The GABA Developmental Shift Is Abolished by Maternal Immune Activation Already at Birth

Abstract Epidemiological and experimental studies suggest that maternal immune activation (MIA) leads to developmental brain disorders, but whether the pathogenic mechanism impacts neurons already at birth is not known. We now report that MIA abolishes in mice the oxytocin-mediated delivery γ-aminobutyric acid (GABA) shift from depolarizing to hyperpolarizing in CA3 pyramidal neurons, and this is restored by the NKCC1 chloride importer antagonist bumetanide. Furthermore, MIA hippocampal pyramidal neurons at birth have a more exuberant apical arbor organization and increased apical dendritic length than age-matched controls. The frequency of spontaneous glutamatergic postsynaptic currents is also increased in MIA offspring, as well as the pairwise correlation of the synchronized firing of active cells in CA3. These alterations produced by MIA persist, since at P14–15 GABA action remains depolarizing, produces excitatory action, and network activity remains elevated with a higher frequency of spontaneous glutamatergic postsynaptic currents. Therefore, the pathogenic actions of MIA lead to important morphophysiological and network alterations in the hippocampus already at birth.

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Maternal immune activation induces methylation changes in schizophrenia genes

10.1101/2022.01.11.22268935 ◽

2022 ◽

Author(s):

Tom Johnson ◽

Defne Saatci ◽

Lahiru Handunnetthi

Keyword(s):

Environmental Risk ◽

Immune Activation ◽

Pyramidal Neurons ◽

Fold Change ◽

Adult Brain ◽

Maternal Immune Activation ◽

Differentially Methylated Genes ◽

A Cell ◽

Layer V ◽

Upregulated Genes

Susceptibility to schizophrenia is mediated by genetic and environmental risk factors. Infection driven maternal immune activation (MIA) during pregnancy is a key environmental risk factor. However, little is known about how MIA during pregnancy could contribute to adult-onset schizophrenia. In this study, we investigated if maternal immune activation induces changes in methylation of genes linked to schizophrenia. We found that differentially expressed genes in schizophrenia brain were significantly enriched among MIA induced differentially methylated genes in the foetal brain in a cell-type-specific manner. Upregulated genes in layer V pyramidal neurons were enriched among hypomethylated genes at gestational day 9 (fold change = 1.57 , FDR = 0.049) and gestational day 17 (fold change = 1.97 , FDR = 0.0006). We also found that downregulated genes in GABAergic Rosehip interneurons were enriched among hypermethylated genes at gestational day 17 (fold change = 1.62, FDR= 0.03). Collectively, our results highlight a connection between MIA driven methylation changes during gestation and schizophrenia gene expression signatures in the adult brain. These findings carry important implications for early preventative strategies in schizophrenia.

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GluA4 subunit of AMPA receptors mediates the early synaptic response to altered network activity in the developing hippocampus

Journal of Neurophysiology ◽

10.1152/jn.00435.2015 ◽

2016 ◽

Vol 115 (6) ◽

pp. 2989-2996 ◽

Cited By ~ 4

Author(s):

J. Huupponen ◽

T. Atanasova ◽

T. Taira ◽

S. E. Lauri

Keyword(s):

Ampa Receptors ◽

Pyramidal Neurons ◽

Activity Patterns ◽

Critical Role ◽

Long Term Potentiation ◽

Postnatal Period ◽

Homeostatic Plasticity ◽

Network Activity ◽

Hippocampal Pyramidal Neurons ◽

Activity Dependent

Development of the neuronal circuitry involves both Hebbian and homeostatic plasticity mechanisms that orchestrate activity-dependent refinement of the synaptic connectivity. AMPA receptor subunit GluA4 is expressed in hippocampal pyramidal neurons during early postnatal period and is critical for neonatal long-term potentiation; however, its role in homeostatic plasticity is unknown. Here we show that GluA4-dependent plasticity mechanisms allow immature synapses to promptly respond to alterations in network activity. In the neonatal CA3, the threshold for homeostatic plasticity is low, and a 15-h activity blockage with tetrodotoxin triggers homeostatic upregulation of glutamatergic transmission. On the other hand, attenuation of the correlated high-frequency bursting in the CA3-CA1 circuitry leads to weakening of AMPA transmission in CA1, thus reflecting a critical role for Hebbian synapse induction in the developing CA3-CA1. Both of these developmentally restricted forms of plasticity were absent in GluA4 −/− mice. These data suggest that GluA4 enables efficient homeostatic upscaling and responsiveness to temporal activity patterns during the critical period of activity-dependent refinement of the circuitry.

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Somatostatin Depresses Excitatory but not Inhibitory Neurotransmission in Rat CA1 Hippocampus

Journal of Neurophysiology ◽

10.1152/jn.1997.78.6.3008 ◽

1997 ◽

Vol 78 (6) ◽

pp. 3008-3018 ◽

Cited By ~ 76

Author(s):

Melanie K. Tallent ◽

George R. Siggins

Keyword(s):

Pyramidal Neurons ◽

Hippocampal Slices ◽

Maximal Effect ◽

Direct Effects ◽

Inhibitory Effects ◽

Hippocampal Pyramidal Neurons ◽

M Current ◽

Postsynaptic Currents ◽

Inhibitory Neurotransmission ◽

Presynaptic Mechanisms

Tallent, Melanie K. and George R. Siggins. Somatostatin depresses excitatory but not inhibitory neurotransmission in rat CA1 hippocampus. J. Neurophysiol. 78: 3008–3018, 1997. In rat CA1 hippocampal pyramidal neurons (HPNs), somatostatin (SST) has inhibitory postsynaptic actions, including hyperpolarization of the membrane at rest and augmentation of the K+ M-current. However, the effects of SST on synaptic transmission in this brain region have not been well-characterized. Therefore we used intracellular voltage-clamp recordings in rat hippocampal slices to assess the effects of SST on pharmacologically isolated synaptic currents in HPNs. SST depressed both (R,S)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate and N-methyl-d-aspartate (NMDA) receptor-mediated excitatory postsynaptic currents (EPSCs) in a reversible manner, with an apparent IC50 of 22 nM and a maximal effect at 100 nM. In contrast, SST at concentrations up to 5 μM had no direct effects on either γ-aminobutyric acid-A (GABAA) or GABAB receptor–mediated inhibitory postsynaptic currents (IPSCs). The depression of EPSCs by SST was especially robust during hyperexcited states when polysynaptic EPSCs were present, suggesting that this peptide could play a compensatory role during seizurelike activity. SST effects were greatly attenuated by the alkylating agent N-ethylmaleimide, thus implicating a transduction mechanism involving the Gi/Go family of G-proteins. Use of 2 M Cs+ in the recording electrode blocked the postsynaptic modulation of K+ currents by SST, but did not alter the effects of SST on EPSCs, indicating that postsynaptic K+ currents are not involved in this action of SST. However, 2 mM external Ba2+ blocked the effect of SST on EPSCs, suggesting that presynaptic K+ channels or other presynaptic mechanisms may be involved. These findings and previous results from our laboratory show that SST has multiple inhibitory effects in hippocampus.

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2-Deoxy-d-glucose reduces epileptiform activity by presynaptic mechanisms

Journal of Neurophysiology ◽

10.1152/jn.00723.2018 ◽

2019 ◽

Vol 121 (4) ◽

pp. 1092-1101 ◽

Cited By ~ 3

Author(s):

Yu-Zhen Pan ◽

Thomas P. Sutula ◽

Paul A. Rutecki

Keyword(s):

Pyramidal Neurons ◽

Epileptiform Activity ◽

Network Activity ◽

Membrane Properties ◽

Extracellular Potassium ◽

Acute Effects ◽

Postsynaptic Currents ◽

Neuronal Network Activity ◽

Presynaptic Mechanisms

2-Deoxy-d-glucose (2DG), a glucose analog that inhibits glycolysis, has acute and chronic antiepileptic effects. We evaluated 2DG’s acute effects on synaptic and membrane properties of CA3 pyramidal neurons in vitro. 2DG (10 mM) had no effects on spontaneously occurring postsynaptic currents (PSCs) in 3.5 mM extracellular potassium concentration ([K+]o). In 7.5 mM [K+]o, 2DG significantly reduced the frequency of epileptiform bursting and the charge carried by postsynaptic currents (PSCs) with a greater effect on inward excitatory compared with outward inhibitory charge (71% vs. 40%). In 7.5 mM [K+]o and bicuculline, 2DG reduced significantly the excitatory charge by 67% and decreased the frequency but not amplitude of excitatory PSCs between bursts. In 7.5 mM [K+]o, 2DG reduced pharmacologically isolated inhibitory PSC frequency without a change in amplitude. The frequency but not amplitude of inward miniature PSCs was reduced when 2DG was applied in 7.5 mM [K+]o before bath application of TTX, but there was no effect when 2DG was applied after TTX, indicating a use-dependent uptake of 2DG was required for its actions at a presynaptic locus. 2DG did not alter membrane properties of CA3 neurons except for reducing the slow afterhyperpolarization in 3.5 but not 7.5 mM [K+]o. The reduction in frequency of spontaneous and inward miniature PSCs in elevated [K+]o indicates a presynaptic mechanism of action. 2DG effects required use-dependent uptake and suggest an important role for glycolysis in neuronal metabolism and energetics in states of high neural activity as occur during abnormal network synchronization and seizures. NEW & NOTEWORTHY 2-Deoxy-d-glucose (2DG) is a glycolytic inhibitor and suppresses epileptiform activity acutely and has chronic antiepileptic effects. The mechanisms of the acute effects are not well delineated. In this study, we show 2DG suppressed abnormal network epileptiform activity without effecting normal synaptic network activity or membrane properties. The effects appear to be use dependent and have a presynaptic locus of action. Inhibition of glycolysis is a novel presynaptic mechanism to limit abnormal neuronal network activity and seizures.

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Metformin Enhances Excitatory Synaptic Transmission onto Hippocampal CA1 Pyramidal Neurons

Brain Sciences ◽

10.3390/brainsci10100706 ◽

2020 ◽

Vol 10 (10) ◽

pp. 706

Author(s):

Wen-Bing Chen ◽

Jiang Chen ◽

Zi-Yang Liu ◽

Bin Luo ◽

Tian Zhou ◽

...

Keyword(s):

Synaptic Transmission ◽

Neuronal Excitability ◽

Pyramidal Neurons ◽

Glutamate Release ◽

Hippocampal Slices ◽

Hippocampal Pyramidal Neurons ◽

Beneficial Effects ◽

Ca1 Pyramidal Neurons ◽

Postsynaptic Currents ◽

Hippocampal Ca1

Metformin (Met) is a first-line drug for type 2 diabetes mellitus (T2DM). Numerous studies have shown that Met exerts beneficial effects on a variety of neurological disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD). However, it is still largely unclear how Met acts on neurons. Here, by treating acute hippocampal slices with Met (1 μM and 10 μM) and recording synaptic transmission as well as neuronal excitability of CA1 pyramidal neurons, we found that Met treatments significantly increased the frequency of miniature excitatory postsynaptic currents (mEPSCs), but not amplitude. Neither frequency nor amplitude of miniature inhibitory postsynaptic currents (mIPSCs) were changed with Met treatments. Analysis of paired-pulse ratios (PPR) demonstrates that enhanced presynaptic glutamate release from terminals innervating CA1 hippocampal pyramidal neurons, while excitability of CA1 pyramidal neurons was not altered. Our results suggest that Met preferentially increases glutamatergic rather than GABAergic transmission in hippocampal CA1, providing a new insight on how Met acts on neurons.

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α5GABAA Receptors Regulate the Intrinsic Excitability of Mouse Hippocampal Pyramidal Neurons

Journal of Neurophysiology ◽

10.1152/jn.00482.2007 ◽

2007 ◽

Vol 98 (4) ◽

pp. 2244-2254 ◽

Cited By ~ 73

Author(s):

Robert P. Bonin ◽

Loren J. Martin ◽

John F. MacDonald ◽

Beverley A. Orser

Keyword(s):

Action Potential ◽

Pyramidal Neurons ◽

Brain Slices ◽

Physiological Role ◽

Network Activity ◽

Equilibrium Potential ◽

Resting Membrane Potential ◽

Action Potential Firing ◽

Membrane Hyperpolarization ◽

Hippocampal Pyramidal Neurons

GABAA receptors generate both phasic and tonic forms of inhibition. In hippocampal pyramidal neurons, GABAA receptors that contain the α5 subunit generate a tonic inhibitory conductance. The physiological role of this tonic inhibition is uncertain, although α5GABAA receptors are known to influence hippocampal-dependent learning and memory processes. Here we provide evidence that α5GABAA receptors regulate the strength of the depolarizing stimulus that is required to generate an action potential in pyramidal neurons. Neurons from α5 knock-out (α5−/−) and wild-type (WT) mice were studied in brain slices and cell cultures using whole cell and perforated-patch-clamp techniques. Membrane resistance was 1.6-fold greater in α5−/− than in WT neurons, but the resting membrane potential and chloride equilibrium potential were similar. Membrane hyperpolarization evoked by an application of exogenous GABA was greater in WT neurons. Inhibiting the function of α5GABAA receptor with nonselective (picrotoxin) or α5 subunit-selective (L-655,708) compounds depolarized WT neurons by ∼3 mV, whereas no change was detected in α5−/− neurons. The depolarizing current required to generate an action potential was twofold greater in WT than in α5−/− neurons, whereas the slope of the input-output relationship for action potential firing was similar. We conclude that shunting inhibition mediated by α5GABAA receptors regulates the firing of action potentials and may synchronize network activity that underlies hippocampal-dependent behavior.

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