Article

The impact of chronic network hyperexcitability on developing glutamatergic synapses

The Cain Foundation Laboratories, Department of Pediatrics, Houston, TX 77030, USA.
European Journal of Neuroscience (Impact Factor: 3.18). 09/2007; 26(4):975-91. DOI: 10.1111/j.1460-9568.2007.05739.x
Source: PubMed

ABSTRACT

The effects recurring seizures have on the developing brain are an important area of debate because many forms of human epilepsy arise in early life when the central nervous system is undergoing dramatic developmental changes. To examine effects on glutamatergic synaptogenesis, epileptiform activity was induced by chronic treatment with GABAa receptor antagonists in slice cultures made from infant rat hippocampus. Experiments in control cultures showed that molecular markers for glutamatergic and GABAergic synapses recapitulated developmental milestones reported previously in vivo. Following a 1-week treatment with bicuculline, the intensity of epileptiform activity that could be induced in cultures was greatly diminished, suggesting induction of an adaptive response. In keeping with this notion, immunoblotting revealed the expression of NMDA and AMPA receptor subunits was dramatically reduced along with the scaffolding proteins, PSD95 and Homer. These effects could not be attributed to neuronal cell death, were reversible, and were not observed in slices taken from older animals. Co-treating slices with APV or TTX abolished the effects of bicuculline suggesting that effects were dependent on NMDA receptors and neuronal activity. Neurophysiological recordings supported the biochemical findings and demonstrated decreases in both the amplitude and frequency of NMDA and AMPA receptor-mediated miniature EPSCs (mEPSCs). Taken together these results suggest that neuronal network hyperexcitability interferes with the normal maturation of glutamatergic synapses, which could have implications for cognitive deficits commonly associated with the severe epilepsies of early childhood.

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    • "We therefore evaluated whether VGLUT1 and VGAT co-expression in cortical axon terminals is sensitive to variations in the excitation–inhibition balance. For this purpose, we used two different protocols: in the first, we reduced spontaneous excitation for 1 week (starting at 14 DIV), using APV (100 mM) and CNQX (20 mM) (Bacci et al., 2001); in the second, again in 14 DIV cultures, we reduced spontaneous inhibition for 1 week by administering bicuculline (100 mM) (Swann et al., 2007). Results showed that after 1 week of reduced excitation the percentage of mixed terminals decreased to 38.3562.99% of controls for VGLUT1-positive (VGLUT1+) terminals (n517,569) and to 33.1566.46% "
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    ABSTRACT: In adult neocortex, VGLUT1, the main glutamate vesicular transporter, and VGAT, the GABA vesicular transporter, are co-expressed in a subset of axon terminals forming both symmetric and asymmetric synapses, where they are sorted to the same vesicles. However, the functional consequence of this co-localization in cortical neurons has not been clarified. Here, we tested the hypothesis that cortical axon terminals co-expressing VGLUT1 and VGAT can evoke simultaneously monosynaptic glutamate and GABA responses and investigated whether the amount of terminals co-expressing VGLUT1 and VGAT is affected by perturbations of excitation-inhibition balance. In rat primary cortical neurons, we found that a proportion of synaptic and autaptic responses were indeed sensitive to consecutive application of selective glutamate and GABAA receptor blockers. These "mixed" synapses exhibited paired-pulse depression. Notably, reducing the activity of the neuronal network by glutamate receptor antagonists decreased the amount of "mixed" synapses, whereas reducing spontaneous inhibition by bicuculline increased them. These synapses may contribute to homeostatic regulation of excitation/inhibition balance.
    Full-text · Article · Mar 2015 · Journal of Cell Science
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    • "In this paper we will review the patterns of subunit composition of the main glutamate [í µí»¼-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-Daspartate (NMDA)] and gamma-aminobutyric acid (GABA) receptors during development [7–13]. We will also review the subunit composition of neurotransmitter receptors that mirrors that of the immature brain, facilitating further seizures and the development of pathologic neuronal networks [14] [15] [16] [17] [18] [19] [20] [21]. Finally, we will discuss the novel therapeutic targets that are being revealed by studying the subunit composition of the neurotransmitter receptors and potential therapeutic translation into clinical practice [3] [4] [5] [6] "
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    ABSTRACT: Neuronal activity is critical for synaptogenesis and the development of neuronal networks. In the immature brain excitation predominates over inhibition facilitating the development of normal brain circuits, but also rendering it more susceptible to seizures. In this paper, we review the evolution of the subunit composition of neurotransmitter receptors during development, how it promotes excitation in the immature brain, and how this subunit composition of neurotransmission receptors may be also present in the epileptic brain. During normal brain development, excitatory glutamate receptors peak in function and gamma-aminobutiric acid (GABA) receptors are mainly excitatory rather than inhibitory. A growing body of evidence from animal models of epilepsy and status epilepticus has demonstrated that the brain exposed to repeated seizures presents a subunit composition of neurotransmitter receptors that mirrors that of the immature brain and promotes further seizures and epileptogenesis. Studies performed in samples from the epileptic human brain have also found a subunit composition pattern of neurotransmitter receptors similar to the one found in the immature brain. These findings provide a solid rationale for tailoring antiepileptic treatments to the specific subunit composition of neurotransmitter receptors and they provide potential targets for the development of antiepileptogenic treatments.
    Full-text · Article · Sep 2014 · BioMed Research International
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    • "For instance, in slice cultures we are able to prevent the bicuculline-induced reductions of branch length and branch points by antagonizing the NMDA receptors with its competitive antagonist, (2R)-amino-5-phosphonovaleric acid (APV) (Nishimura et al., 2008). Moreover, not only APV but the sodium channel antagonist, tetrodotoxin (TTX), prevents the alterations in glutamatergic postsynaptic proteins resulting from bicuculline treatment (Swann et al., 2007a). These data clearly show that the anatomic and biochemical results reviewed above are activity dependent. "
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    ABSTRACT: Childhood epilepsy can be severe and even catastrophic. In these instances, cognition can be impaired-leading to long-term intellectual disabilities. One factor that could potentially cause cognitive deficits is the frequent seizures that characterize intractable epilepsy. However, it has been difficult to separate the effects seizures may have from those of preexisting neuropathologies and/or the effects of ongoing anticonvulsant therapies. Therefore, important questions are: Do early life seizures produce the learning deficits? And if they do, how do they do it? Results from recent animal models studies reviewed here show that recurrent seizures in infancy stop the growth of CA1 hippocampal dendrites. We speculate that the molecular mechanisms responsible for seizure-induced growth suppression are homeostatic/neuroprotective, used by the developing nervous system in an attempt to limit neuronal and network excitability and prevent the continued generation of seizures. However, by preventing the normal growth of dendrites, there is a reduction in CA1 glutamatergic synapses that supports long-lasting forms of synaptic plasticity thought to be the cellular basis of learning and memory. Therefore, dendrite growth suppression would reduce the neuroanatomic substrates for learning and memory, and in so doing could contribute in important ways to spatial learning and memory deficits that may be relevant to the cognitive deficits associated with childhood epilepsy.
    Preview · Article · Jun 2012 · Epilepsia
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