Protein Information

Name CA3
Synonyms CA III; Carbonic anhydrase C; CA3; CAIII; Car3; Carbonate dehydratase III; Carbonic anhydrase 3; Carbonic anhydrase III…

Compound Information

Name 4-aminopyridine
CAS 4-pyridinamine

Reference List

PubMed Abstract RScore(About this table)
15101824 Martin ED, Pozo MA: Valproate reduced synaptic activity increase induced by 4-aminopyridine at the hippocampal CA3-CA1 synapse. Epilepsia. 2004 May;45(5):436-40.

PURPOSE: We investigated the effects of valproate (VPA) on excitatory synaptic transmission changes induced by 4-aminopyridine (4-AP) to determine whether the antiepileptic effects shown by VPA can be ascribed to a modulation of spontaneous excitatory postsynaptic currents (sEPSCs) in the CA3-CA1 synapse.
113(1,2,2,3) Details
11430896 Yang Q, Michelson HB: Gap junctions synchronize the firing of inhibitory interneurons in guinea pig hippocampus. Brain Res. 2001 Jul 13;907(1-2):139-43.

The convulsant 4-aminopyridine (4AP) facilitates the synchronous firing of interneurons in the hippocampus, eliciting giant inhibitory postsynaptic potentials (IPSPs) in CA3 pyramidal cells.
84(1,1,1,4) Details
11520313 Avoli M: Do interictal discharges promote or control seizures? Experimental evidence from an in vitro model of epileptiform discharge. Epilepsia. 2001;42 Suppl 3:2-4.

In this preparation, application of 4-aminopyridine or Mg2+-free medium induce (a) interictal discharges that originated from CA3 and propagate (via the Schaffer collaterals) to CA1 and entorhinal cortex, to return to the hippocampus through the dentate area; and (b) ictal discharges that initiate in the entorhinal cortex and propagate to the hippocampus via the dentate gyrus.
9(0,0,1,4) Details
18165320 Jacobs S, Ruusuvuori E, Sipila ST, Haapanen A, Damkier HH, Kurth I, Hentschke M, Schweizer M, Rudhard Y, Laatikainen LM, Tyynela J, Praetorius J, Voipio J, Hubner CA: Mice with targeted Slc4a10 gene disruption have small brain ventricles and show reduced neuronal excitability. Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):311-6. Epub 2007 Dec 28.

In the CA3 area, propionate-induced intracellular acidification and attenuation of 4-aminopyridine-induced network activity were prolonged in KO mice.
7(0,0,1,2) Details
15249428 Leniger T, Thone J, Bonnet U, Hufnagel A, Bingmann D, Wiemann M: Levetiracetam inhibits Na+-dependent Cl-/HCO3- exchange of adult hippocampal CA3 neurons from guinea-pigs. Br J Pharmacol. 2004 Aug;142(7):1073-80. Epub 2004 Jul 12.

In 4-aminopyridine-treated slices, LEV (10-100 microm) reduced the frequency of action potentials and epileptiform bursts of CA3 neurons by 30-55%, while the shape of these potentials remained largely unchanged.
83(1,1,1,3) Details
10759297 Baraban SC, Wenzel HJ, Hochman DW, Schwartzkroin PA: Characterization of heterotopic cell clusters in the hippocampus of rats exposed to methylazoxymethanol in utero. Epilepsy Res. 2000 Apr;39(2):87-102.

Slice perfusion with bicuculline or 4-aminopyridine leads to epileptiform activity in dysplastic cell clusters that can occur independent of input from CA3.
6(0,0,1,1) Details
14751281 de Guzman P, D'Antuono M, Avoli M: Initiation of electrographic seizures by neuronal networks in entorhinal and perirhinal cortices in vitro. Neuroscience. 2004;123(4):875-86.

In the presence of 4-aminopyridine, slow interictal- (duration=2.34+/-0.29 s; interval of occurrence=25.75+/-2.11 s, n=16) and ictal-like (duration=31.25+/-3.34 s; interval of occurrence=196.96+/-21.56 s, n=17) discharges were recorded in entorhinal and perirhinal cortices after abating the propagation of CA3-driven interictal activity to these areas following extended hippocampal knife cuts.
6(0,0,1,1) Details
10890901 Sanna PP, Berton F, Cammalleri M, Tallent MK, Siggins GR, Bloom FE, Francesconi W: A role for Src kinase in spontaneous epileptiform activity in the CA3 region of the hippocampus. Proc Natl Acad Sci U S A. 2000 Jul 18;97(15):8653-7.

Spontaneous epileptiform discharges were induced in vitro in the CA3 region of rat hippocampal slices by superfusion with the potassium channel blocker 4-aminopyridine in Mg (2+)-free medium.
7(0,0,1,2) Details
11516410 Tattersall JE, Scott IR, Wood SJ, Nettell JJ, Bevir MK, Wang Z, Somasiri NP, Chen X: Effects of low intensity radiofrequency electromagnetic fields on electrical activity in rat hippocampal slices. Brain Res. 2001 Jun 15;904(1):43-53.

To eliminate the possibility of RF-induced artefacts due to the metal stimulating electrode, the effect of RF exposure on spontaneous epileptiform activity induced in CA3 by 4-aminopyridine (50-100 microM) was investigated.
6(0,0,1,1) Details
11877515 Perkins KL: GABA application to hippocampal CA3 or CA1 stratum lacunosum-moleculare excites an interneuron network. J Neurophysiol. 2002 Mar;87(3):1404-14.

Recordings were done in the presence of 4-aminopyridine (4-AP) and blockers of ionotropic glutamatergic synaptic transmission.
6(0,0,0,6) Details
15548214 Cammalleri M, Cervia D, Langenegger D, Liu Y, Dal Monte M, Hoyer D, Bagnoli P: Somatostatin receptors differentially affect spontaneous epileptiform activity in mouse hippocampal slices. Eur J Neurosci. 2004 Nov;20(10):2711-21.

Recordings of epileptiform discharge induced by Mg2+ -free medium with 4-aminopyridine were performed from the CA3 region before and after the application of SRIF compounds.
7(0,0,1,2) Details
12948618 Salazar P, Tapia R, Rogawski MA: Effects of neurosteroids on epileptiform activity induced by picrotoxin and 4-aminopyridine in the rat hippocampal slice. Epilepsy Res. 2003 Jun-Jul;55(1-2):71-82.

The neurosteroids allopregnanolone (5alpha-pregnan-3alpha-ol-20-one; 5alpha,3alpha-P) and its 5beta-epimer pregnanolone (5beta,3alpha-P), and pregnenolone sulfate (PS) were examined for effects on spontaneous epileptiform discharges induced by 100 microM picrotoxin (PTX) and 55 microM 4-aminopyridine (4-AP) in the CA3 region of the rat hippocampal slice.
6(0,0,1,1) Details
12720572 Hosseinzadeh H, Nassiri Asl M: Anticonvulsant, sedative and muscle relaxant effects of carbenoxolone in mice. BMC Pharmacol. 2003 Apr 29;3:3. Epub 2003 Apr 29.

In vitro studies have shown, carbenoxolone to abolish the generation of full or partial ectopic spike generation, by 4-aminopyridine, as well as spontaneous epileptiform activity in CA3 or CA1 regions of the rat hippocampal slices via closing GJ channels.
6(0,0,1,1) Details
10963750 Bonnet U, Leniger T, Wiemann M: Moclobemide reduces intracellular pH and neuronal activity of CA3 neurones in guinea-pig hippocampal slices-implication for its neuroprotective properties. Neuropharmacology. 2000 Aug 23;39(11):2067-74.

Therefore, we studied effects of 10-700 microM moclobemide (i) on the intracellular pH (pH (i)) of BCECF-AM loaded CA3 neurones as well as (ii) on spontaneous action potentials and epileptiform activity (induced by bicuculline-methiodide, caffeine, or 4-aminopyridine) of CA3 neurones in the stratum pyramidale.
7(0,0,1,2) Details
11698549 Xiong ZQ, Stringer JL: Prolonged bursts occur in normal calcium in hippocampal slices after raising excitability and blocking synaptic transmission. J Neurophysiol. 2001 Nov;86(5):2625-8.

Spontaneous interictal activity was induced in CA1 and CA3 by perfusing hippocampal slices with high potassium, cesium, 4-aminopyridine, or tetraethylammonium chloride, in normal levels of calcium.
6(0,0,1,1) Details
19049601 Stafstrom CE, Roopra A, Sutula TP: Seizure suppression via glycolysis inhibition with 2-deoxy-D-glucose (2DG). Epilepsia. 2008 Nov;49 Suppl 8:97-100.

Acutely, 2DG decreases the frequency of high-K (+)-, bicuculline- and 4-aminopyridine-induced interictal bursts in the CA3 region of hippocampal slices; 2DG also exerts anticonvulsant effects in vivo against perforant path kindling in rats.
6(0,0,1,1) Details
14561833 Saviane C, Mohajerani MH, Cherubini E: An ID-like current that is downregulated by Ca2+ modulates information coding at CA3-CA3 synapses in the rat hippocampus. J Physiol. 2003 Oct 15;552(Pt 2):513-24.

In both cases, this effect was reversed by blocking this conductance with a low concentration of 4-aminopyridine (4-AP, 10-50 muM).
4(0,0,0,4) Details
10971618 Luhmann HJ, Dzhala VI, Ben-Ari Y: Generation and propagation of 4-AP-induced epileptiform activity in neonatal intact limbic structures in vitro. Eur J Neurosci. 2000 Aug;12(8):2757-68.

We examined the generation, propagation and pharmacology of 4-aminopyridine (4-AP)-induced epileptiform activity (EA) in the intact interconnected limbic structure of the newborn (P0-7) rat in vitro.
Whole-cell recordings of CA3 pyramidal cells and multisite field potential recordings in CA3, CA1, dentate gyrus, and lateral and medial entorhinal cortex revealed 4-AP-induced EA as early as P0-1.
4(0,0,0,4) Details
18394864 Zhu L, Polley N, Mathews GC, Delpire E: NKCC1 and KCC2 prevent hyperexcitability in the mouse hippocampus. . Epilepsy Res. 2008 May;79(2-3):201-12. Epub 2008 Apr 3.

Here we show that absence of NKCC1 in P9-P13 CA3 pyramidal neurons, through genetic manipulation or through bumetanide inhibition, results in a significant increase in cell excitability.
Furthermore, the pro-convulsant agent 4-aminopyridine induces seizure-like events in NKCC1-null mice but not in wild-type mice.
3(0,0,0,3) Details
14529953 Roshan-Milani S, Ferrigan L, Khoshnood MJ, Davies CH, Cobb SR: Regulation of epileptiform activity in hippocampus by nicotinic acetylcholine receptor activation. Epilepsy Res. 2003 Sep;56(1):51-65.

Bath application of the potassium channel blocker 4-aminopyridine (4AP; 10-50 microM) resulted in the development of spontaneous epileptiform bursting activity in area CA3 that consisted of short duration (257+/-15 ms) field events occurring regularly at a frequency of 0.4+/-0.02 Hz.
6(0,0,1,1) Details
15390159 Brown JT, Richardson JC, Collingridge GL, Randall AD, Davies CH: Synaptic transmission and synchronous activity is disrupted in hippocampal slices taken from aged TAS10 mice. Hippocampus. 2005;15(1):110-7.

A significant deficit in the input-output relationship of glutamatergic synapses in the CA3-CA1 Schaffer collateral pathway was observed, while synaptic transmission in the medial perforant pathway of the dentate gyrus was comparatively preserved.
However, synchronized network activity induced by bath application of 4-aminopyridine (4-AP) was compromised.
2(0,0,0,2) Details
15961234 Wong T, Zhang XL, Asl MN, Wu CP, Carlen PL, Zhang L: Postnatal development of intrinsic GABAergic rhythms in mouse hippocampus. . Neuroscience. 2005;134(1):107-20.

High frequency afferent stimulation or applications of 4-aminopyridine at low micromolar concentrations failed to induce persistent field rhythm in neonatal hippocampi, suggesting that an overall weak glutamatergic drive is not the sole causing factor.
In postnatal days 11-14 mouse hippocampi, the properties of these rhythmic potentials were in keeping with a CA3-driven, IPSP-based intrinsic network activity.
2(0,0,0,2) Details
15946323 Kaminski RM, Marini H, Kim WJ, Rogawski MA: Anticonvulsant activity of androsterone and etiocholanolone. Epilepsia. 2005 Jun;46(6):819-27.

The steroids also were examined for activity against extracellularly recorded epileptiform discharges in the CA3 region of the rat hippocampal slice induced by perfusion with 55 microM 4-aminopyridine (4-AP).
6(0,0,1,1) Details
12451111 Mitterdorfer J, Bean BP: Potassium currents during the action potential of hippocampal CA3 neurons. . J Neurosci. 2002 Dec 1;22(23):10106-15.

The overall voltage-dependent potassium current in the neurons could be split into three major components based on pharmacology and kinetics during step voltage pulses: I (D) (fast activating, slowly inactivating, and sensitive to 4-aminopyridine at 30 microm), I (A) (fast activating, fast inactivating, and sensitive to 4-aminopyridine at 3 mm), and I (K) (slowly activating, noninactivating, and sensitive to external TEA at 3-25 mm).
2(0,0,0,2) Details
15197104 Leniger T, Thone J, Wiemann M: Topiramate modulates pH of hippocampal CA3 neurons by combined effects on carbonic anhydrase and Cl-/HCO3- exchange. Br J Pharmacol. 2004 Jul;142(5):831-42. Epub 2004 Jun 14.

2(0,0,0,2) Details
12356895 Murakami S, Zhang T, Hirose A, Okada YC: Physiological origins of evoked magnetic fields and extracellular field potentials produced by guinea-pig CA3 hippocampal slices. J Physiol. 2002 Oct 1;544(Pt 1):237-51.

The revised model also accounts for selective effects of 4-aminopyridine (4-AP) and tetraethylammonium (TEA), which block the potassium channels of A and C type, respectively, on the slow wave of the magnetic fields.
4(0,0,0,4) Details
15537816 Skov J, Nedergaard S, Andreasen M: New type of synaptically mediated epileptiform activity independent of known glutamate and GABA receptors. J Neurophysiol. 2005 Apr;93(4):1845-56. Epub 2004 Nov 10.

It is well known that excitatory synaptic transmission at the hippocampal CA3-CA1 synapse depends on the binding of released glutamate to ionotropic receptors.
The effect of Cs+ was partly mimicked by 4-aminopyridine (4-AP; 2 mM), suggesting that an increase in transmitter release is involved.
2(0,0,0,2) Details
14975678 Dougalis A, Lees G, Ganellin CR: The sleep lipid oleamide may represent an endogenous anticonvulsant: an in vitro comparative study in the 4-aminopyridine rat brain-slice model. Neuropharmacology. 2004 Mar;46(4):541-54.

Interictal activity in CA3 was significantly depressed by CRX and cOA (irreversible by AM251), increased by CBZ and remained unaffected by PB.
1(0,0,0,1) Details
12576146 Szakacs R, Weiczner R, Mihaly A, Krisztin-Peva B, Zador Z, Zador E: Non-competitive NMDA receptor antagonists moderate seizure-induced c-fos expression in the rat cerebral cortex. Brain Res Bull. 2003 Feb 15;59(6):485-93.

MK-801, ketamine and dextrometorphan decreased significantly Fos immunoreactivity also in area CA3.
We examined the effects of non-competitive NMDA glutamate receptor antagonists on seizures elicited by 4-aminopyridine (4-AP), and in particular, on the expression of the transcription factor c-fos induced by these seizures.
1(0,0,0,1) Details
11110805 Zhou M, Kimelberg HK: Freshly isolated astrocytes from rat hippocampus show two distinct current patterns and different [K (+)](o) uptake capabilities. J Neurophysiol. 2000 Dec;84(6):2746-57.

The I (Ka) of VRAs was most sensitive to 4-aminopyridine (4-AP), while I (Kdr) of ORAs was more sensitive to tetraethylammonium (TEA).
In the present study, we have addressed some of these questions in glial fibrillary acidic protein [GFAP (+)], freshly isolated astrocytes (FIAs) from CA1 and CA3 regions of P7-15 rat hippocampus.
3(0,0,0,3) Details
10634883 Hochman DW, Schwartzkroin PA: Chloride-cotransport blockade desynchronizes neuronal discharge in the "epileptic" hippocampal slice. J Neurophysiol. 2000 Jan;83(1):406-17.

Spontaneous epileptiform discharges were recorded from the CA1 and CA3 cell body layers of hippocampal slices.
Intracellular recordings during 4-aminopyridine (4-AP) treatment showed that prolonged low-[Cl (-)](o) exposure did not diminish the frequency or amplitude of spontaneous postsynaptic potentials.
3(0,0,0,3) Details
16634058 Kilb W, Dierkes PW, Sykova E, Vargova L, Luhmann HJ: Hypoosmolar conditions reduce extracellular volume fraction and enhance epileptiform activity in the CA3 region of the immature rat hippocampus. J Neurosci Res. 2006 Jul;84(1):119-29.

2(0,0,0,2) Details
10712442 Barbarosie M, Louvel J, Kurcewicz I, Avoli M: CA3-Released entorhinal seizures disclose dentate gyrus epileptogenicity and unmask a temporoammonic pathway. J Neurophysiol. 2000 Mar;83(3):1115-24.

We have investigated the propagation of epileptiform discharges induced by 4-aminopyridine (4-AP, 50 microM) in adult mouse hippocampus-entorhinal cortex slices, before and after Schaffer collateral cut. 4-AP application induced 1) ictal epileptiform activity that disappeared over time and 2) interictal epileptiform discharges, which continued throughout the experiment.
2(0,0,0,2) Details
15837567 D'Arcangelo G, Panuccio G, Tancredi V, Avoli M: Repetitive low-frequency stimulation reduces epileptiform synchronization in limbic neuronal networks. Neurobiol Dis. 2005 Jun-Jul;19(1-2):119-28.

In keeping with this clinical evidence, we have reported that repetitive electrical stimuli delivered at approximately 1 Hz in mouse hippocampus-entorhinal cortex (EC) slices depress the EC ability to generate ictal activity induced by the application of 4-aminopyridine (4AP) or Mg (2+)-free medium (Barbarosie, M., Avoli, M., 1997.
CA3-driven hippocampal-entorhinal loop controls rather than sustains in vitro limbic seizures.
1(0,0,0,1) Details
12941378 Ayala GX, Tapia R: Expression of heat shock protein 70 induced by 4-aminopyridine through glutamate-mediated excitotoxic stress in rat hippocampus in vivo. Neuropharmacology. 2003 Oct;45(5):649-60.

The first signs of histological neuronal damage were observed in CA1 and CA3 subfields of the perfused hippocampus 3 h after treatment and progressed until reaching a maximal neuronal loss at 24 h.
1(0,0,0,1) Details
12849742 Benini R, D'Antuono M, Pralong E, Avoli M: Involvement of amygdala networks in epileptiform synchronization in vitro. Neuroscience. 2003;120(1):75-84.

Thus, CA3 outputs in intact slices entrain EC and BLA networks into an interictal-like pattern that inhibits the propensity of these parahippocampal areas to generate prolonged ictal-like paroxysms.
Bath application of the convulsant 4-aminopyridine (50 microM) to slices (n=12) with reciprocally connected areas, induced short-lasting interictal-like epileptiform discharges that (i) occurred at intervals of 1.2-2.8 s, (ii) originated in CA3, and (iii) spread to EC and BLA.
3(0,0,0,3) Details
20302917 Damodharan P, Baginskas A, Raastad M: Bursts and hyperexcitability in non-myelinated axons of the rat hippocampus. Neuroscience. 2010 Mar 16.

We describe a new site for burst initiation in rat hippocampal CA3 neurons: the Schaffer collateral axons.
We found that single action potentials were converted into bursts of two to six action potentials after blocking 4-aminopyridine (4-AP) sensitive K (+) channels.
3(0,0,0,3) Details
19906779 Jones NA, Hill AJ, Smith I, Bevan SA, Williams CM, Whalley BJ, Stephens GJ: Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. J Pharmacol Exp Ther. 2010 Feb;332(2):569-77. Epub 2009 Nov 11.

CBD (0.01-100 muM) effects were assessed in vitro using the Mg (2+)-free and 4-aminopyridine (4-AP) models of epileptiform activity in hippocampal brain slices via multielectrode array recordings.
In the 4-AP model, CBD decreased LFP burst amplitude (in CA1 only at 100 muM CBD), burst duration (in CA3 and DG), and burst frequency (in all regions).
1(0,0,0,1) Details
16914619 Lasztoczi B, Kardos J: Cyclothiazide prolongs low [Mg2+]-induced seizure-like events. J Neurophysiol. 2006 Dec;96(6):3538-44. Epub 2006 Aug 16.

Here we address the effects of cyclothiazide (CTZ), an allosteric inhibitor of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor desensitization, on low [Mg (2+)]-induced seizure-like events (SLEs) recorded from the CA3 pyramidal layer of juvenile rat hippocampal slices.
Effects of GYKI-52466 and GYKI-52466 with CTZ on SLE dynamics were indistinguishable. 4-aminopyridine (4-AP; 50 microM) alone (n = 5) or in combination with CTZ (n = 6) transformed recurrent SLE pattern into incessant epileptiform activity with patterns distinguishable from those under 100 microM CTZ application.
1(0,0,0,1) Details
18665350 Ristori C, Cammalleri M, Martini D, Pavan B, Liu Y, Casini G, Dal Monte M, Bagnoli P: Involvement of the cAMP-dependent pathway in the reduction of epileptiform bursting caused by somatostatin in the mouse hippocampus. Naunyn Schmiedebergs Arch Pharmacol. 2008 Dec;378(6):563-77. Epub 2008 Jul 30.

Using a well-established model of epileptiform activity induced by Mg (2+)-free medium with 4-aminopyridine [0 Mg (2+)/4-aminopyridine (4-AP)] in mouse hippocampal slices, we demonstrated that protein kinase A (PKA)-related signaling is upregulated by hippocampal bursting and that treatment with SRIF normalizes this upregulation.
Extracellular recordings of the 0 Mg (2+)/4-AP-induced hippocampal discharge from the CA3 region demonstrated that treating slices with compounds, which interfere with PKA activity, prevent SRIF inhibition of epileptiform bursting.
1(0,0,0,1) Details
15829253 Ogita K, Okuda H, Watanabe M, Nagashima R, Sugiyama C, Yoneda Y: In vivo treatment with the K+ channel blocker 4-aminopyridine protects against kainate-induced neuronal cell death through activation of NMDA receptors in murine hippocampus. Neuropharmacology. 2005 May;48(6):810-21.

Further immunohistochemical study on deoxyribonuclease II revealed that the pretreatment with 4-AP led to complete abolition of deoxyribonuclease II expression induced by kainate in the CA1 and CA3 pyramidal cells.
1(0,0,0,1) Details
12450487 Avoli M, D'Antuono M, Louvel J, Kohling R, Biagini G, Pumain R, D'Arcangelo G, Tancredi V: Network and pharmacological mechanisms leading to epileptiform synchronization in the limbic system in vitro. Prog Neurobiol. 2002 Oct;68(3):167-207.


These data indicate that in control animals: (i) prolonged, NMDA receptor-dependent epileptiform discharges, resembling electrographic limbic seizures, originate in the entorhinal cortex from where they propagate to the hippocampus via the perforant path-dentate gyrus route; (ii) the initiation and maintenance of these ictal discharges is paradoxically contributed by GABA (mainly type A) receptor-mediated mechanisms; and (iii) CA3 outputs, which relay a continuous pattern of interictal discharge at approximately 1Hz, control rather than sustain ictal discharge generation in entorhinal cortex.
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15932889 Benini R, Avoli M: Rat subicular networks gate hippocampal output activity in an in vitro model of limbic seizures. J Physiol. 2005 Aug 1;566(Pt 3):885-900. Epub 2005 Jun 2.

Hence, we used rat hippocampus-entorhinal cortex (EC) slices to identify the role of subiculum in epileptiform synchronization during bath application of 4-aminopyridine (4AP, 50 microM).
However, antagonizing GABA (A) receptors with picrotoxin (50 microM) made CA3-driven interictal activity spread to EC.
2(0,0,0,2) Details
15086522 Merlo D, Cifelli P, Cicconi S, Tancredi V, Avoli M: 4-Aminopyridine-induced epileptogenesis depends on activation of mitogen-activated protein kinase ERK. J Neurochem. 2004 May;89(3):654-9.

We also found that application of the ERK pathway inhibitors U0126 (50 micro m) or PD98059 (100 micro m) markedly reduced 4AP-induced epileptiform synchronization, thus abolishing ictal discharges in the CA3 area.
1(0,0,0,1) Details
18329054 Ristori C, Cammalleri M, Martini D, Pavan B, Casini G, Cervia D, Bagnoli P: The cyclooxygenase-2/prostaglandin E2 pathway is involved in the somatostatin-induced decrease of epileptiform bursting in the mouse hippocampus. Neuropharmacology. 2008 Apr;54(5):874-84. Epub 2008 Feb 3.


In particular, COX-2 protein increased in CA1/CA3 pyramidal layer and in the granular layer of the dentate gyrus.
1(0,0,0,1) Details
16840518 Vervaeke K, Gu N, Agdestein C, Hu H, Storm JF: Kv7/KCNQ/M-channels in rat glutamatergic hippocampal axons and their role in regulation of excitability and transmitter release. J Physiol. 2006 Oct 1;576(Pt 1):235-56. Epub 2006 Jul 13.

Finally, we compared the effects of blocking I (M) on the spike after-depolarization and bursting in CA3 pyramidal neuron somata versus their axons.
However, I (M) contributed to the refractory period in the axons when spikes were broadened by a low dose 4-aminopyridine (200 microm).
1(0,0,0,1) Details
10684888 Grosse G, Draguhn A, Hohne L, Tapp R, Veh RW, Ahnert-Hilger G: Expression of Kv1 potassium channels in mouse hippocampal primary cultures: development and activity-dependent regulation. J Neurosci. 2000 Mar 1;20(5):1869-82.

In adult hippocampus, Kv1 (1-6) channel alpha-subunits were present, whereas at postnatal day 2, none of these proteins could be detected in CA1-CA3 and dentate gyrus.
This developmental upregulation was paralleled by a dramatic increase in total K (+) current, as well as an elevated GABA release in the presence of 4-aminopyridine.
1(0,0,0,1) Details
18538357 Salah A, Perkins KL: Effects of subtype-selective group I mGluR antagonists on synchronous activity induced by 4-aminopyridine/CGP 55845 in adult guinea pig hippocampal slices. Neuropharmacology. 2008 Jul;55(1):47-54. Epub 2008 Apr 23.

Electrophysiological field recordings were performed in the CA3 region of hippocampal slices from adult guinea pigs.
1(0,0,0,1) Details
10656523 Wu J, Okada YC: Roles of calcium- and voltage-sensitive potassium currents in the generation of neuromagnetic signals and field potentials in a CA3 longitudinal slice of the guinea-pig. Clin Neurophysiol. 2000 Jan;111(1):150-60.

METHODS: Their roles were evaluated by using selective channel blockers (tetraethyl-ammonium (TEA) and 4-aminopyridine (4AP)) and measuring their effects on the two types of signals and intracellular potentials.
2(0,0,0,2) Details
18359199 Thone J, Leniger T, Splettstosser F, Wiemann M: Antiepileptic activity of zonisamide on hippocampal CA3 neurons does not depend on carbonic anhydrase inhibition. Epilepsy Res. 2008 May;79(2-3):105-11. Epub 2008 Mar 21.

Intracellular recordings from CA3 neurons (hippocampal slice, adult guinea pigs) were carried out under bicarbonate-buffered conditions.
Epileptiform activity was induced by either 4-aminopyridine or theophylline.
2(0,0,0,2) Details
11113304 Pena F, Tapia R: Seizures and neurodegeneration induced by 4-aminopyridine in rat hippocampus in vivo: role of glutamate- and GABA-mediated neurotransmission and of ion channels. Neuroscience. 2000;101(3):547-61.

Tetrodotoxin largely prevented the increase of extracellular glutamate, the electroencephalographic epileptic discharges and the neuronal death in the CA1 and CA3 hippocampal regions.
1(0,0,0,1) Details
11431518 Sinha SR, Saggau P: Imaging of 4-AP-induced, GABA (A)-dependent spontaneous synchronized activity mediated by the hippocampal interneuron network. J Neurophysiol. 2001 Jul;86(1):381-91.

Under conditions of increased excitability, such as application of the K (+) channel blocker 4-aminopyridine (4-AP, 100 microM), interneurons in the hippocampal slice show an additional form of synchronized activity that is distinct from the ictal and interictal epileptiform activity induced by these manipulations.
Unlike interictal activity, which originated in area CA2/CA3 and spread from there, SIA was most prominent in area CA1 and originated either there or in the subiculum.
1(0,0,0,1) Details
12694926 Sayin U, Rutecki PA: Group I metabotropic glutamate receptor activation produces prolonged epileptiform neuronal synchronization and alters evoked population responses in the hippocampus. Epilepsy Res. 2003 Mar;53(3):186-95.

We used the CA3 region of the adult rat hippocampal slice to evaluate group I metabotropic glutamate receptor (mGluR) activation on epileptiform activity and the population response recorded extracellularly evoked by stratum radiatum stimulation.
To test the possibility that a reduction of the first evoked population spike and loss of inhibition of a second evoked population spike generated prolonged ictal discharges, we used 4-aminopyridine (4-AP 50 microM) to enhance synaptic transmission. 4-AP converted ictal discharges produced by DHPG to an interictal pattern of synchronous activity, reversed the DHPG-induced reduction in the first evoked population spike, and changed paired-pulse facilitation to inhibition.
1(0,0,0,1) Details
18930118 Su T, Cong WD, Long YS, Luo AH, Sun WW, Deng WY, Liao WP: Altered expression of voltage-gated potassium channel 4.2 and voltage-gated potassium channel 4-interacting protein, and changes in intracellular calcium levels following lithium-pilocarpine-induced status epilepticus. Neuroscience. 2008 Dec 2;157(3):566-76. Epub 2008 Sep 27.

We found that Kv4.2 and KChIP1 expression was transiently up-regulated following SE, whereas it was down-regulated during the chronic phase: this was most prominent in the CA1 and CA3 regions.
We compared the difference in 4-aminopyridine (4-AP)-induced intracellular calcium ([Ca (2+)] i) elevation between model and control brain slices.
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12438533 Motalli R, D'Antuono M, Louvel J, Kurcewicz I, D'Arcangelo G, Tancredi V, Manfredi M, Pumain R, Avoli M: Epileptiform synchronization and GABA (B) receptor antagonism in the juvenile rat hippocampus. J Pharmacol Exp Ther. 2002 Dec;303(3):1102-13.

The GABA (B) receptor agonist baclofen enhances the epileptiform activity induced by 4-aminopyridine (4AP) in juvenile rat hippocampal slices.
In this study, we used a similar experimental approach (i.e., field potential, intracellular, and [K+] o recordings in the CA3 area of slices obtained from 15-23-day-old rats) to establish whether antagonizing GABA (B) receptors could exert opposite (presumably anticonvulsant) effects.
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11739569 Hu H, Shao LR, Chavoshy S, Gu N, Trieb M, Behrens R, Laake P, Pongs O, Knaus HG, Ottersen OP, Storm JF: Presynaptic Ca2+-activated K+ channels in glutamatergic hippocampal terminals and their role in spike repolarization and regulation of transmitter release. J Neurosci. 2001 Dec 15;21(24):9585-97.

By combining electrophysiology and immunogold cytochemistry, we demonstrate the existence of functional BK channels in presynaptic terminals in the hippocampus and compare their functional roles in somata and terminals of CA3 pyramidal cells.
This was observed in the presence of 4-aminopyridine (4-AP, 40-100 microm), which broadened the presynaptic compound action potential.
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19732136 Fernandez M, Lao-Peregrin C, Martin ED: Flufenamic acid suppresses epileptiform activity in hippocampus by reducing excitatory synaptic transmission and neuronal excitability. Epilepsia. 2010 Mar;51(3):384-90. Epub 2009 Sep 3.

METHODS: The mechanisms of FFA action were analyzed using an in vitro model in which epileptiform activity was induced in hippocampal slices by perfusion with 100 microm 4-aminopyridine (4-AP) added to a modified Mg (2+)-free solution.
The activity of CA1 pyramidal neurons as well as the synaptic connection between CA3 and CA1 was monitored using extracellular and patch-clamp recordings.
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11741395 D'Arcangelo G, Tancredi V, Avoli M: Intrinsic optical signals and electrographic seizures in the rat limbic system. Neurobiol Dis. 2001 Dec;8(6):993-1005.

We measured the intrinsic optical signals (IOSs) generated by rat hippocampus-entorhinal cortex (EC) slices in response to single shock electrical stimuli delivered in the EC deep layers during application of the convulsant drug 4-aminopyridine (50 microM).
IOS changes initiated in the medial EC, near to the stimulation site, and spread to the lateral EC, the dentate, and the CA3/CA1 areas.
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12686578 Pais I, Hormuzdi SG, Monyer H, Traub RD, Wood IC, Buhl EH, Whittington MA, LeBeau FE: Sharp wave-like activity in the hippocampus in vitro in mice lacking the gap junction protein connexin 36. J Neurophysiol. 2003 Apr;89(4):2046-54.

However, bath application of the potassium channel blocker 4-aminopyridine (4-AP; 20-80 microM) produced a pattern of activity in control mice (13/16 slices), consisting of burst discharges occurring in conjunction with kainate-evoked gamma-frequency oscillations, that was similar to that seen in Cx36KO mice.
Bath application of kainate (100-300 nM) induced a persistent gamma-frequency (30-80 Hz) oscillation that could be recorded in stratum radiatum of the CA3 region in vitro.
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12750426 Lamsa K, Taira T: Use-dependent shift from inhibitory to excitatory GABAA receptor action in SP-O interneurons in the rat hippocampal CA3 area. J Neurophysiol. 2003 Sep;90(3):1983-95. Epub 2003 May 15.

Similar but spontaneous GABAergic bursting was induced by application of 4-aminopyridine (100 microM) to slices.
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11826078 Liang Y, Yuan LL, Johnston D, Gray R: Calcium signaling at single mossy fiber presynaptic terminals in the rat hippocampus. J Neurophysiol. 2002 Feb;87(2):1132-7.

Experiments with alternative lower affinity indicators for Ca (2+) (fura-2FF and calcium green-2) and the transient K (+) channel blocker, 4-aminopyridine were performed to control for the possible saturation of fura-2.
We investigated internal Ca (2+) release at mossy fiber synapses on CA3 pyramidal neurons (mossy fiber terminals, MFTs) in the hippocampus.
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15013053 Brown JT, Gill CH, Farmer CE, Lanneau C, Randall AD, Pangalos MN, Collingridge GL, Davies CH: Mechanisms contributing to the exacerbated epileptiform activity in hippocampal slices of GABAB1 receptor subunit knockout mice. Epilepsy Res. 2003 Dec;57(2-3):121-36.


Deletion of the GABAB1 receptor subunit had no effect on a range of passive membrane properties of CA3 pyramidale neurones, non-synaptic epileptiform field bursting and spreading depression recorded in 6mM K+/Ca2+-free medium, and inter-ictal synaptically-induced epileptiform activity induced by 100 microM 4-aminopyridine (4-AP).
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19399874 Stafstrom CE, Ockuly JC, Murphree L, Valley MT, Roopra A, Sutula TP: Anticonvulsant and antiepileptic actions of 2-deoxy-D-glucose in epilepsy models. Ann Neurol. 2009 Apr;65(4):435-47.


METHODS: Acute anticonvulsant actions of 2DG were assessed in vitro in rat hippocampal slices perfused with 7.5mM [K (+)](o), 4-aminopyridine, or bicuculline, and in vivo against seizures evoked by 6 Hz stimulation in mice, audiogenic stimulation in Fring's mice, and maximal electroshock and subcutaneous pentylenetetrazol (Metrazol) in rats.
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11311981 Sequeira SM, Malva JO, Carvalho AP, Carvalho CM: Presynaptic N-methyl-D-aspartate receptor activation inhibits neurotransmitter release through nitric oxide formation in rat hippocampal nerve terminals. Brain Res Mol Brain Res. 2001 Apr 18;89(1-2):111-8.


N-Methyl-D-aspartate dose-dependently inhibited the release of glutamate evoked by 4-aminopyridine (IC (50)=155 microM), and this effect was reversed by the N-methyl-D-aspartate receptor antagonist D-(-)-2-amino-5-phosphopentanoic acid and by the nitric oxide synthase inhibitor, L-nitroarginine, in synaptosomes isolated from whole hippocampus, CA3 and CA1 areas, but not from the dentate gyrus.
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11877514 Watabe AM, Carlisle HJ, O'Dell TJ: Postsynaptic induction and presynaptic expression of group 1 mGluR-dependent LTD in the hippocampal CA1 region. J Neurophysiol. 2002 Mar;87(3):1395-403.


Enhancing Ca (2+) influx by prolonging action potential duration with bath applications of the K (+) channel blocker 4-aminopyridine (4-AP) also strongly reduced the effects of DHPG in the presence of normal [Ca (2+)](o) (2 mM).
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19154779 Borbely S, Dobo E, Czege D, Molnar E, Bakos M, Szucs B, Vincze A, Vilagi I, Mihaly A: Modification of ionotropic glutamate receptor-mediated processes in the rat hippocampus following repeated, brief seizures. Neuroscience. 2009 Mar 3;159(1):358-68. Epub 2008 Dec 27.


Daily repeated epileptic seizures were induced for 12 days by intraperitoneal administration of 4-aminopyridine (4-AP; 4.5 mg/kg) in adult Wistar rats.
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15590725 Kantrowitz JT, Francis NN, Salah A, Perkins KL: Synaptic depolarizing GABA Response in adults is excitatory and proconvulsive when GABAB receptors are blocked. J Neurophysiol. 2005 May;93(5):2656-67. Epub 2004 Dec 8.

In the presence of 4-aminopyridine, interneurons fire synchronously, causing giant GABA-mediated postsynaptic potentials (GPSPs; GPSCs in voltage clamp) in CA3 pyramidal cells in hippocampal slices from adult guinea pigs.
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12712959 Abraham H, Losonczy A, Czeh G, Lazar GY: Potassium channel blockers tetraethylammonium and 4-aminopyridine fail to prevent microglial activation induced by elevated potassium concentration. Acta Biol Hung. 2003;54(1):63-78.

In order to check whether the functional alteration of the neuronal population induced by 4-aminopyridine caused the activation of the microglial cells, Schaffer collaterals were cut to block spreading of epileptiform hyperactivity of the CA3 pyramidal cells to the CA1 region.
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14654096 Avoli M, Benini R, de Guzman P, Omar A: GABA (B) receptor activation and limbic network ictogenesis. Neuropharmacology. 2004 Jan;46(1):43-51.

Rat brain slices containing interconnected hippocampus and entorhinal cortex (EC) responded to 4-aminopyridine (50 microM) application by generating: (i) CA3-driven interictal discharges that propagated to the EC; and (ii) N-methyl-D-aspartic (NMDA) acid receptor-dependent ictal events originating in EC (cf.
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12460247 Barbarosie M, Louvel J, D'Antuono M, Kurcewicz I, Avoli M: Masking synchronous GABA-mediated potentials controls limbic seizures. Epilepsia. 2002 Dec;43(12):1469-79.

PURPOSE: We determined how CA3-driven interictal discharges block ictal activity generated in the entorhinal cortex during bath application of 4-aminopyridine (4AP, 50 microM).
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16971683 Fernandez de Sevilla D, Garduno J, Galvan E, Buno W: Calcium-activated afterhyperpolarizations regulate synchronization and timing of epileptiform bursts in hippocampal CA3 pyramidal neurons. J Neurophysiol. 2006 Dec;96(6):3028-41. Epub 2006 Sep 13.

We investigated in rat CA3 pyramidal neurons the contribution of the Ca (2+)-activated K (+)-mediated afterhyperpolarizations (AHPs) in the genesis and regulation of epileptiform activity induced in vitro by 4-aminopyridine (4-AP) in Mg (2+)-free Ringer.
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10924683 Bonnet U, Leniger T, Wiemann M: Alteration of intracellular pH and activity of CA3-pyramidal cells in guinea pig hippocampal slices by inhibition of transmembrane acid extrusion. Brain Res. 2000 Jul 28;872(1-2):116-24.

To get further information about the relation of neuronal pH (i) and activity of cortical neurones we investigated the effect of NHE- and/or NCHE-inhibition on (i) spontaneous action potentials and epileptiform burst-activity (induced by bicuculline-methiodide, caffeine or 4-aminopyridine) and (ii) on pH (i) of CA3-neurones.
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12027906 Leniger T, Wiemann M, Bingmann D, Widman G, Hufnagel A, Bonnet U: Carbonic anhydrase inhibitor sulthiame reduces intracellular pH and epileptiform activity of hippocampal CA3 neurons. Epilepsia. 2002 May;43(5):469-74.

METHODS: The effects of sulthiame (a) on pHi of 2',7-bis (2-carboxyethyl)-5 (6)-carboxyfluorescein-acetoxymetyl ester (BCECF-AM) loaded CA3 neurones as well as (b) on epileptiform activity (induced by 50 microM 4-aminopyridine) were compared with those of the CA inhibitors acetazolamide and benzolamide.
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10805716 Calcagnotto ME, Barbarosie M, Avoli M: Hippocampus-entorhinal cortex loop and seizure generation in the young rodent limbic system. J Neurophysiol. 2000 May;83(5):3183-7.

Application of the convulsant 4-aminopyridine (4AP, 50 microM) to adult mouse combined hippocampus-entorhinal cortex (EC) slices induces interictal and ictal discharges originating from CA3 and EC respectively.
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11784779 D'Antuono M, Benini R, Biagini G, D'Arcangelo G, Barbarosie M, Tancredi V, Avoli M: Limbic network interactions leading to hyperexcitability in a model of temporal lobe epilepsy. J Neurophysiol. 2002 Jan;87(1):634-9.

Here we tested this hypothesis and found that CA3-driven interictal discharges induced by 4-aminopyridine (4AP, 50 microM) in hippocampus-EC slices from mice injected with pilocarpine 13-22 days earlier have a lower frequency than in age-matched control slices.
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