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At least 433 records · Page 24Linked to original sources
PubMed1999

The GABA(B) receptor antagonist CGP 55845A reduces presynaptic GABA(B) actions in neocortical neurons of the rat in vitro.

Use-dependent depression of inhibitory postsynaptic potentials was investigated with intracellular recordings and the paired-pulse paradigm in rat neocortical neurons in vitro. Pairs of stimuli invariably reduced the second inhibitory postsynaptic potential-A (GABA(A) receptor-mediated inhibitory postsynaptic potential) of a pair; at interstimulus intervals of 500 ms, the amplitude of the second inhibitory postsynaptic potential-A was considerably smaller than the first (36.2 +/- 6.2%, n= 17). Decreasing the interstimulus interval reduced the second inhibitory postsynaptic potential-A further and with interstimulus intervals shorter than 330 ms the compound excitatory postsynaptic potential-inhibitory postsynaptic potential response reversed from a hyperpolarizing to a depolarizing response. The depression of the inhibitory postsynaptic potential-A exhibited a maximum at interstimulus intervals near 150 ms and recovered with a time constant of 282 +/- 96.2 ms. Elimination of excitatory transmission by the application of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and D(-)-2-amino-5-phosphonovaleric acid yielded an essentially unaltered time-course of paired-pulse depression (maximum depression near 150 ms, time constant of recovery 232 +/- 98 ms). The polarity change of the compound excitatory postsynaptic potential response at shorter interstimulus intervals was abolished in the presence of CNQX and D(- )-2-amino-5-phosphonovaleric acid. CNQX and D(-)-2-amino-5-phosphonovaleric acid also reduced the apparent depolarizing shift of the reversal potential between the first and second inhibitory postsynaptic potential-A from about 6 mV to less than 2 mV. Application of the GABA(B) receptor antagonist CGP 55845A in the presence of CNQX and (-)-2-amino-5-phosphonovaleric acid abolished the inhibitory postsynaptic potential-B and paired-pulse depression. Under these conditions, the amplitude of the second inhibitory postsynaptic potential was, on average, about 90% of the first, i.e. reduced by about 10%. The second inhibitory postsynaptic potential-A was approximately constant at interstimulus intervals between 100 and 500 ms. It is concluded that paired-pulse depression of cortical inhibition is predominantly mediated by presynaptic GABA(B) receptors of GABAergic interneurons. The abolition of net inhibition at interstimulus intervals near 330 ms may facilitate spread of excitation and neuronal synchrony during repetitive cortical activation near 3 Hz. This use-dependent depression of inhibition may contribute to highly synchronized slow electroencephalogram activity during spike-and-wave or delta activity.

2-Amino-5-phosphonovalerate↗
PubMed2005

Presynaptic NMDA autoreceptors facilitate axon excitability: a new molecular target for the anticonvulsant gabapentin.

Gabapentin is a drug with anticonvulsant and analgesic properties causing the reduction of neurotransmitter release. We show that one of the mechanisms implicated in this effect of gabapentin is the reduction of the axon excitability measured as an amplitude change of the presynaptic fibre volley (FV) in the CA1 area of rat hippocampal slices. Interestingly, we found that gabapentin-induced depression of FV is mimicked and occluded by NMDA receptor (NMDA-R) antagonists, indicating that these receptors are located presynaptically and are activated by ambient levels of glutamate. Conversely, NMDA application (20 microM, 10 min) elicits a reversible FV potentiation which is reduced by gabapentin. Both NMDA- and gabapentin-induced FV changes are partially explained by modifications in the firing threshold of individual fibres. Increasing [K(+)](o) does not mimic or occlude (at a concentration of 6.5 mM) the effect of NMDA on FV amplitude, which makes it unlikely that a rise in [K(+)](o) induced by NMDA receptor activation could indirectly participate in the potentiation of the FV. The NMDA-induced FV potentiation is independent of extracellular calcium presence but is completely inhibited in a low-Na(+) solution (50% reduction) or under NMDA channel block (high Mg(2+) or MK 801). These findings suggest that sodium entry through presynaptic NMDA-R channels facilitates axon excitability. The interaction of gabapentin with this newly described mechanism might contribute to its therapeutic benefits.

Amines↗
PubMed2005

Distinct mechanisms of presynaptic inhibition at GABAergic synapses of the rat substantia nigra pars compacta.

We investigated the mechanisms of presynaptic inhibition of GABAergic neurotransmission by group III metabotropic glutamate receptors (mGluRs) and GABA(B) receptors, in dopamine (DA) neurons of the substantia nigra pars compacta (SNc). Both the group III mGluRs agonist L-(+)-2-amino-4-phosphonobutyric acid (AP4, 100 microM) and the GABA(B) receptor agonist baclofen (10 microM) reversibly depressed the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) to 48.5 +/- 2.7 and 79.3 +/- 1.6% (means +/- SE) of control, respectively. On the contrary, the frequency of action potential-independent miniature IPSCs (mIPSCs), recorded in tetrodotoxin (TTX, 1 microM) and cadmium (100 microM) were insensitive to AP4 but were reduced by baclofen to 49.7 +/- 8.6% of control. When the contribution of voltage-dependent calcium channels (VDCCs) to synaptic transmission was boosted with external barium (1 mM), AP4 became effective in reducing TTX-resistant mIPSCs to 65.4 +/- 3.9% of control, thus confirming a mechanism of presynaptic inhibition involving modulation of VDCCs. Differently from AP4, baclofen inhibited to 58.5 +/- 6.7% of control the frequency mIPSCs recorded in TTX and the calcium ionophore ionomycin (2 microM), which promotes Ca2+-dependent, but VDCC-independent, transmitter release. Moreover, in the presence of alpha-latrotoxin (0.3 nM), to promote a Ca2+-independent vesicular release of GABA, baclofen reduced mIPSC frequency to 48.1 +/- 3.2% of control, while AP4 was ineffective. These results indicate that group III mGluRs depress GABA release to DA neurons of the SNc through inhibition of presynaptic VDCCs, while presynaptic GABA(B) receptors directly impair transmitter exocytosis.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2001

Electrophysiological characterization of "giant" cells in stratum radiatum of the CA3 hippocampal region.

Whole cell patch-clamp recording and intracellular staining with biocytin allowed the morphological and electrophysiological characterization of "giant" cells, studied in stratum (st.) radiatum of the CA3 region in 17- to 21-day-old rat hippocampal slices. These neurons had extensive dendritic arborization, a triangular soma, and a bipolar vertical orientation with axons directed to the pyramidal layer or extended into the st. oriens. Giant cells had significantly higher input resistance and shorter action potentials compared with CA3 pyramidal cells. Evoked action potentials were typically followed by an afterdepolarizing potential (ADP). During depolarizing current injection, most (80%) of recorded giant cells displayed a regular firing pattern (maximum steady-state firing rate, approximately 30 Hz) characterized by a modest early accommodation, whereas irregular firing was observed in the remaining 20% of giant cells. Hyperpolarizing current pulses induced a slow inward rectification of the electrotonic voltage responses, blocked by 2 mM external Cs(+). N-methyl-D-aspartate (NMDA) and non-NMDA-mediated excitatory postsynaptic currents (EPSCs) measured under voltage clamp were distinguished on the basis of their voltage dependence and sensitivity to specific NMDA and non-NMDA glutamate receptor blockers. Non-NMDA EPSCs possessed a linear current-voltage relationship. EPSCs elicited by st. lucidum stimulation were reversibly reduced (mean, 23%) by the group II metabotropic glutamate receptor agonist (2S, 1'R, 2'R, 3'R)-2-(2,3-dicarboxyl-cyclopropyl)-glycine (DCG-IV, 1 microM). GABA(A)-mediated postsynaptic currents were subject to paired-pulse depression that was inhibited by the GABA(B) antagonist CGP 55845A (5 microM). We conclude that CA3 giant cells represent a particular class of hippocampal neuron located in st. radiatum that shares only some morphological and physiological properties with principal cells.

2-Amino-5-phosphonovalerate↗
PubMed2003

Coordination chemistry of the water-soluble ligand TPPTP and formation of a [Mo(CO)5(m-TPPTP)] monolayer on an alumina surface.

Phosphonate and phosphonic acid functionalized phosphine complexes of platinum(II) were prepared via direct reaction of the ligands with K2PtCl4 in water. Either cis or trans geometries were found depending on the nature of the ligand. The crystal structure of P(3-C6H4PO3H2)3.2H2O (6b) (triclinic, P1, a = 8.3501(6) A, b = 10.1907(6) A, c = 14.6529(14) A, alpha = 94.177(6) degrees, beta = 105.885(6) degrees, gamma = 108.784(5) degrees, Z = 2) shows a layered arrangement of the phosphonic acid. The phosphonodiamide complex cis-[PtCl2(P[4-C6H4PO[N(CH3]2]]3)2].3H2O (10) was synthesized in 89% yield and hydrolyzed to the phosphonic acid complex using dilute HCl. Aqueous phase and silica gel supported catalytic phosphonylation of phenyl triflate using palladium phosphine complexes was achieved. A molybdenum complex, Mo(CO)5[P3-C6H4PO3H2)3] (11), was synthesized in situ and grafted to an alumina surface. XPS, RBS, and AFM studies confirm the formation of a monolayer of 11 on the alumina surface.

Journal Article↗
PubMed2001

Synthesis, characterization, and applicability of neutral polyhydroxy phospholane derivatives and their rhodium(I) complexes for reactions in organic and aqueous media.

Two different protocols for the preparation of water-soluble, enantiomerically pure polyhydroxybisphospholanes from acid-labile acetal and tert-butyldimethylsilyl-protected derivatives are reported. These procedures circumvent two of the commonly encountered limitations in the synthesis of these potentially important ligands: (a) formation of phosphonium salts from the highly basic phosphine under acidic conditions, and (b) the need to start with preformed, fully protected cationic metal complex. Thus, cationic Rh complexes of these ligands have been prepared in a separate step, and they have been found to be excellent catalysts for organic and aqueous phase hydrogenation of dehydroamino acids. The viability of catalyst recovery has been demonstrated in three different systems, including two cases where > 99% ee can be achieved under recycling conditions.

Journal Article↗
PubMed2005

Mechanisms contributing to the exacerbated epileptiform activity in hippocampal slices expressing a C-terminal truncated GABA(B2) receptor subunit.

GABAergic synaptic transmission plays an important role in the patterning of epileptiform activity. We have previously shown that global loss of GABA(B) receptor function due to transgenic deletion of the GABA(B1) receptor subunit exacerbates epileptiform activity induced by pharmacological manipulations in hippocampal slices. Here we show that a similar hyperexcitable phenotype is observed in hippocampal slices prepared from a transgenic mouse expressing a GABA(B2) receptor subunit lacking its C terminal tail (the DeltaGB2-Ct mouse); a molecular manipulation that also produces complete loss of GABA(B) receptor function. Thus, epileptiform bursts that are sensitive to NMDA receptor antagonists (induced by either the GABA(A) receptor antagonist bicuculline (10muM) or removal of extracellular Mg(2+)) were significantly longer in duration in DeltaGB2-Ct slices relative to WT slices. We now extend these observations to demonstrate that a stimulus train induced bursting (STIB) protocol also evokes significantly longer bicuculline sensitive bursts of activity in DeltaGB2-Ct slices compared to WT. Furthermore, synchronous GABA(A) receptor-mediated potentials recorded in the presence of the potassium channel blocker 4-aminopyridine (4-AP, 100muM) and the ionotropic glutamate receptor antagonists NBQX (20muM) and D-AP5 (50muM) were significantly prolonged in duration in DeltaGB2-Ct versus WT slices. These data suggest that the loss of GABA(B) receptor function in DeltaGB2-Ct hippocampal slices promotes depolarising GABA(A) receptor-mediated events, which in turn, leads to the generation of ictal-like events, which may contribute to the epilepsy phenotype observed in vivo.

4-Aminopyridine↗
PubMed2001

Substance P and neurokinin A mediate sensory synaptic transmission in young rat dorsal horn neurons.

Spinal nociceptive transmission is mediated by glutamate and neuropeptides such as substance P (SP) and neurokinin A (NKA). The neuropeptide-mediated excitatory postsynaptic potentials (EPSPs) had a slow onset and long duration. Here, we demonstrate SP- and NKA-mediated excitatory postsynaptic currents (EPSCs) in dorsal horn neurons of young rats using whole-cell patch-clamp recording techniques. After complete blockade of glutamate receptor-mediated currents, we observed a small residual EPSC. The residual EPSCs exhibited temporal summation in response to a train of stimulation (six pulses delivered at 10-50 Hz). High intensity stimulation (the same or greater than the stimulation threshold for nociceptive fibers in vivo) was required for evoking these summated EPSCs. Summated EPSCs were attenuated or abolished by capsaicin pretreatment, which depletes SP and NKA from presynaptic terminals; SP and NKA pretreatment; NK(1) or NK(2) receptor antagonists; and inhibition of postsynaptic G proteins. EPSCs were neither blocked by a metabotropic glutamate receptor antagonist nor a gamma-aminobutyric acid(B) receptor antagonist. The summated EPSCs were also sensitive to voltage-gated calcium channel antagonists or mu-opioid receptor activation by DAMGO. The present study provides electrophysiological evidence that suggests the possible contribution of SP and NKA to sensory synaptic transmission between primary afferent fibers and dorsal horn neurons.

2-Amino-5-phosphonovalerate↗
PubMed2003

The structural basis for the selectivity of benzotriazole inhibitors of PTP1B.

Protein tyrosine phosphatase 1B (PTP1B) has been implicated in the regulation of the insulin signaling pathway and represents an attractive target for the design of inhibitors in the treatment of type 2 diabetes and obesity. Inspection of the structure of PTP1B indicates that potent PTP1B inhibitors may be obtained by targeting a secondary aryl phosphate-binding site as well as the catalytic site. We report here the crystal structures of PTP1B in complex with first and second generation aryldifluoromethyl-phosphonic acid inhibitors. While all compounds bind in a previously unexploited binding pocket near the primary binding site, the second generation compounds also reach into the secondary binding site, and exhibit moderate selectivity for PTP1B over the closely related T-cell phosphatase. The molecular basis for the selectivity has been confirmed by single point mutation at position 52, where the two phosphatases differ by a phenylalanine-to-tyrosine switch. These compounds present a novel platform for the development of potent and selective PTP1B inhibitors.

Amino Acids↗
PubMed1998

Limbic gamma rhythms. II. Synaptic and intrinsic mechanisms underlying spike doublets in oscillating subicular neurons.

Gamma oscillations were evoked in the subiculum in rat transverse hippocampal slices by tetanic stimulation (200 ms/100 Hz) of either CA1 or subiculum. Gamma oscillations in the subiculum differed from those in CA1 in containing population spike doublets as well as singlets. The present study addresses the origin of this more complex form of gamma oscillation in the subiculum. Intracellular recordings from subicular neurons revealed that 63% of them fired double action potentials on cycles of the gamma oscillation that generated population spike doublets after tetanic stimulation of either CA1 or subiculum. The remaining cells produced excitatory postsynaptic potentials (EPSPs), and occasional single spikes, on each cycle. Neurons that fired occasional single action potentials during gamma rhythms were "regular spiking" cells. They did not produce burst discharges during depolarizing steps, had minimal membrane potential sags on hyperpolarizing steps, and responded to single afferent volleys with a single action potential on an EPSP followed by a large inhibitory postsynaptic potential complex. Fast spiking cells were observed too infrequently to be studied in detail. Neurons that fired doublets during gamma rhythms were "intrinsic burst" (IB) cells. They generated bursts of action potentials on step membrane depolarizations, had significant membrane potential sags on step hyperpolarizations with an anodal break potential on return to rest, and fired multiple action potentials in response to high-intensity single afferent volleys. IB neurons did not fire action potential doublets during 1-s membrane depolarizations. Double action potentials, however, were evoked in these cells by depolarizing pulses at 40 Hz from hyperpolarized membrane potentials (-100 mV). Computer simulations suggest that the hyperpolarization between the depolarizations was essential for action potential doublets. The results in this and the previous paper suggest the following: either CA1 or subiculum alone can generate gamma oscillations gated by local networks of interneurons, oscillations in CA1 project through pyramidal cell axons to subiculum with a time lag expected from axon conduction delays, and oscillating sequences of EPSPs and intrinsic and/or synaptic hyperpolarizing potentials in IB subicular neurons generate gamma frequency spike doublets, which depend on both the intrinsic properties of these neurons and their temporally patterned synaptic input. This phenomenon could amplify gamma output from CA1 and modify its coupling to gamma oscillations in the wider limbic system.

Action Potentials↗
PubMed2001

Enhanced temporal stability of cholinergic hippocampal gamma oscillations following respiratory alkalosis in vitro.

The decrease in brain CO(2) partial pressure (pCO(2)) that takes place both during voluntary and during pathological hyperventilation is known to induce gross alterations in cortical functions that lead to subjective sensations and altered states of consciousness. The mechanisms that mediate the effects of the decrease in pCO(2) at the neuronal network level are largely unexplored. In the present work, the modulation of gamma oscillations by hypocapnia was studied in rat hippocampal slices. Field potential oscillations were induced by the cholinergic agonist carbachol under an N-methyl-D-aspartate (NMDA)-receptor blockade and were recorded in the dendritic layer of the CA3 region with parallel measurements of changes in interstitial and intraneuronal pH (pH(o) and pH(i), respectively). Hypocapnia from 5 to 1% CO(2) led to a stable monophasic increase of 0.5 and 0.2 units in pH(o) and pH(i), respectively. The mean oscillation frequency increased slightly but significantly from 32 to 34 Hz and the mean gamma-band amplitude (20 to 80 Hz) decreased by 20%. Hypocapnia induced a dramatic enhancement of the temporal stability of the oscillations, as was indicated by a two-fold increase in the exponential decay time constant fitted to the autocorrelogram. A rise in pH(i) evoked by the weak base trimethylamine (TriMA) was associated with a slight increase in oscillation frequency (37 to 39 Hz) and a decrease in amplitude (30%). Temporal stability, on the other hand, was decreased by TriMA, which suggests that its enhancement in 1% CO(2) was related to the rise in pH(o). In 1% CO(2), the decay-time constant of the evoked monosynaptic pyramidal inhibitory postsynaptic current (IPSC) was unaltered but its amplitude was enhanced. This increase in IPSC amplitude seems to significantly contribute to the enhancement of temporal stability because the enhancement was almost fully reversed by a low concentration of bicuculline. These results suggest that changes in brain pCO(2) can have a strong influence on the temporal modulation of gamma rhythms.

2-Amino-5-phosphonovalerate↗
PubMed2004

Structural determinants of RXPA380, a potent and highly selective inhibitor of the angiotensin-converting enzyme C-domain.

RXPA380 (Cbz-PhePsi[PO(2)CH]Pro-Trp-OH) was reported recently as the first highly selective inhibitor of the C-domain of somatic angiotensin-converting enzyme (ACE), able to differentiate the two active sites of somatic ACE by a selectivity factor of more than 3 orders of magnitude. The contribution of each RXPA380 residue toward this remarkable selectivity was evaluated by studying several analogues of RXPA380. This analysis revealed that both pseudo-proline and tryptophan residues in the P(1)' and P(2)' positions of RXPA380 play a critical role in the selectivity of this inhibitor for the C-domain. This selectivity is not due to a preference of the C-domain for inhibitors bearing pseudo-proline and tryptophan residues, but rather reflects the poor accommodation of these inhibitor residues by the N-domain. A model of RXPA380 in complex with the ACE C-domain, based on the crystal structure of germinal ACE, highlights residues that may contribute to RXPA380 selectivity. From this model, striking differences between the N- and C-domains of ACE are observed for residues defining the S(2)' pocket. Of the twelve residues that surround the tryptophan side chain of RXPA380 in the C-domain, five are different in the N-domain. These differences in the S(2)' composition between the N- and C-domains are suggested to contribute to RXPA380 selectivity. The structural insights provided by this study should enhance understanding of the factors controlling the selectivity of the two domains of somatic ACE and allow the design of new selective ACE inhibitors.

Amino Acids↗
PubMed2001

A GABA(B) mystery: the search for pharmacologically distinct GABA(B) receptors.

The classification of neurotransmitter receptors into distinct pharmacological subtypes is of major importance in drug discovery. This quest is particularly important for neurotransmitter systems that are widely distributed. Because gamma-aminobutyric acid (GABA) receptors, both GABA(A) and GABA(B), are found throughout the neuroaxis, they are likely involved in all central nervous system functions. Accordingly, the therapeutic promise of GABA(B) receptor manipulation depends upon the identification of subtypes than can be specifically targeted.

Acetates↗
PubMed1995

Farnesyltransferase inhibitors block the neurofibromatosis type I (NF1) malignant phenotype.

Neurofibromatosis type I (NF1) is a hereditary tumor and developmental disorder whose defective gene was cloned previously. The protein product of the NF1 gene, neurofibromin, contains a domain that shows significant sequence homology to the known catalytic domains of mammalian Ras GTPase-activating proteins (GAP) and the yeast IRA1 and IRA2 proteins. This homologous region of neurofibromin has been shown to exhibit GAP activity toward Ras proteins. Malignant schwannoma cell lines from NF1 patients contain normal levels of GAP and nonmutated Ras proteins but barely detectable levels of neurofibromin, based on genetic mutations in the NF1 gene. Because these cells contain constitutively activated Ras.GTP, it has been proposed that neurofibromin may be the sole negative regulator of Ras in these cells. Overall, these results have implied an important role of the Ras signaling pathway in NF1 malignant schwannomas. Recently, several laboratories have developed small molecule inhibitors of Ras function that inhibit the enzyme farnesyltransferase (FT). FT-mediated post-translational farnesylation of Ras proteins is absolutely necessary for Ras function since this modification is required for the anchoring of Ras proteins to the plasma cell membrane. Although previous studies have shown that FT inhibitors can block the growth of tumor cells carrying mutant Ras proteins, it remained unclear how this class of inhibitors would affect tumor cells such as in NF1, whose malignant growth appears to be mediated by up-regulation of wild-type Ras activity. Thus, in the current study, we investigated whether BMS-186511, a bisubstrate analogue inhibitor of FT, would inhibit the malignant growth properties of a cell line established from malignant schwannoma of an NF1 patient. Our results indicate that the malignant growth properties of ST88-14 cells, the most malignant cell line among several well-characterized NF1 cells, are inhibited by BMS-186511 in a concentration-dependent manner. Following treatment with BMS-186511, ST88-14 cells became flat, nonrefractile, were contact-inhibited, and lost their ability to grow in soft agar. In the drug-exposed cells, Ras proteins were prevented from FT-mediated membrane association. BMS-186511 was found to specifically inhibit FT, but not geranylgeranyltransferase I, a closely related enzyme. Thus, it is conceivable that FT inhibitors may ultimately become the first generation of drugs against the malignant phenotype in NF1 based on rational insights into the mechanism of action of neurofibromin.

Alkyl and Aryl Transferases↗
PubMed1998

Mouse cerebellar granule cell differentiation: electrical activity regulates the GABAA receptor alpha 6 subunit gene.

GABAA receptor alpha6 subunit gene expression marks cerebellar granule cell maturation. To study this process, we used the Deltaalpha6lacZ mouse line, which has a lacZ reporter inserted into the alpha6 gene. At early stages of postnatal cerebellar development, alpha6-lacZ expression is mosaic; expression starts at postnatal day 5 in lobules 9 and 10, and alpha6-lacZ is switched on inside-out, appearing first in the deepest postmigratory granule cells. We looked for factors regulating this expression in cell culture. Membrane depolarization correlates inversely with alpha6-lacZ expression: granule cells grown in 25 mM [K+]o for 11-15 d do not express the alpha6 gene, whereas cultures grown for the same period in 5 mM [K+]o do. This is influenced by a critical early period: culturing for >/=3 d in 25 mM [K+]o curtails the ability to induce the alpha6 gene on transfer to 5 mM [K+]o. If the cells start in 5 mM [K+]o, however, they still express the alpha6-lacZ gene in 25 mM [K+]o. In contrast to granule cells grown in 5 mM [K+]o, cells cultured in 25 mM [K+]o exhibit no action potentials, mEPSCs, or mIPSCs. In chronic 5 mM [K+]o, factors may therefore be released that induce alpha6. Blockade of ionotropic and metabotropic GABA and glutamate receptors or L-, N-, and P/Q-type Ca2+ channels did not prevent alpha6-lacZ expression, but inhibition of action potentials with tetrodotoxin blocked expression in a subpopulation of cells.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1997

Properties of carbachol-induced oscillatory activity in rat hippocampus.

Properties of carbachol-induced oscillatory activity in rat hippocampus. J. Neurophysiol. 78: 2631-2640, 1997. The recent resurgence of interest in carbachol oscillations as an in vitro model of theta rhythm in the hippocampus prompted us to evaluate the circuit mechanisms involved. In extracellular recordings, a regularly spaced bursting pattern of field potentials was observed in both CA3 and CA1 subfields in the presence of carbachol. Removal of the CA3 region abolished oscillatory activity observed in CA1, suggesting that the oscillatory generator is located in CA3. An alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX), blocked carbachol oscillations, indicating that AMPA receptor-mediated synaptic currents are necessary for the population oscillation. Moreover, the spread of oscillatory activity into CA1 required intact N-methyl--aspartate receptors. These data are more consistent with epileptiform bursting than with theta rhythm described in vivo. In the presence of carbachol, individual CA3 pyramidal cells exhibited a slow, rhythmic intrinsic oscillation that was not blocked by DNQX and that was enhanced by membrane hyperpolarization. We hypothesize that this slower oscillation is the fundamental oscillator that participates in triggering the population oscillation by exciting multiple synaptically connected CA3 neurons. gamma-aminobutyric acid-A (GABAA) receptors are not necessary for carbachol to elicit synchronous CA3 field events but are essential to the bursting pattern observed. Neither GABAB nor metabotropic glutamate receptors appear to be necessary for carbachol oscillations. However, both nicotinic and M1 and M3 muscarinic cholinergic receptors contribute to the generation of this activity. These results establish the local circuit elements and neurotransmitter receptors that contribute to carbachol-induced oscillations and indicate that carbachol-induced oscillations are fundamentally distinct from theta rhythm in vivo.

2-Amino-5-phosphonovalerate↗