Neonatal allopregnanolone or finasteride administration modifies hippocampal K+ Cl− co-transporter expression during early development in male rats

Mòdol, Laura; Casas, Caty; Llidó, Anna; Navarro, Xavier; Pallarès, Marc; Darbra, Sònia

doi:10.1016/j.jsbmb.2014.05.002

Cited by 12 publications

(8 citation statements)

References 25 publications

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“…A limitation of this study is that we did not have an adequate sample size to clarify sex differences in inhibitory tone. Developmental upregulation of KCC2 expression varies between male and female Wistar rats (Murguia-Castillo et al, 2013 ), and neonatal allopregnanolone promotes KCC2 expression in male rats (Modol et al, 2014 ); however, sex differences in KCC2 have not been studied in Sprague-Dawley rats. In this model, males tended to show a lower seizure threshold than females, although both males and females were significantly lower than shams (Mazur et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Prenatal Hypoxia–Ischemia Induces Abnormalities in CA3 Microstructure, Potassium Chloride Co-Transporter 2 Expression and Inhibitory Tone

Jantzie

Getsy

Denson

et al. 2015

Front. Cell. Neurosci.

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Infants who suffer perinatal brain injury, including those with encephalopathy of prematurity, are prone to chronic neurological deficits, including epilepsy, cognitive impairment, and behavioral problems, such as anxiety, inattention, and poor social interaction. These deficits, especially in combination, pose the greatest hindrance to these children becoming independent adults. Cerebral function depends on adequate development of essential inhibitory neural circuits and the appropriate amount of excitation and inhibition at specific stages of maturation. Early neuronal synaptic responses to γ-amino butyric acid (GABA) are initially excitatory. During the early postnatal period, GABAAR responses switch to inhibitory with the upregulation of potassium-chloride co-transporter KCC2. With extrusion of chloride by KCC2, the Cl− reversal potential shifts and GABA and glycine responses become inhibitory. We hypothesized that prenatal hypoxic–ischemic brain injury chronically impairs the developmental upregulation of KCC2 that is essential for cerebral circuit formation. Following late gestation hypoxia–ischemia (HI), diffusion tensor imaging in juvenile rats shows poor microstructural integrity in the hippocampal CA3 subfield, with reduced fractional anisotropy and elevated radial diffusivity. The loss of microstructure correlates with early reduced KCC2 expression on NeuN-positive pyramidal neurons, and decreased monomeric and oligomeric KCC2 protein expression in the CA3 subfield. Together with decreased inhibitory post-synaptic currents during a critical window of development, we document for the first time that prenatal transient systemic HI in rats impairs hippocampal CA3 inhibitory tone. Failure of timely development of inhibitory tone likely contributes to a lower seizure threshold and impaired cognitive function in children who suffer perinatal brain injury.

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Section: Discussionmentioning

confidence: 99%

Prenatal Hypoxia–Ischemia Induces Abnormalities in CA3 Microstructure, Potassium Chloride Co-Transporter 2 Expression and Inhibitory Tone

Jantzie

Getsy

Denson

et al. 2015

Front. Cell. Neurosci.

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“…Chronic treatment with the BZ agonist zolpidem up-regulated the KCC2 expression in mouse limbic forebrain ( Shibasaki et al, 2013 ). Also the neurosteroid allopregnanolone transiently modifies KCC2 expression and protein levels during brain maturation in male rats ( Modol et al, 2014 ). However, treatment with general anesthetics, midazolam, propofol, and ketamine, does not alter the expression of KCC2 in rats during the first two postnatal weeks when developmental maturation of KCC2 expression is going on ( Lacoh et al, 2013 ).…”

Section: Kcc2-mediated Spine Morphogenesismentioning

confidence: 99%

GABAA receptor drugs and neuronal plasticity in reward and aversion: focus on the ventral tegmental area

Vashchinkina¹,

Panhelainen²,

Aitta-aho³

et al. 2014

Front. Pharmacol.

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GABAA receptors are the main fast inhibitory neurotransmitter receptors in the mammalian brain, and targets for many clinically important drugs widely used in the treatment of anxiety disorders, insomnia and in anesthesia. Nonetheless, there are significant risks associated with the long-term use of these drugs particularly related to development of tolerance and addiction. Addictive mechanisms of GABAA receptor drugs are poorly known, but recent findings suggest that those drugs may induce aberrant neuroadaptations in the brain reward circuitry. Recently, benzodiazepines, acting on synaptic GABAA receptors, and modulators of extrasynaptic GABAA receptors (THIP and neurosteroids) have been found to induce plasticity in the ventral tegmental area (VTA) dopamine neurons and their main target projections. Furthermore, depending whether synaptic or extrasynaptic GABAA receptor populations are activated, the behavioral outcome of repeated administration seems to correlate with rewarding or aversive behavioral responses, respectively. The VTA dopamine neurons project to forebrain centers such as the nucleus accumbens and medial prefrontal cortex, and receive afferent projections from these brain regions and especially from the extended amygdala and lateral habenula, forming the major part of the reward and aversion circuitry. Both synaptic and extrasynaptic GABAA drugs inhibit the VTA GABAergic interneurons, thus activating the VTA DA neurons by disinhibition and this way inducing glutamatergic synaptic plasticity. However, the GABAA drugs failed to alter synaptic spine numbers as studied from Golgi-Cox-stained VTA dendrites. Since the GABAergic drugs are known to depress the brain metabolism and gene expression, their likely way of inducing neuroplasticity in mature neurons is by disinhibiting the principal neurons, which remains to be rigorously tested for a number of clinically important anxiolytics, sedatives and anesthetics in different parts of the circuitry.

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“…In this scenario, the emergence of mature (hyperpolarizing) GABA-ergic signalling would inversely correlate with the decline of neurosteroid production. Adding complexity, a recent report has demonstrated that neonatal administration of 5α3α influences the hippocampal expression of the K + Cl − co-transporter KCC2 ( Modol et al., 2014 ).…”

Section: Discussionmentioning

confidence: 99%

During postnatal development endogenous neurosteroids influence GABA-ergic neurotransmission of mouse cortical neurons

et al. 2016

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As neuronal development progresses, GABAergic synaptic transmission undergoes a defined program of reconfiguration. For example, GABAA receptor (GABAAR)-mediated synaptic currents, (miniature inhibitory postsynaptic currents; mIPSCs), which initially exhibit a relatively slow decay phase, become progressively reduced in duration, thereby supporting the temporal resolution required for mature network activity. Here we report that during postnatal development of cortical layer 2/3 pyramidal neurons, GABAAR-mediated phasic inhibition is influenced by a resident neurosteroid tone, which wanes in the second postnatal week, resulting in the brief phasic events characteristic of mature neuronal signalling. Treatment of cortical slices with the immediate precursor of 5α-pregnan-3α-ol-20-one (5α3α), the GABAAR-inactive 5α-dihydroprogesterone, (5α-DHP), greatly prolonged the mIPSCs of P20 pyramidal neurons, demonstrating these more mature neurons retain the capacity to synthesize GABAAR-active neurosteroids, but now lack the endogenous steroid substrate. Previously, such developmental plasticity of phasic inhibition was ascribed to the expression of synaptic GABAARs incorporating the α1 subunit. However, the duration of mIPSCs recorded from L2/3 cortical neurons derived from α1 subunit deleted mice, were similarly under the developmental influence of a neurosteroid tone. In addition to principal cells, synaptic GABAARs of L2/3 interneurons were modulated by native neurosteroids in a development-dependent manner. In summary, local neurosteroids influence synaptic transmission during a crucial period of cortical neurodevelopment, findings which may be of importance for establishing normal network connectivity.

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Neonatal allopregnanolone or finasteride administration modifies hippocampal K+ Cl− co-transporter expression during early development in male rats

Cited by 12 publications

References 25 publications

Prenatal Hypoxia–Ischemia Induces Abnormalities in CA3 Microstructure, Potassium Chloride Co-Transporter 2 Expression and Inhibitory Tone

Prenatal Hypoxia–Ischemia Induces Abnormalities in CA3 Microstructure, Potassium Chloride Co-Transporter 2 Expression and Inhibitory Tone

GABAA receptor drugs and neuronal plasticity in reward and aversion: focus on the ventral tegmental area

During postnatal development endogenous neurosteroids influence GABA-ergic neurotransmission of mouse cortical neurons

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