Altered mRNA expression for brain-derived neurotrophic factor and type II calcium/Calmodulin-dependent protein kinase in the hippocampus of patients with intractable temporal lobe epilepsy

Murray, Karl D.; Isackson, Paul J.; Eskin, Thomas A.; King, Michael A.; Montesinos, Sylvia P.; Abraham, LA; Roper, Steven N.

doi:10.1002/(sici)1096-9861(20000320)418:4<411::aid-cne4>3.0.co;2-f

Cited by 96 publications

(64 citation statements)

References 89 publications

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“…Alternatively, the changed mRNA levels in the TLE brain may simply ref lect altered tissue composition rather than altered specific subunit transcription. However, that possibility seems unlikely because (i) our tissue specimens were rather homogeneous and lacked obvious gliosis; (ii) the highest expression of GABA A -receptor subunit mRNAs was found in the patient with the most severe TLE; (iii) the putative overexpression in the epileptic temporal cortex of GABA A -receptor subunit mRNAs is in agreement with previous results obtained in an epilepsy animal model (32); and (iv) our data are compatible with the view that chronic seizure activity in humans leads to persistent alterations in gene expression (33). Further work is required to determine precisely the origin of the excessive GABA-current run-down of human epileptic nerve cells.…”

Section: Discussionmentioning

confidence: 91%

Phosphatase inhibitors remove the run-down of γ-aminobutyric acid type A receptors in the human epileptic brain

Palma

Ragozzino

Angelantonio

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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The properties of ␥-aminobutyric acid (GABA) type A receptors (GABA A receptors) microtransplanted from the human epileptic brain to the plasma membrane of Xenopus oocytes were compared with those recorded directly from neurons, or glial cells, in human brains slices. Cell membranes isolated from brain specimens, surgically obtained from six patients afflicted with drug-resistant temporal lobe epilepsy (TLE) were injected into frog oocytes. Within a few hours, these oocytes acquired GABA A receptors that generated GABA currents with an unusual run-down, which was inhibited by orthovanadate and okadaic acid. In contrast, receptors derived from membranes of a nonepileptic hippocampal uncus, membranes from mouse brain, or recombinant rat ␣1␤2␥2-GABA receptors exhibited a much less pronounced GABA-current rundown. Moreover, the GABA A receptors of pyramidal neurons in temporal neocortex slices from the same six epileptic patients exhibited a stronger run-down than the receptors of rat pyramidal neurons. Interestingly, the GABA A receptors of neighboring glial cells remained substantially stable after repetitive activation. Therefore, the excessive GABA-current run-down observed in the membrane-injected oocytes recapitulates essentially what occurs in neurons, rather than in glial cells. Quantitative RT-PCR analyses from the same TLE neocortex specimens revealed that GABA Areceptor ␤1, ␤2, ␤3, and ␥2 subunit mRNAs were significantly overexpressed (8-to 33-fold) compared with control autopsy tissues. Our results suggest that an abnormal GABA-receptor subunit transcription in the TLE brain leads to the expression of run-down-enhanced GABA A receptors. Blockage of phosphatases stabilizes the TLE GABAA receptors and strengthens GABAergic inhibition. It may be that this process can be targeted to develop new treatments for intractable epilepsy.temporal lobe epilepsy ͉ microtransplantation into Xenopus oocyte ͉ okadaic acid ͉ ␥-aminobutyric acid-current run-down ͉ human tissue slices

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Section: Discussionmentioning

confidence: 91%

Phosphatase inhibitors remove the run-down of γ-aminobutyric acid type A receptors in the human epileptic brain

Palma

Ragozzino

Angelantonio

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…After the epileptogenic stimulus that brings about these cellular alterations, critical mediators are produced, as suggested by the induction of complex changes in gene expression (BrooksKayal et al, 1998;Chiang et al, 2001), including a dramatic increase of BDNF (Ernfors et al, 1991;Isackson et al, 1991;Bengzon et al, 1993;Murray et al, 2000;Huang et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Brain-Derived Neurotrophic Factor mRNA and Protein Are Targeted to Discrete Dendritic Laminas by Events That Trigger Epileptogenesis

Tongiorgi¹,

Armellin²,

Giulianini³

et al. 2004

J. Neurosci.

131

121

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Dendritic targeting of mRNA and local protein synthesis are mechanisms that enable neurons to deliver proteins to specific postsynaptic sites. Here, we demonstrate that epileptogenic stimuli induce a dramatic accumulation of BDNF mRNA and protein in the dendrites of hippocampal neurons in vivo. BDNF mRNA and protein accumulate in dendrites in all hippocampal subfields after pilocarpine seizures and in selected subfields after other epileptogenic stimuli (kainate and kindling). BDNF accumulates selectively in discrete dendritic laminas, suggesting targeting to synapses that are active during seizures. Dendritic targeting of BDNF mRNA occurs during the time when the cellular changes that underlie epilepsy are occurring and is not seen after intense stimuli that are non-epileptogenic, including electroconvulsive seizures and high-frequency stimulation. MK801, an NMDA receptor antagonist that can prevent epileptogenesis but not acute seizures, prevents the dendritic accumulation of BDNF mRNA, indicating that dendritic targeting is mediated via NMDA receptor activation. Together, these results suggest that dendritic accumulation of BDNF mRNA and protein play a critical role in the cellular changes leading to epilepsy.

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“…A possible endogenous mediator of Egr3 signaling in TLE has yet to be identified. Because brainderived neurotrophic factor (BDNF) mRNAs and protein are elevated during seizures in TLE patients (17,18) and in several animal models of TLE (19 -21), we used cultured primary hippocampal neurons to determine whether BDNF could be the seizure-induced signal that up-regulates GABRA4 transcription and down-regulates GABRA1.…”

mentioning

confidence: 99%

Brain-derived Neurotrophic Factor (BDNF)-induced Synthesis of Early Growth Response Factor 3 (Egr3) Controls the Levels of Type A GABA Receptorα4 Subunits in Hippocampal Neurons

Roberts

Lund

et al. 2006

Journal of Biological Chemistry

127

126

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Altered function of ␥-aminobutyric acid type A receptors (GABA A Rs) in dentate granule cells of the hippocampus has been associated with temporal lobe epilepsy (TLE) in humans and in animal models of TLE. Such altered receptor function (including increased inhibition by zinc and lack of modulation by benzodiazepines) is related, in part, to changes in the mRNA levels of certain GABA A R subunits, including ␣4, and may play a role in epileptogenesis. The majority of GABA A Rs that contain ␣4 subunits are extra-synaptic due to lack of the ␥2 subunit and presence of ␦. However, it has been hypothesized that seizure activity may result in expression of synaptic receptors with altered properties driven by an increased pool of ␣4 subunits. Results of our previous work suggests that signaling via protein kinase C (PKC) and early growth response factor 3 (Egr3) is the plasticity trigger for aberrant ␣4 subunit gene (GABRA4) expression after status epilepticus. We now report that brain derived neurotrophic factor (BDNF) is the endogenous signal that induces Egr3 expression via a PKC/MAPK-dependent pathway. Taken together with the fact that blockade of tyrosine kinase (Trk) neurotrophin receptors reduces basal GABRA4 promoter activity by 50%, our findings support a role for BDNF as the mediator of Egr3-induced GABRA4 regulation in developing neurons and epilepsy and, moreover, suggest that BDNF may alter inhibitory processing in the brain by regulating the balance between phasic and tonic inhibition.The type A ␥-aminobutyric acid (GABA) 5 receptor (GABA A R) is an integral ligand gated ion channel that mediates the majority of inhibition in the central nervous system. Being a hetero-oligomeric complex, it is composed of five membrane spanning subunits that are chosen from the products of 19 different genes (␣ 1-6 , ␤ 1-3 , ␥ 1-3 , ␦, ⑀, , 1-3 , and ). These genes are differentially transcribed during development and in various regions of the adult brain and spinal cord (1-5). Alteration in the function of GABA A Rs has been associated with a variety of diseases whose etiology leads to an imbalance between inhibition and excitation in specific populations of neurons (6 -8).For instance, changes in certain GABA A R subunit levels occur in dentate granule cells (DGCs) of both humans with temporal lobe epilepsy (TLE) and in animal models of TLE (6, 9). These molecular responses have been hypothesized to underlie persistent changes in GABA A R function associated with epileptogenesis. Most notably, individual DGCs display an elevation of ␣4 subunit mRNAs and a decrease in ␣1 (6). Receptors that contain ␣4 subunits have unique pharmacological properties that include heightened blockade of receptor function by zinc (11-13) and decreased benzodiazepine modulation (14). In addition, the majority of GABA A Rs that contain ␣4 subunits (co-assembled with a ␤ and ␦) are located extrasynaptically and mediate tonic GABA currents, while those containing ␣(1, 2, 3, or 5) without ␦ and with ␥2 are targeted to the synapse (1, 15). Although...

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Altered mRNA expression for brain-derived neurotrophic factor and type II calcium/Calmodulin-dependent protein kinase in the hippocampus of patients with intractable temporal lobe epilepsy

Cited by 96 publications

References 89 publications

Phosphatase inhibitors remove the run-down of γ-aminobutyric acid type A receptors in the human epileptic brain

Phosphatase inhibitors remove the run-down of γ-aminobutyric acid type A receptors in the human epileptic brain

Brain-Derived Neurotrophic Factor mRNA and Protein Are Targeted to Discrete Dendritic Laminas by Events That Trigger Epileptogenesis

Brain-derived Neurotrophic Factor (BDNF)-induced Synthesis of Early Growth Response Factor 3 (Egr3) Controls the Levels of Type A GABA Receptorα4 Subunits in Hippocampal Neurons

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