Loss of MeCP2 increases GABA uptake by astrocytes to suppress tonic inhibition of CA1 pyramidal neurons

Rett syndrome (RTT) is a neurodevelopmental disorder characterized a spectrum of phenotypes affecting neuronal and glial populations. Recent work by Dong et al. (Dong Q, Kim J, Nguyen L, Bu Q, Chang Q. J Neurosci 40: 6250–6261, 2020) suggests that augmented GABA uptake by astrocytes diminishes tonic inhibition in the hippocampus and contributes to increased seizure propensity in RTT. Here, I will review evidence supporting this possibility and critically evaluate how increased expression of a GABA transporter might contribute to this mechanism.

Download Full-text

An Astrocytic Influence on Impaired Tonic Inhibition in Hippocampal CA1 Pyramidal Neurons in a Mouse Model of Rett Syndrome

Journal of Neuroscience ◽

10.1523/jneurosci.3042-19.2020 ◽

2020 ◽

Vol 40 (32) ◽

pp. 6250-6261

Author(s):

Qiping Dong ◽

Jason Kim ◽

Linh Nguyen ◽

Qian Bu ◽

Qiang Chang

Keyword(s):

Mouse Model ◽

Rett Syndrome ◽

Pyramidal Neurons ◽

Tonic Inhibition ◽

Ca1 Pyramidal Neurons ◽

Hippocampal Ca1

Download Full-text

Enhanced Hypoxia Susceptibility in Hippocampal Slices From a Mouse Model of Rett Syndrome

Journal of Neurophysiology ◽

10.1152/jn.91124.2008 ◽

2009 ◽

Vol 101 (2) ◽

pp. 1016-1032 ◽

Cited By ~ 25

Author(s):

Marc Fischer ◽

Julia Reuter ◽

Florian J. Gerich ◽

Belinda Hildebrandt ◽

Sonja Hägele ◽

...

Keyword(s):

Rett Syndrome ◽

Molecular Mechanisms ◽

Pyramidal Neurons ◽

Neurodevelopmental Disorder ◽

Hippocampal Slices ◽

Field Potential ◽

Synaptic Function ◽

Cell Swelling ◽

Arterial Oxygen ◽

Ca1 Pyramidal Neurons

Rett syndrome is a neurodevelopmental disorder caused by mutations in the X-chromosomal MECP2 gene encoding for the transcriptional regulator methyl CpG binding protein 2 (MeCP2). Rett patients suffer from episodic respiratory irregularities and reduced arterial oxygen levels. To elucidate whether such intermittent hypoxic episodes induce adaptation/preconditioning of the hypoxia-vulnerable hippocampal network, we analyzed its responses to severe hypoxia in adult Rett mice. The occurrence of hypoxia-induced spreading depression (HSD)—an experimental model for ischemic stroke—was hastened in Mecp2− /y males. The extracellular K+ rise during HSD was attenuated in Mecp2− /y males and the input resistance of CA1 pyramidal neurons decreased less before HSD onset. CA1 pyramidal neurons were smaller and more densely packed, but the cell swelling during HSD was unaffected. The intrinsic optical signal and the propagation of HSD were similar among the different genotypes. Basal synaptic function was intact, but Mecp2− /y males showed reduced paired-pulse facilitation and higher field potential/fiber volley ratios, but no increased seizure susceptibility. Synaptic failure during hypoxia was complete in all genotypes and the final degree of posthypoxic synaptic recovery indistinguishable. Cellular ATP content was normal in Mecp2− /y males, but their hematocrit was increased as was HIF-1α expression throughout the brain. This is the first study showing that in Rett syndrome, the susceptibility of telencephalic neuronal networks to hypoxia is increased; the underlying molecular mechanisms apparently involve disturbed K+ channel function. Such an increase in hypoxia susceptibility may potentially contribute to the vulnerability of male Rett patients who are either not viable or severely disabled.

Download Full-text

Development of dendritic tonic GABAergic inhibition regulates excitability and plasticity in CA1 pyramidal neurons

Journal of Neurophysiology ◽

10.1152/jn.00066.2014 ◽

2014 ◽

Vol 112 (2) ◽

pp. 287-299 ◽

Cited By ~ 25

Author(s):

Martine R. Groen ◽

Ole Paulsen ◽

Enrique Pérez-Garci ◽

Thomas Nevian ◽

J. Wortel ◽

...

Keyword(s):

Synaptic Plasticity ◽

Action Potential ◽

Pyramidal Neurons ◽

Spike Timing ◽

Tonic Inhibition ◽

Developmental Changes ◽

Gabaergic Inhibition ◽

Gaba A ◽

Ca1 Pyramidal Neurons ◽

Mature Neurons

Synaptic plasticity rules change during development: while hippocampal synapses can be potentiated by a single action potential pairing protocol in young neurons, mature neurons require burst firing to induce synaptic potentiation. An essential component for spike timing-dependent plasticity is the backpropagating action potential (BAP). BAP along the dendrites can be modulated by morphology and ion channel composition, both of which change during late postnatal development. However, it is unclear whether these dendritic changes can explain the developmental changes in synaptic plasticity induction rules. Here, we show that tonic GABAergic inhibition regulates dendritic action potential backpropagation in adolescent, but not preadolescent, CA1 pyramidal neurons. These developmental changes in tonic inhibition also altered the induction threshold for spike timing-dependent plasticity in adolescent neurons. This GABAergic regulatory effect on backpropagation is restricted to distal regions of apical dendrites (>200 μm) and mediated by α5-containing GABA(A) receptors. Direct dendritic recordings demonstrate α5-mediated tonic GABA(A) currents in adolescent neurons which can modulate BAPs. These developmental modulations in dendritic excitability could not be explained by concurrent changes in dendritic morphology. To explain our data, model simulations propose a distally increasing or localized distal expression of dendritic α5 tonic inhibition in mature neurons. Overall, our results demonstrate that dendritic integration and plasticity in more mature dendrites are significantly altered by tonic α5 inhibition in a dendritic region-specific and developmentally regulated manner.

Download Full-text

Impact of inhibitory constraint of interneurons on neuronal excitability

Journal of Neurophysiology ◽

10.1152/jn.00047.2013 ◽

2013 ◽

Vol 110 (11) ◽

pp. 2520-2535 ◽

Cited By ~ 25

Author(s):

Vallent Lee ◽

Jamie Maguire

Keyword(s):

Neuronal Excitability ◽

Pyramidal Neurons ◽

Molecular Layer ◽

Critical Role ◽

Tonic Inhibition ◽

Stratum Radiatum ◽

Gabaergic Inhibition ◽

Seizure Susceptibility ◽

Ca1 Pyramidal Neurons ◽

The Impact

Tonic inhibition is thought to dampen the excitability of principal neurons; however, little is known about the role of tonic GABAergic inhibition in interneurons and the impact on principal neuron excitability. In many brain regions, tonic GABAergic inhibition is mediated by extrasynaptic, δ-subunit-containing GABAA receptors (GABAARs). In the present study we demonstrate the importance of GABAAR δ-subunit-mediated tonic inhibition in interneurons. Selective elimination of the GABAAR δ-subunit from interneurons was achieved by crossing a novel floxed Gabrd mouse model with GAD65-Cre mice ( Gabrd/Gad mice). Deficits in GABAAR δ-subunit expression in GAD65-positive neurons result in a decrease in tonic GABAergic inhibition and increased excitability of both molecular layer (ML) and stratum radiatum (SR) interneurons. Disinhibition of interneurons results in robust alterations in the neuronal excitability of principal neurons and decreased seizure susceptibility. Gabrd/Gad mice have enhanced tonic and phasic GABAergic inhibition in both CA1 pyramidal neurons and dentate gyrus granule cells (DGGCs). Consistent with alterations in hippocampal excitability, CA1 pyramidal neurons and DGGCs from Gabrd/Gad mice exhibit a shift in the input-output relationship toward decreased excitability compared with those from Cre−/− littermates. Furthermore, seizure susceptibility, in response to 20 mg/kg kainic acid, is significantly decreased in Gabrd/Gad mice compared with Cre−/− controls. These data demonstrate a critical role for GABAAR δ-subunit-mediated tonic GABAergic inhibition of interneurons on principal neuronal excitability and seizure susceptibility.

Download Full-text