Differential expression of glutamate and GABA-A receptor subunit mRNA in cortical dysplasia.
ABSTRACT Focal cortical dysplasia is characterized by disorganized cortical lamination, dysplastic and heterotopic neurons, and an association with epilepsy. The contribution that dysplastic and heterotopic neurons make to epileptogenesis in focal cortical dysplasia is unknown and the phenotype of these cells may be distinct. The authors hypothesized that the expression of genes encoding glutamatergic (glutamate [GluR] and N-methyl-D-aspartate NMDA receptors [NR]) and gamma-aminobutyric acid A receptor (GABA(A)R) subunits is distinct in dysplastic and heterotopic neurons and that changes in receptor gene expression could be defined in a cell-specific pattern.
Single immunohistochemically labeled dysplastic and heterotopic neurons were microdissected from human focal cortical dysplasia specimens obtained during epilepsy surgery. Pyramidal neurons were microdissected from postmortem control cortex and from temporal cortex without dysplasia resected during temporal lobectomy. Poly (A) messenger RNA (mRNA) from single neurons was amplified, radiolabeled, and used to probe complementary DNA (cDNA) arrays containing GluR(1-6), NR(1A,1B), NR(2A-D), and GABA(A)Ralpha(1-6), and -Rbeta(1-3) subunit cDNAS: The relative hybridization intensities of each mRNA-cDNA hybrid were quantified by phosphorimaging.
GluR, NR, and GABA(A)R subunit mRNA expression did not differ between control neurons and nondysplastic epilepsy specimens. Expression of GluR(4), NR(2B), and NR(2C) subunit mRNA was increased, and NR(2A) and GABA(A)Rbeta(1) subunit mRNA was decreased in dysplastic compared with pyramidal and heterotopic neurons. In contrast, GABA(A)Ralpha(1), -Ralpha(2), and -Rbeta(2) as well as GluR(1) mRNA levels were reduced in both dysplastic and heterotopic neurons.
Differential expression of GluR, NR, and GABA(A)R mRNA in dysplastic and heterotopic neurons demonstrates cell specific gene transcription changes in focal cortical dysplasia. These results suggest that dysplastic and heterotopic neurons may be pharmacologically distinct and make differential contributions epileptogenesis in focal cortical dysplasia.
SourceAvailable from: Tobias Loddenkemper[Show abstract] [Hide abstract]
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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ABSTRACT: Objective To investigate growth-associated protein 43 (GAP-43), a marker for axonal growth and synaptic plasticity, as potential substrate for progressive epilepsy and potential predictor of postsurgical seizure outcome in patients with focal cortical dysplasia (FCD).MethodsGAP-43 immunohistochemistry was performed on cortical specimens from 21 patients with FCD: 12 with FCD type II (IIA or IIB) and nine with FCD type IA. Twenty normal anterior temporal lobe specimens from patients with mesial temporal lobe epilepsy due to hippocampal sclerosis (mTLE/HS) were used as controls. Semiquantitative analysis of GAP-43 staining patterns was performed. Additionally, GAP-43 immunoblotting was performed on resected tissue from three patients with FCD type IIA/B; GAP-43 protein levels in electroencephalography-verified epileptic, and distal nonepileptic, areas were compared within each patient. Two outcome categories were used: completely seizure free (Engel IA) versus not seizure free. We examined the relationship of GAP-43 scores with epilepsy duration and seizure-free outcome for each of the three pathologies.ResultsWithin-patient GAP-43 expression is selectively increased in the epileptic as compared to nonepileptic cortex. GAP-43 immunoreactivity (IRs) patterns were seen on the cell surface and tubular punctate structures intercellularly only in FCD cortex. Higher GAP-43 scores were correlated (P < 0.0001) with longer epilepsy duration only in FCD IIA/B. Lower GAP-43 scores were associated with better surgical outcome in the same group. No such relationship was observed in FCD IA.InterpretationGAP-43 proteins are not only associated with intrinsic epileptogenicity but may be markers of progressive epilepsy and predictors of postoperative seizure outcome in patients with pharmacoresistant epilepsy due to FCD IIA/B.07/2014; 1(7). DOI:10.1002/acn3.69
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ABSTRACT: Epilepsy is the most common and chronic neurological disorder characterized by recurrent unprovoked seizures. The key aim in treating patients with epilepsy is the suppression of seizures. An understanding of focal changes that are involved in epileptogenesis may therefore provide novel approaches for optimal treatment of the seizure. Although the actual pathogenesis of epilepsy is still uncertain, recently growing lines of evidence declare that microglia and astrocyte activation, oxidative stress and reactive oxygen species (ROS) production, mitochondria dysfunction, and damage of blood-brain barrier (BBB) are involved in its pathogenesis. Impaired GABAergic function in the brain is probably the most accepted hypothesis regarding the pathogenesis of epilepsy. Clinical neuroimaging of patients and experimental modeling have demonstrated that seizures may induce neuronal apoptosis. Apoptosis signaling pathways are involved in the pathogenesis of several types of epilepsy such as temporal lobe epilepsy (TLE). The quality of life of patients is seriously affected by treatment-related problems and also by unpredictability of epileptic seizures. Moreover, the available antiepileptic drugs (AED) are not significantly effective to prevent epileptogenesis. Thus, novel therapies that are proficient to control seizure in people who are suffering from epilepsy are needed. The preconditioning method promises to serve as an alternative therapeutic approach because this strategy has demonstrated the capability to curtail epileptogenesis. For this reason, understanding of molecular mechanisms underlying brain tolerance induced by preconditioning is crucial to delineate new neuroprotective ways against seizure damage and epileptogenesis. In this review, we summarize the work to date on the pathogenesis of epilepsy and discuss recent therapeutic strategies in the treatment of epilepsy. We will highlight that novel therapy targeting such as preconditioning process holds great promise. In addition, we will also highlight the role of gene reprogramming and mitochondrial biogenesis in the preconditioning-mediated neuroprotective events.Molecular Neurobiology 09/2014; DOI:10.1007/s12035-014-8876-5 · 5.29 Impact Factor