Neonatal maternal separation delays the GABA excitatory-to-inhibitory functional switch by inhibiting KCC2 expression

Furukawa, Minami; Tsukahara, Takao; Tomita, Kazuo; Iwai, Haruki; Sonomura, Takahiro; Miyawaki, Shouichi; Sato, Tomoaki

doi:10.1016/j.bbrc.2017.09.143

Cited by 54 publications

(33 citation statements)

References 26 publications

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“…Similarly, adolescent nicotine administration was found to result in long-term depolarizing shifts in GABAA receptor signaling in adulthood (Thomas et al, 2018). Adult acute proximal stress and adolescent nicotine-induced depolarizing shifts in GABAA signaling were shown to be due to decreases in the function of the K + , Cltransporter, KCC2, which is critical for maintenance of Clhomeostasis (Furukawa et al, 2017;Ostroumov et al, 2016;Plotkin, Snyder, Hebert, & Delpire, 1997).…”

Section: Discussionmentioning

confidence: 99%

Adolescent Stress Increases Adult Ethanol Self-administration and Alters Ventral Tegmental Area GABA Signaling

Connor

Wittenberg

Drogin

et al. 2019

Preprint

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Alcohol use disorders (AUDs) continue to be a significant public health problem.Early life stress and adversity have long-lasting effects on a wide range of behaviors, including responses to drugs of abuse. Epidemiological evidence indicates that exposure to early life stress contributes to alcohol use disorders and, while it is known that stress and alcohol both act on overlapping mesolimbic circuitry, the cellular mechanisms underlying the relationship between stress and alcohol intake are not well understood.Previous work has demonstrated that acute stress increases ethanol intake mediated by changes in GABA signaling within the ventral tegmental area (VTA). Here we investigated if adolescent stress exposure might elicit long-term, persistent increases in ethanol selfadministration associated with altered VTA GABA signaling. To this end, we exposed adolescent postnatal day (PND) 28 male rats to 14 days of chronic variable stress (CVS) and then examined operant ethanol self-administration begun at least 30 days later. We found that adolescent stress exposure resulted in significantly increased ethanol selfadministration in adulthood. In contrast, adult (PND 82) male rats exposed to the same CVS protocol did not display increased ethanol self-administration that was begun 30 days later. Furthermore, we found that adolescent stress exposure resulted in enhancement of ethanol-induced GABA signaling onto VTA dopamine neurons and impairments in VTA GABA chloride homeostasis. The results indicate that adolescence is a period vulnerable to stress, which produces long-term changes in VTA GABA signaling associated with increased ethanol self-administration behavior.

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Section: Discussionmentioning

confidence: 99%

Adolescent Stress Increases Adult Ethanol Self-administration and Alters Ventral Tegmental Area GABA Signaling

Connor

Wittenberg

Drogin

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Another mechanism is via disruption of the GABA switch, a developmentally regulated functional change in GABA signaling from excitatory to inhibitory that occurs in the first 1-2 postnatal weeks (Ben-Ari, 2002). Neonatal stress from maternal separation has been found to delay the timing of the GABA switch in the mouse hippocampus, with consequences for behavior at adolescence (Furukawa et al, 2017). This study suggests that early life insults can disrupt or modify this essential step in GABAergic maturation and the resulting neuronal excitation/inhibition balance-which could have consequences for seizure propensity also.…”

Section: Maternal and Environmental Stress Throughout Developmentmentioning

confidence: 99%

Immune Challenges and Seizures: How Do Early Life Insults Influence Epileptogenesis?

2020

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The development of epilepsy, a process known as epileptogenesis, often occurs later in life following a prenatal or early postnatal insult such as cerebral ischemia, stroke, brain trauma, or infection. These insults share common pathophysiological pathways involving innate immune activation including neuroinflammation, which is proposed to play a critical role in epileptogenesis. This review provides a comprehensive overview of the latest preclinical evidence demonstrating that early life immune challenges influence neuronal hyperexcitability and predispose an individual to later life epilepsy. Here, we consider the range of brain insults that may promote the onset of chronic recurrent spontaneous seizures at adulthood, spanning intrauterine insults (e.g. maternal immune activation), perinatal injuries (e.g. hypoxic-ischemic injury, perinatal stroke), and insults sustained during early postnatal life-such as fever-induced febrile seizures, traumatic brain injuries, infections, and environmental stressors. Importantly, all of these insults represent, to some extent, an immune challenge, triggering innate immune activation and implicating both central and systemic inflammation as drivers of epileptogenesis. Increasing evidence suggests that pro-inflammatory cytokines such as interleukin-1 and subsequent signaling pathways are important mediators of seizure onset and recurrence, as well as neuronal network plasticity changes in this context. Our current understanding of how early life immune challenges prime microglia and astrocytes will be explored, as well as how developmental age is a critical determinant of seizure susceptibility. Finally, we will consider the paradoxical phenomenon of preconditioning, whereby these same insults may conversely provide neuroprotection. Together, an improved appreciation of the neuroinflammatory mechanisms underlying the long-term epilepsy risk following early life insults may provide insight into opportunities to develop novel immunological antiepileptogenic therapeutic strategies.

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“…The switch to inhibitory GABAergic neurons is completed during the first postnatal year and depends on the activity of the chloride transporters, potassium‐chloride transporter member and Na‐K‐Cl cotransporter 1. Impaired GABA switch interferes with E/I balance, which can likely have lasting effects …”

Section: Impaired Embryogenic Gaba: An Early Clue To Alsmentioning

confidence: 99%

“…Impaired GABA switch interferes with E/I balance, which can likely have lasting effects. 18,19 Excitatory GABAergic neurons migrate into the cerebral cortex via the white matter throughout the second half of gestation, and the switch to the inhibitory phenotype is completed during the first postnatal year. This transition is associated with a gradual shift from electrical to chemical synaptic transmission.…”

Section: Impaired Embryogenic Gaba: An Early Clue To Alsmentioning

confidence: 99%

Amyotrophic lateral sclerosis: Origins traced to impaired balance between neural excitation and inhibition in the neonatal period

2019

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Amyotrophic lateral sclerosis (ALS) is an adult onset disease but with an increasingly recognized preclinical prodrome. A wide spectrum of investigative approaches has identified loss of inhibitory function at the heart of ALS. In developing an explanation for the onset of ALS, it remains a consideration that ALS has its origins in neonatal derangement of the γ‐aminobutyric acid (GABA)‐ergic system, with delayed conversion from excitatory to mature inhibitory GABA and impaired excitation/inhibition balance. If this is so, the resulting chronic excitotoxicity could marginalize cortical network functioning very early in life, laying the path for neurodegeneration. The possibility that adult‐onset neurodegenerative conditions might have their roots in early developmental derangements is worthy of consideration, particularly in relation to current models of disease pathogenesis. Unraveling the very early molecular events will be crucial in developing a better understanding of ALS and other adult neurodegenerative disorders. Muscle Nerve, 2019

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Neonatal maternal separation delays the GABA excitatory-to-inhibitory functional switch by inhibiting KCC2 expression

Cited by 54 publications

References 26 publications

Adolescent Stress Increases Adult Ethanol Self-administration and Alters Ventral Tegmental Area GABA Signaling

Adolescent Stress Increases Adult Ethanol Self-administration and Alters Ventral Tegmental Area GABA Signaling

Immune Challenges and Seizures: How Do Early Life Insults Influence Epileptogenesis?

Amyotrophic lateral sclerosis: Origins traced to impaired balance between neural excitation and inhibition in the neonatal period

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