during seizure progression could underlie the development of pharmacoresistant SE and implicate a role for chloride plasticity in this process.
Asunto(s)
Anticonvulsivantes/farmacología , Bumetanida/farmacología , Diazepam/farmacología , Epilepsia Refractaria/fisiopatología , Corteza Entorrinal/efectos de los fármacos , Hipocampo/efectos de los fármacos , Convulsiones/fisiopatología , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/farmacología , Estado Epiléptico/fisiopatología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Progresión de la Enfermedad , Electroencefalografía , Corteza Entorrinal/fisiopatología , Agonistas de Aminoácidos Excitadores/toxicidad , Hipocampo/fisiopatología , Técnicas In Vitro , Ácido Kaínico/toxicidad , Masculino , Ratones , Ratones Endogámicos C57BL , Técnicas de Placa-Clamp , Convulsiones/inducido químicamenteRESUMEN
Maternal depression has been shown to negatively impact offspring development. Investigation into the impact of maternal depression and offspring behavior has relied on correlative studies in humans. Further investigation into the underlying mechanisms has been hindered by the lack of useful animal models. We previously characterized a mouse model which exhibits depression-like behaviors restricted to the postpartum period and abnormal/fragmented maternal care (Gabrd (-/-) mice). Here we utilized this unique mouse model to investigate the mechanism(s) through which maternal depression-like behaviors adversely impact offspring development. Cross-fostering experiments reveal increased anxiety-like and depression-like behaviors in mice reared by Gabrd (-/-) mothers. Wild type and Gabrd (-/-) mice subjected to unpredictable stress during late pregnancy exhibit decreased pup survival and depression-like behavior in the postpartum period. Exogenous corticosterone treatment in wild type mice during late pregnancy is sufficient to decrease pup survival and induce anxiety-like and depression-like behaviors in the offspring. Further, the abnormal behaviors in juvenile mice reared by Gabrd (-/-) mice are alleviated by treatment of the mothers with the corticotropin-releasing hormone (CRH) antagonist, Antalarmin. These studies suggest that hyperresponsiveness of the HPA axis is associated with postpartum depression and may mediate the adverse effects of maternal depression on offspring behavior.
Asunto(s)
Ansiedad/metabolismo , Conducta Animal/fisiología , Depresión Posparto/metabolismo , Depresión/metabolismo , Conducta Materna/fisiología , Animales , Ansiedad/psicología , Conducta Animal/efectos de los fármacos , Depresión/psicología , Depresión Posparto/psicología , Modelos Animales de Enfermedad , Femenino , Conducta Materna/efectos de los fármacos , Ratones , Ratones Noqueados , Pirimidinas/farmacología , Pirroles/farmacología , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismoRESUMEN
Developmental cortical malformations are associated with a high incidence of drug-resistant epilepsy. The underlying epileptogenic mechanisms, however, are poorly understood. In rodents, cortical malformations can be modeled using neonatal freeze-lesion (FL), which has been shown to cause in vitro cortical hyperexcitability. Here, we investigated the therapeutic potential of gabapentin, a clinically used anticonvulsant and analgesic, in preventing FL-induced in vitro and in vivo hyperexcitability. Gabapentin has been shown to disrupt the interaction of thrombospondin (TSP) with α2δ-1, an auxiliary calcium channel subunit. TSP/α2δ-1 signaling has been shown to drive the formation of excitatory synapses during cortical development and following injury. Gabapentin has been reported to have neuroprotective and anti-epileptogenic effects in other models associated with increased TSP expression and reactive astrocytosis. We found that both TSP and α2δ-1 were transiently upregulated following neonatal FL. We therefore designed a one-week GBP treatment paradigm to block TSP/α2δ-1 signaling during the period of their upregulation. GBP treatment prevented epileptiform activity following FL, as assessed by both glutamate biosensor imaging and field potential recording. GBP also attenuated FL-induced increases in mEPSC frequency at both P7 and 28. Additionally, GBP treated animals had decreased in vivo kainic acid (KA)-induced seizure activity. Taken together these results suggest gabapentin treatment immediately after FL can prevent the formation of a hyperexcitable network and may have therapeutic potential to minimize epileptogenic processes associated with developmental cortical malformations.
Asunto(s)
Aminas/uso terapéutico , Anticonvulsivantes/uso terapéutico , Ácidos Ciclohexanocarboxílicos/uso terapéutico , Epilepsia/tratamiento farmacológico , Epilepsia/etiología , Malformaciones del Desarrollo Cortical/complicaciones , Corteza Somatosensorial/lesiones , Ácido gamma-Aminobutírico/uso terapéutico , Factores de Edad , Animales , Animales Recién Nacidos , Canales de Calcio/metabolismo , Modelos Animales de Enfermedad , Estimulación Eléctrica , Potenciales Evocados/efectos de los fármacos , Agonistas de Aminoácidos Excitadores/toxicidad , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Congelación/efectos adversos , Gabapentina , Proteína Ácida Fibrilar de la Glía , Ácido Glutámico/metabolismo , Técnicas In Vitro , Ácido Kaínico/toxicidad , Malformaciones del Desarrollo Cortical/etiología , Ratones , Ratones Endogámicos C57BL , Neuroimagen , Técnicas de Placa-Clamp , Corteza Somatosensorial/crecimiento & desarrollo , Trombospondinas/metabolismoRESUMEN
Like other classes of treatments described in this issue's section, neuroactive steroids have been studied for decades but have risen as a new class of rapid-acting, durable antidepressants with a distinct mechanism of action from previous antidepressant treatments and from other compounds covered in this issue. Neuroactive steroids are natural derivatives of progesterone but are proving effective as exogenous treatments. The best understood mechanism is that of positive allosteric modulation of GABAA receptors, where subunit selectivity may promote their profile of action. Mechanistically, there is some reason to think that neuroactive steroids may separate themselves from liabilities of other GABA modulators, although research is ongoing. It is also possible that intracellular targets, including inflammatory pathways, may be relevant to beneficial actions. Strengths and opportunities for further development include exploiting non-GABAergic targets, structural analogs, enzymatic production of natural steroids, precursor loading, and novel formulations. The molecular mechanisms of behavioral effects are not fully understood, but study of brain network states involved in emotional processing demonstrate a robust influence on affective states not evident with at least some other GABAergic drugs including benzodiazepines. Ongoing studies with neuroactive steroids will further elucidate the brain and behavioral effects of these compounds as well as likely underpinnings of disease.
Asunto(s)
Neuroesteroides , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Encéfalo/metabolismo , Receptores de GABA-A/metabolismo , ProgesteronaRESUMEN
Despite the vast number of seizure detection publications there are no validated open-source tools for automating seizure detection based on electrographic recordings. Researchers instead rely on manual curation of seizure detection that is highly laborious, inefficient, error prone, and heavily biased. Here we developed an open-source software called SeizyML that uses sensitive machine learning models coupled with manual validation of detected events reducing bias and promoting efficient and accurate detection of electrographic seizures. We compared the validity of four interpretable machine learning models (decision tree, gaussian naïve bayes, passive aggressive classifier, and stochastic gradient descent classifier) on an extensive electrographic seizure dataset that we collected from chronically epileptic mice. We find that the gaussian naïve bayes and stochastic gradient descent models achieved the highest precision and f1 scores, while also detecting all seizures in our mouse dataset and only require a small amount of data to train the model and achieve good performance. Further, we demonstrate the utility of this approach to detect electrographic seizures in a human EEG dataset. This approach has the potential to be a transformative research tool overcoming the analysis bottleneck that slows research progress.
RESUMEN
Background: Adverse childhood experiences (ACEs) are associated with numerous detriments in health, including increased vulnerability to psychiatric illnesses. Early life stress (ELS) in rodents has been shown to effectively model several of the behavioral and endocrine impacts of ACEs and has been utilized to investigate the underlying mechanisms contributing to disease. However, the precise neural mechanisms responsible for mediating the impact of ELS on vulnerability to psychiatric illnesses remain largely unknown. Methods: We use behavior, immunoassay, in vivo LFP recording, histology, and patch clamp to describe the effects of ELS on stress behaviors, endocrinology, network states, protein expression, and cellular physiology in male and female mice. Results: We demonstrate that a murine maternal separation (MS) ELS model causes sex-dependent alterations in behavioral and hormonal responses following an acute stressor. Local field potential (LFP) recordings in the basolateral amygdala (BLA) and frontal cortex (FC) reveal similar sex-dependent alterations at baseline, in response to acute ethological stress, and during fear memory extinction, supporting a large body of literature demonstrating that these network states contribute to stress reactivity and vulnerability to psychiatric illnesses. Sex differences were accompanied by altered physiology of BLA principal neurons in males and BLA PV interneurons in females. Conclusions: Collectively, these results implicate novel, sex-dependent mechanisms through which ACEs may impact psychiatric health, involving altered cellular physiology and network states involved in emotional processing.
RESUMEN
Although most adults in the United States will drink alcohol in their life, only about 6% will go on to develop an alcohol use disorder (AUD). While a great deal of work has furthered our understanding of the cycle of addiction, it remains unclear why certain people transition to disordered drinking. Altered activity in regions implicated in AUDs, like the basolateral amygdala (BLA), has been suggested to play a role in the pathophysiology of AUDs, but how these networks contribute to alcohol misuse remains unclear. Our recent work demonstrated that alcohol can modulate BLA network states and that GABAergic parvalbumin (PV) interneurons are crucial modulators of network activity in the BLA. Further, our lab has demonstrated that δ subunit-containing GABA A receptors, which are modulated by alcohol, are highly expressed on PV interneurons in the BLA. These receptors on PV interneurons have also been shown to influence alcohol intake in a voluntary binge drinking paradigm and anxiety-like behavior in withdrawal. Therefore, we hypothesized that alcohol may impact BLA network states via δ subunit-containing GABA A receptors on PV interneurons to impact the extent of alcohol use. To test this hypothesis, we measured the impact of acute alcohol exposure on oscillatory states in the basolateral amygdala and then assessed the relationship to the extent of voluntary ethanol consumption in the Intermittent Access, Drinking-in-the-Dark-Multiple Scheduled Access, and Chronic Intermittent Ethanol exposure paradigms. Remarkably, we demonstrate that the average alcohol intake negatively correlates with δ subunit-containing GABA A receptor expression on PV interneurons and gamma power in the BLA after the first exposure to alcohol. These data implicate δ subunit-containing GABA A receptor expression on PV interneurons in the BLA in voluntary alcohol intake and suggest that BLA network states may serve as a useful biomarker for those at risk for alcohol misuse. Significance Statement: Oscillatory states in the BLA have been demonstrated to drive behavioral states involved in emotional processing, including negative valence processing. Given that negative emotional states/hyperkatifeia contribute to the cycle of AUDs, our previous work demonstrating the ability of alcohol to modulate BLA network states and thereby behavioral states suggests that this mechanism may influence alcohol intake. Here we demonstrate a relationship between the ability of alcohol to modulate oscillations in the BLA and future alcohol intake such that the extent to which alcohol influences BLA network states predict the extent of future voluntary alcohol intake. These findings suggest that individual variability in the sensitivity of the BLA network to alcohol influences voluntary alcohol consumption.
RESUMEN
The basolateral amygdala (BLA) mediates both fear and reward learning.1,2 Previous work has shown that parvalbumin (PV) interneurons in the BLA contribute to BLA oscillatory states integral to fear expression.3,4,5,6,7 However, despite it being critical to our understanding of reward behaviors, it is unknown whether BLA oscillatory states and PV interneurons similarly contribute to reward processing. Local field potentials in the BLA were collected as male and female mice consumed sucrose reward, where prominent changes in the beta band (15-30 Hz) emerged with reward experience. During consumption of one water bottle during a two-water-bottle choice test, rhythmic optogenetic stimulation of BLA PVs produced a robust bottle preference, showing that PVs can sufficiently drive reward seeking. Finally, to demonstrate that PV activity is necessary for reward value use, PVs were chemogenetically inhibited following outcome devaluation, rendering mice incapable of using updated reward representations to guide their behavior. Taken together, these experiments provide novel information about the physiological signatures of reward while highlighting BLA PV interneuron contributions to behaviors that are BLA dependent. This work builds upon established knowledge of PV involvement in fear expression and provides evidence that PV orchestration of unique BLA network states is involved in both learning types.