The impact of chronic network hyperexcitability on developing glutamatergic synapses.
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.
- SourceAvailable from: Tobias Loddenkemper
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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        . 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     "
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.BioMed Research International 09/2014; 2014:301950. DOI:10.1155/2014/301950 · 2.71 Impact Factor
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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. "
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.Epilepsia 06/2012; 53 Suppl 1:116-24. DOI:10.1111/j.1528-1167.2012.03482.x · 4.58 Impact Factor
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- "As animals matured the differences between them and their controls increased. Additional experiments in slice cultures showed that similar biochemical alterations take place in response to seizure-like activity (Swann et al., 2007a) but neuroanatomical experiments revealed that these effects may be best explained by a suppression of dendrite growth (Nishimura et al., 2008). "
ABSTRACT: Impaired learning and memory are common in epilepsy syndromes of childhood. Clinical investigations suggest that the developing brain may be particularly vulnerable to the effects of intractable seizure disorders. Magnetic resonance imaging (MRI) studies have demonstrated reduced volumes in brain regions involved in learning and memory. The earlier the onset of an epilepsy the larger the effects seem to be on both brain anatomy and cognition. Thus, childhood epilepsy has been proposed to interfere in some unknown way with brain development. Experiments reported here explore these ideas by examining the effects of seizures in infant mice on learning and memory and on the growth of CA1 hippocampal pyramidal cell dendrites. Fifteen brief seizures were induced by flurothyl between postnatal days 7 and 11 in mice that express green fluorescent protein (GFP) in hippocampal pyramidal cells. One to 44days later, dendritic arbors were reconstructed to measure growth. Spatial learning and memory were also assessed in a water maze. Our results show that recurrent seizures produced marked deficits in learning and memory. Seizures also dramatically slowed the growth of basilar dendrites while neurons in littermate control mice continued to add new dendritic branches and lengthen existing branches. When experiments were performed in older mice, seizures had no measureable effects on either dendrite arbor complexity or spatial learning and memory. Our results suggest that the recurring seizures of intractable childhood epilepsy contribute to associated learning and memory deficits by suppressing dendrite growth.Neurobiology of Disease 07/2011; 44(2):205-14. DOI:10.1016/j.nbd.2011.07.002 · 5.20 Impact Factor