GABAB autoreceptors mediate activity-dependent disinhibition and enhance signal transmission in the dentate gyrus

1993 ◽  
Vol 69 (3) ◽  
pp. 674-691 ◽  
Author(s):  
D. D. Mott ◽  
C. W. Xie ◽  
W. A. Wilson ◽  
H. S. Swartzwelder ◽  
D. V. Lewis
Keyword(s):  
Dentate Gyrus ◽  
Receptor Antagonist ◽  
Granule Cells ◽  
Gabab Receptor ◽  
Mossy Fiber ◽  
Signal Transmission ◽  
Paired Pulse ◽  
Activity Dependent ◽  
Paired Pulse Depression ◽  
Stimulation Of

1. Activity-dependent depression (fading) of polysynaptic inhibition and the effects of this disinhibition on signal transmission were studied in the dentate gyrus of the rat hippocampal slice with the use of intracellular and extracellular recordings. 2. Polysynaptic inhibitory postsynaptic potentials/currents (IPSP/Cs) were evoked in dentate granule cells by stimulation of mossy fibers in stratum lucidum of area CA3b/c. These mossy fiber-evoked IPSP/Cs consisted of an early GABAA receptor-mediated component (IPSP/CA) and a late GABAB receptor-mediated component (IPSP/CB). 3. When paired stimuli were delivered 200 ms apart under voltage clamp, the amplitude of the IPSCA and IPSCB evoked by the second stimulus was reduced by 37.0 +/- 4.0 and 61.6 +/- 7.8% (mean +/- SE), respectively. Paired-pulse depression of both IPSCA and IPSCB was greatest at interstimulus intervals of 100-400 ms with a maximal effect when stimuli were delivered 200 ms apart. 4. (+/-) Baclofen, a GABAB receptor agonist, suppressed both components of the mossy fiber-evoked IPSP in a concentration-dependent fashion. At a concentration that only partially suppressed the initial IPSP, baclofen occluded paired-pulse depression of IPSPA. In addition, paired-pulse depression of IPSPA was blocked in a concentration-dependent fashion by 2-hydroxy-saclofen (10-400 microM), a GABAB receptor antagonist. 5. The contribution of the IPSPB conductance increase to paired-pulse depression of IPSPA was evaluated. Paired-pulse depression of IPSPA was significantly greater than was the depression of the response to a current pulse delivered 200 ms after the mossy fiber stimulus. In addition, injection of granule cells with GTP gamma S, a nonhydrolyzable guanosine triphosphate (GTP) analogue, occluded both IPSPB as well as the effects of baclofen on the granule cell membrane by activating G proteins but did not reduce paired-pulse depression of IPSPA or suppression of IPSPA by baclofen. Finally, examination of the first and second IPSCA evoked by paired stimuli 200 ms apart revealed no significant differences in response kinetics. Taken together, these results indicate that postsynaptic GABAB receptors on the granule cells are not responsible for paired-pulse depression of IPSPA. 6. Monosynaptic IPSPs were evoked by direct stimulation of inhibitory neurons in the inner molecular layer of the dentate gyrus during pharmacological blockade of excitatory transmission with D(-)-2-amino-5-phosphonovaleric acid (D-APV), an N-methyl-D-aspartate (NMDA) receptor antagonist and 6,7-dinitroquinoxaline-2,3-dione (DNQX), a non-NMDA glutamate receptor antagonist.(ABSTRACT TRUNCATED AT 400 WORDS)

The GABAB receptor antagonist, CGP-35348, inhibits paired-pulse disinhibition in the rat dentate gyrus in vivo

1992 ◽  
Vol 588 (1) ◽  
pp. 150-153 ◽  
Author(s):  
Frederic H. Brucato ◽  
Richard A. Morrisett ◽  
Wilkie A. Wilson ◽  
H.Scott Swartzwelder
Keyword(s):  
Dentate Gyrus ◽  
Receptor Antagonist ◽  
Gabab Receptor ◽  
Paired Pulse ◽  
Cgp 35348 ◽  
Gabab Receptor Antagonist

Recurrent Mossy Fiber Pathway in Rat Dentate Gyrus: Synaptic Currents Evoked in Presence and Absence of Seizure-Induced Growth

1999 ◽  
Vol 81 (4) ◽  
pp. 1645-1660 ◽  
Author(s):  
Maxine M. Okazaki ◽  
Péter Molnár ◽  
J. Victor Nadler
Keyword(s):  
Status Epilepticus ◽  
Dentate Gyrus ◽  
Granule Cells ◽  
Mossy Fiber ◽  
Molecular Layer ◽  
Mossy Fibers ◽  
Fiber Growth ◽  
Antidromic Stimulation ◽  
Mossy Fiber Pathway ◽  
Stimulation Of

Recurrent mossy fiber pathway in rat dentate gyrus: synaptic currents evoked in presence and absence of seizure-induced growth. A common feature of temporal lobe epilepsy and of animal models of epilepsy is the growth of hippocampal mossy fibers into the dentate molecular layer, where at least some of them innervate granule cells. Because the mossy fibers are axons of granule cells, the recurrent mossy fiber pathway provides monosynaptic excitatory feedback to these neurons that could facilitate seizure discharge. We used the pilocarpine model of temporal lobe epilepsy to study the synaptic responses evoked by activating this pathway. Whole cell patch-clamp recording demonstrated that antidromic stimulation of the mossy fibers evoked an excitatory postsynaptic current (EPSC) in ∼74% of granule cells from rats that had survived >10 wk after pilocarpine-induced status epilepticus. Recurrent mossy fiber growth was demonstrated with the Timm stain in all instances. In contrast, antidromic stimulation of the mossy fibers evoked an EPSC in only 5% of granule cells studied 4–6 days after status epilepticus, before recurrent mossy fiber growth became detectable. Notably, antidromic mossy fiber stimulation also evoked an EPSC in many granule cells from control rats. Clusters of mossy fiber-like Timm staining normally were present in the inner third of the dentate molecular layer at the level of the hippocampal formation from which slices were prepared, and several considerations suggested that the recorded EPSCs depended mainly on activation of recurrent mossy fibers rather than associational fibers. In both status epilepticus and control groups, the antidromically evoked EPSC was glutamatergic and involved the activation of both AMPA/kainate and N-methyl-d-aspartate (NMDA) receptors. EPSCs recorded in granule cells from rats with recurrent mossy fiber growth differed in three respects from those recorded in control granule cells: they were much more frequently evoked, a number of them were unusually large, and the NMDA component of the response was generally much more prominent. In contrast to the antidromically evoked EPSC, the EPSC evoked by stimulation of the perforant path appeared to be unaffected by a prior episode of status epilepticus. These results support the hypothesis that recurrent mossy fiber growth and synapse formation increases the excitatory drive to dentate granule cells and thus facilitates repetitive synchronous discharge. Activation of NMDA receptors in the recurrent pathway may contribute to seizure propagation under depolarizing conditions. Mossy fiber-granule cell synapses also are present in normal rats, where they may contribute to repetitive granule cell discharge in regions of the dentate gyrus where their numbers are significant.

Hippocampal CA1 lacunosum-moleculare interneurons: modulation of monosynaptic GABAergic IPSCs by presynaptic GABAB receptors

1995 ◽  
Vol 74 (5) ◽  
pp. 2126-2137 ◽  
Author(s):  
R. Khazipov ◽  
P. Congar ◽  
Y. Ben-Ari
Keyword(s):  
Receptor Antagonist ◽  
Transmitter Release ◽  
Gabab Receptor ◽  
Molecular Layer ◽  
Pyramidal Cells ◽  
Gabab Receptors ◽  
Stratum Radiatum ◽  
Paired Pulse ◽  
High Level ◽  
Paired Pulse Depression

1. Whole cell patch-clamp recordings were employed to characterize monosynaptic inhibitory postsynaptic currents (IPSCs) in morphologically and electrophysiologically identified interneurons located in the stratum lacunosum moleculare, or near the border of the stratum radiatum (LM interneurons), in the CA1 region of hippocampal slices taken from 3- to 4-wk-old rats. Monosynaptic IPSCs, evoked in the presence of glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 20 microM) and D-2-amino-5-phosphopentanoate (APV; 50 microM) were biphasic. The gamma-aminobutyric acid-A (GABAA) receptor antagonist, bicuculline (20 microM), blocked the fast IPSC, and the slow IPSC was blocked by the GABAB receptor antagonist CGP35348 (500 microM). 2. Monosynaptic IPSCs were evoked by electrical stimulation in several distant regions including the stratum radiatum, the stratum oriens, the stratum lacunosum-moleculare, and the molecular layer of dentate gyrus, suggesting an extensive network of inhibitory interneurons in the hippocampus. In paired recordings of CA1 interneurons and pyramidal cells, IPSCs were evoked by electrical stimulation of most of these distal regions with the exception of the molecular layer of dentate gyrus, which evoked an IPSC only in LM interneurons. 3. Frequent (> 0.1 Hz) stimulation depressed the evoked IPSCs. With a paired-pulse protocol, the second IPSC was depressed and the maximal depression (40-50%) was observed with an interstimulus interval of 100-200 ms. 4. The GABAB receptor agonist baclofen (1 microM) reduced the amplitude of evoked IPSCs and the paired-pulse depression of the second IPSC. The GABAB receptor antagonist CGP35348 (0.5-1 mM) had no significant effect on the amplitude of isolated IPSCs. However, CGP35348 reduced but did not fully block paired-pulse depression, suggesting that this depression is partly due to the activation of presynaptic GABAB receptors. 5. The paired-pulse depression depended on the level of transmitter release. Potentiation of synaptic release of GABA, by increasing the extracellular Ca2+ concentration to 4 mM and reducing the extracellular Mg2+ concentration to 0.1 mM, enhanced the depression. Reduction of transmitter release by increasing extracellular Mg2+ concentration to 7 mM diminished the paired-pulse depression of IPSCs. After potentiation of transmitter release, CGP35348 was less efficient in reducing the paired-pulse depression, suggesting that enhancement of depression by high-calcium/low-magnesium medium was preferentially due to the potentiation of a GABAB-independent component. 6. In summary, monosynaptic IPSCs recorded in LM interneurons show similar features to those recorded in pyramidal cells. The strong correlation between the level of transmitter release and the degree of paired-pulse depression may have important physiological consequences, because in synapses with a high level of activity and a high level of GABA release, inhibition is powerful, but depression can develop more readily.

Physiological Unmasking of New Glutamatergic Pathways in the Dentate Gyrus of Hippocampal Slices From Kainate-Induced Epileptic Rats

1998 ◽  
Vol 79 (1) ◽  
pp. 418-429 ◽  
Author(s):  
Peter R. Patrylo ◽  
F. Edward Dudek
Keyword(s):  
Dentate Gyrus ◽  
Receptor Antagonist ◽  
Granule Cells ◽  
Mossy Fiber ◽  
Hippocampal Slices ◽  
Receptor Activation ◽  
Field Potentials ◽  
Mossy Fiber Sprouting ◽  
Glutamatergic Pathways ◽  
Abnormal Events

Patrylo, Peter R. and F. Edward Dudek. Physiological unmasking of new glutamatergic pathways in the dentate gyrus of hippocampal slices from kainate-induced epileptic rats. J. Neurophysiol. 79: 418–429, 1998. In humans with temporal lobe epilepsy and kainate-treated rats, the mossy fibers of the dentate granule cells send collateral axons into the inner molecular layer. Prior investigations on kainate-treated rats demonstrated that abnormal hilar-evoked events can occasionally be observed in slices with mossy fiber sprouting when γ-aminobutyric acid-A (GABAA)–mediated inhibition is blocked with bicuculline. However, these abnormalities were observed infrequently, and it was unknown whether these rats were epileptic. Wuarin and Dudek reported that in slices from kainate-induced epileptic rats (3–13 mo after treatment), hilar stimulation evoked abnormal events in most slices with mossy fiber sprouting exposed simultaneously to bicuculline and elevated extracellular potassium concentration [K+]o. Using the same rats, extracellular recordings were obtained from granule cells in hippocampal slices to determine whether 1) hilar stimulation could evoke abnormal events in slices with sprouting in normal artificial cerebrospinal fluid (ACSF), 2) adding only bicuculline could unmask hilar-evoked abnormalities and glutamate-receptor antagonists could block these events, and 3) increasing only [K+]o could unmask these abnormalities. In normal ACSF, hilar stimulation evoked abnormal field potentials in 27% of slices with sprouting versus controls without sprouting (i.e., saline-treated or only 2–4 days after kainate treatment). In bicuculline (10 μM) alone, hilar stimulation triggered prolonged field potentials in 84% of slices with sprouting, but not in slices from the two control groups. Addition of the N-methyl-d-aspartate (NMDA) receptor antagonist, dl-2-amino-5-phosphonopentanoic acid (AP5), either blocked the bursts or reduced their probability of occurrence. The α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX), always eliminated the epileptiform bursts. In kainate-treated rats with sprouting, but not in saline-treated controls, abnormal hilar-evoked responses were also revealed in 6–9 mM [K+]o. Additionally, 63% of slices with sprouting generated spontaneous bursts lasting 1–40 s in ACSF containing 9 mm [K+]o; similar bursts were not observed in controls. These results indicate that 1) mossy fiber sprouting is associated with new glutamatergic pathways, and although NMDA receptors are important for propagation through these circuits, AMPA receptor activation is crucial, 2) modest elevations of [K+]o, in a range that would have relatively little effect on granule cells, can unmask these new excitatory circuits and generate epileptiform bursts, and 3) this new circuitry underlies an increased electrographic seizure susceptibility when inhibition is depressed or membrane excitability is increased.

Evidence for common expression mechanisms underlying heterosynaptic and associative long-term depression in the dentate gyrus

1995 ◽  
Vol 74 (3) ◽  
pp. 1244-1247 ◽  
Author(s):  
B. R. Christie ◽  
D. Stellwagen ◽  
W. C. Abraham
Keyword(s):  
Dentate Gyrus ◽  
High Frequency ◽  
Granule Cells ◽  
Perforant Path ◽  
Long Term Depression ◽  
Anesthetized Rats ◽  
Data Support ◽  
Activity Dependent ◽  
Stimulation Of

1. The extent to which heterosynaptic and prime-associative stimulation protocols generate different forms of long-term depression (LTD) was assessed in the lateral perforant path synapses terminating on dentate gyrus granule cells in pentobarbital-anesthetized rats. 2. Heterosynaptic LTD was induced in the lateral path by repeated tetanization of the medial path. Prime-associative LTD of the lateral path was induced by alternating high-frequency conditioning trains to the medial path and single shocks to the lateral path at 100-ms intervals, all occurring 10 min after priming stimulation of the lateral path (5 Hz, 80 pulses). 3. Induction of LTD by one administration of the prime-associative protocol was normally greater in magnitude than the LTD induced by the heterosynaptic protocol. Saturation of LTD by repeated delivery of the prime-associative protocol completely occluded the subsequent induction of LTD by the heterosynaptic protocol. Saturation of LTD by repeated delivery of the heterosynaptic protocol produced an 80% occlusion of the LTD generated by the prime-associative protocol. 4. These data support the hypothesis that activity-dependent (associative) and activity-independent (heterosynaptic) LTD involve overlapping expression mechanisms, despite having demonstrably different induction mechanisms.

Properties of Unitary IPSCs in Hippocampal Pyramidal Cells Originating From Different Types of Interneurons in Young Rats

1997 ◽  
Vol 77 (4) ◽  
pp. 1939-1949 ◽  
Author(s):  
Mohamed Ouardouz ◽  
Jean-Claude Lacaille
Keyword(s):  
Reversal Potential ◽  
Pyramidal Cells ◽  
Mean Amplitude ◽  
Paired Pulse ◽  
Young Rats ◽  
Different Types ◽  
The Mean ◽  
Paired Pulse Depression ◽  
Types Of Interneurons ◽  
Stimulation Of

Ouardouz, Mohamed and Jean-Claude Lacaille. Properties of unitary IPSCs in hippocampal pyramidal cells originating from different types of interneurons in young rats. J. Neurophysiol. 77: 1939–1949, 1997. Whole cell recordings were used in hippocampal slices of young rats to examine unitary inhibitory postsynaptic currents (uIPSCs) evoked in CA1 pyramidal cells at room temperature. Loose cell-attached stimulation was applied to activate single interneurons of different subtypes located in stratum oriens (OR), near stratum pyramidale (PYR), and at the border of stratum radiatum and lacunosum-moleculare (LM). uIPSCs evoked by stimulation of PYR and OR interneurons had similar onset latency, rise time, peak amplitude, and decay. In contrast, uIPSCs elicited by activation of LM interneurons were significantly smaller in amplitude and had a slower time course. The mean reversal potential of uIPSCs was −53.1 ± 2.1 (SE) mV during recordings with intracellular solution containing potassium gluconate. With the use of recording solution containing the potassium channel blocker cesium, the reversal potential of uIPSCs was not significantly different (−58.5 ± 2.6 mV), suggesting that these synaptic currents were not mediated by potassium conductances. Bath application of the γ-aminobutyric acid-A (GABAA) receptor antagonist bicuculline (25 μM) reversibly blocked uIPSCs evoked by stimulation of all interneuron subtypes. In bicuculline, the mean peak amplitude of uIPSCs recorded with potassium gluconate was reduced to 3.5 ± 4.4% of control ( n = 7). Similarly, with cesium methanesulfonate, the mean amplitude in bicuculline was 2.9 ± 3.1% of control ( n = 13). Application of the GABAB receptor antagonist CGP 55845A (5 μM) resulted in a significant and reversible increase in the mean amplitude of uIPSCs recorded with cesium-containing intracellular solution. Thus uIPSCs from all cell types appeared under tonic presynaptic inhibition by GABAB receptors. Paired stimulation of individual interneurons at 100- to 200-ms intervals did not result in paired pulse depression of uIPSCs. For individual responses, a significant negative correlation was observed between the amplitude of the first and second uIPSCs. A significant paired pulse facilitation (154.0 ± 8.0%) was observed when the first uIPSC was smaller than the mean of all first uIPSCs. A small, but not significant, paired pulse depression (90.8 ± 4.0%) was found when the first uIPSC was larger than the mean of all first uIPSCs. Our results indicate that these different subtypes of hippocampal interneurons generate Cl−-mediated GABAA uIPSCs. uIPSCs originating from different types of interneurons may have heterogeneous properties and may be subject to tonic presynaptic inhibition via heterosynaptic GABAB receptors. These results suggest a specialization of function for inhibitory interneurons and point to complex presynaptic modulation of interneuron function.

scholarly journals Regionally Localized Recurrent Excitation in the Dentate Gyrus of a Cortical Contusion Model of Posttraumatic Epilepsy

2010 ◽  
Vol 103 (3) ◽  
pp. 1490-1500 ◽  
Author(s):  
Robert F. Hunt ◽  
Stephen W. Scheff ◽  
Bret N. Smith
Keyword(s):  
Head Injury ◽  
Dentate Gyrus ◽  
Action Potentials ◽  
Granule Cells ◽  
Mossy Fiber ◽  
Granule Cell Layer ◽  
Mossy Fiber Sprouting ◽  
Posttraumatic Epilepsy ◽  
Dentate Granule Cells ◽  
Cortical Contusion

Posttraumatic epilepsy is a frequent consequence of brain trauma, but relatively little is known about how neuronal circuits are chronically altered after closed head injury. We examined whether local recurrent excitatory synaptic connections form between dentate granule cells in mice 8–12 wk after cortical contusion injury. Mice were monitored for behavioral seizures shortly after brain injury and ≤10 wk postinjury. Injury-induced seizures were observed in 15% of mice, and spontaneous seizures were observed weeks later in 40% of mice. Timm's staining revealed mossy fiber sprouting into the inner molecular layer of the dorsal dentate gyrus ipsilateral to the injury in 95% of mice but not contralateral to the injury or in uninjured controls. Whole cell patch-clamp recordings were made from granule cells in isolated hippocampal brain slices. Cells in slices with posttraumatic mossy fiber sprouting had an increased excitatory postsynaptic current (EPSC) frequency compared with cells in slices without sprouting from injured and control animals ( P < 0.001). When perfused with Mg2+-free artificial cerebrospinal fluid containing 100 μM picrotoxin, these cells had spontaneous bursts of EPSCs and action potentials. Focal glutamate photostimulation of the granule cell layer evoked a burst of EPSCs and action potentials indicative of recurrent excitatory connections in granule cells of slices with mossy fiber sprouting. In granule cells of slices without sprouting from injured animals and controls, spontaneous or photostimulation-evoked epileptiform activity was never observed. These results suggest that a new regionally localized excitatory network forms between dentate granule cells near the injury site within weeks after cortical contusion head injury.

scholarly journals Heterosynaptic NMDA Receptor Plasticity in Hippocampal Dentate Granule Cells

2022 ◽  
Author(s):  
Alma Rodenas-Ruano ◽  
Kaoutsar Nasrallah ◽  
Stefano Lutzu ◽  
Maryann Castillo ◽  
Pablo E. Castillo
Keyword(s):  
Dentate Gyrus ◽  
Entorhinal Cortex ◽  
Information Transfer ◽  
Granule Cells ◽  
Hippocampal Slices ◽  
Dentate Granule Cells ◽  
Hippocampus Proper ◽  
Receptor Plasticity ◽  
Activity Dependent

The dentate gyrus is a key relay station that controls information transfer from the entorhinal cortex to the hippocampus proper. This process heavily relies on dendritic integration by dentate granule cells (GCs) of excitatory synaptic inputs from medial and lateral entorhinal cortex via medial and lateral perforant paths (MPP and LPP, respectively). N-methyl-D-aspartate receptors (NMDARs) can contribute significantly to the integrative properties of neurons. While early studies reported that excitatory inputs from entorhinal cortex onto GCs can undergo activity-dependent long-term plasticity of NMDAR-mediated transmission, the input-specificity of this plasticity along the dendritic axis remains unknown. Here, we examined the NMDAR plasticity rules at MPP-GC and LPP-GC synapses using physiologically relevant patterns of stimulation in acute rat hippocampal slices. We found that MPP-GC, but not LPP-GC synapses, expressed homosynaptic NMDAR-LTP. In addition, induction of NMDAR-LTP at MPP-GC synapses heterosynaptically potentiated distal LPP-GC NMDAR plasticity. The same stimulation protocol induced homosynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-LTP at MPP-GC but heterosynaptic AMPAR-LTD at distal LPP synapses, demonstrating that NMDAR and AMPAR are governed by different plasticity rules. Remarkably, heterosynaptic but not homosynaptic NMDAR-LTP required Ca2+ release from intracellular, ryanodine-dependent Ca2+ stores. Lastly, the induction and maintenance of both homo- and heterosynaptic NMDAR-LTP were blocked by GluN2D antagonism, suggesting the recruitment of GluN2D-containing receptors to the synapse. Our findings uncover a mechanism by which distinct inputs to the dentate gyrus may interact functionally and contribute to hippocampal-dependent memory formation.

scholarly journals Ontogenesis of Presynaptic GABAB Receptor-Mediated Inhibition in the CA3 Region of the Rat Hippocampus

1998 ◽  
Vol 79 (3) ◽  
pp. 1341-1348 ◽  
Author(s):  
Olivier Caillard ◽  
Heather A. McLean ◽  
Yehezkel Ben-Ari ◽  
Jean-Luc Gaïarsa
Keyword(s):  
Pyramidal Neurons ◽  
Gabab Receptor ◽  
Hippocampal Slices ◽  
Reversal Potential ◽  
Rat Hippocampus ◽  
Dependent Manner ◽  
Paired Pulse ◽  
Ca3 Pyramidal Neurons ◽  
Paired Pulse Depression ◽  
Ca3 Region

Caillard, Olivier, Heather A. McLean, Yehezkel Ben-Ari, and Jean-Luc Gaı̈arsa. Ontogenesis of presynaptic GABAB receptor-mediated inhibition in the CA3 region of the rat hippocampus. J. Neurophysiol. 79: 1341–1348, 1998. γ-Aminobutyric acid-B(GABAB) receptor-dependent and -independent components of paired-pulse depression (PPD) were investigated in the rat CA3 hippocampal region. Intracellular and whole cell recordings of CA3 pyramidal neurons were performed on hippocampal slices obtained from neonatal (5–7 day old) and adult (27–34 day old) rats. Electrical stimulation in the hilus evoked monosynaptic GABAA postsynaptic currents (eIPSCs) isolated in the presence of the ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 μM) and d(−)2-amino-5-phosphovaleric acid (d-AP5, 50 μM) with 2(triethylamino)- N-(2,6-dimethylphenyl) acetamine (QX314) filled electrodes. In adult CA3 pyramidal neurons, when a pair of identical stimuli was applied at interstimulus intervals (ISIs) ranging from 50 to 1,500 ms the amplitude of the second eIPSC was depressed when compared with the first eIPSC. This paired-pulse depression (PPD) was partially blockedb y  P - 3 - a m i n o p r o p y l - P - d i e t h o x y m e t h y l  p h o s p h o r i c  a c i d(CGP35348, 0.5 mM), a selective GABAB receptor antagonist. In neonates, PPD was restricted to ISIs shorter than 200 ms and was not affected by CGP35348. The GABAB receptor agonist baclofen reduced the amplitude of eIPSCs in a dose-dependent manner with the same efficiency in both adults and neonates. Increasing the probability of transmitter release with high Ca2+ (4 mM)/low Mg2+ (0.3 mM) external solution revealed PPD in neonatal CA3 pyramidal neurons that was 1) partially prevented by CGP35348, 2) independent of the membrane holding potential of the recorded cell, and 3) not resulting from a change in the reversal potential of GABAA eIPSCs. In adults the GABA uptake blocker tiagabine (20 μM) increased the duration of eIPSCs and the magnitude of GABAB receptor-dependent PPD. In neonates, tiagabine also increased duration of eIPSCs but to a lesser extent than in adult and did not reveal a GABAB receptor-dependent PPD. These results demonstrate that although GABAB receptor-dependent and -independent mechanisms of presynaptic inhibition are present onGABAergic terminals and functional, they do not operate at the level of monosynaptic GABAergic synaptic transmission at early stages of development. Absence of presynaptic autoinhibition of GABA release seems to be due to the small amount of transmitter that can access presynaptic regulatory sites.

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