Duration Of Excitatory Postsynaptic Potentials Research Articles

P23-F Re-examining the origin of medium latency reflex response of soleus using single motor units

Background This study is inquiring the origin of the medium latency reflex response (MLR) that occurs in soleus muscle when common peroneal nerve is electrically stimulated. Material and methods In total, 23 SingleMUs from 9 males were obtained. During SMU recruitment, 308 ± 141 stimuli were delivered. We investigated the duration of the inhibitory postsynaptic potential (IPSP) and excitatory postsynaptic potential (EPSP). Results Common peroneal nerve stimulation resulted in M-response at SEMG of TA muscle and MLR in SOL-SEMG as well as accumulation of SMUs between 50 and 120 ms after the stimulus. A reduction in firing probability of SMUs was also observed and the reduction in discharge rate continued much longer than the spike reduction probability in PSTH and CUSUM. This reduction in discharge rate was followed by an increased discharge rate of SMUs. Duration of the IPSP obtained at PSF, 24.5 ± 6.3 ms, and the duration of EPSP, i.e. MLR, in PSF was found as 119.3 ± 54.3 The latency of EPSP was found higher in PSF and SEMG as 68.3 ± 9.9 ms and 74.5 ± 9.7 ms, than PSTH and MMU which were 56.3 ± 4.6 ms and 57.6 ± 4.2 ms, respectively. Conclusions There was a genuine Ia reciprocal inhibition followed by a stretch-induced reflex response in the SOL. The first response was due to the well-known Ia-IPSP pathway connecting antagonist muscles and the second response, the so-called MLR in the literature, was an indirect stretch reflex response caused by the M-response in the TA muscle. This Project (3135) was supported by Akdeniz University Scientific Research Unit .

Postpartum estrogen withdrawal impairs GABAergic inhibition and LTD induction in basolateral amygdala complex via down-regulation of GPR30

Postpartum estrogen (E2) withdrawal is known to be a particularly vulnerable time for depressive symptoms. In this study, ovariectomized (OVX) mice were treated with co-administration of estradiol benzoate and progesterone (E2/P4) followed by administration of E2 alone (E2) and a subsequent E2 withdrawal (EW) to mimic the hormonal changes during pregnancy and postpartum. The objective of this study was to investigate the influence of E2 withdrawal after hormone-simulated pregnancy on synaptic function and plasticity in basolateral amygdala complex (BLA). In comparison to control mice, EW mice spent less time in the central portion of open-field test and open arms of elevated plus-maze. Excitatory postsynaptic potentials (EPSPs) slopes at external capsule BLA synapse were reduced in E2/P4-mice, recovered in E2-mice, and increased in EW-mice. EW-mice showed a significant increase in duration of EPSPs and paired-pulse inhibition (PPI) with multi-spike responses of EPSPs and impairment of long-term depression (LTD) induction, which were corrected by GABAAR agonist muscimol. Levels of estrogen receptor (ER) GPR30, ERα and ERβ expression in BLA of EW-mice were lower than those in control mice. The bath-application of GPR30 agonist G-1 in BLA of EW-mice recovered the GABAAR-mediated inhibition and LTD indication, but ERβ agonist DPN or ERα agonist PPT could not. A single BLA-injection of G-1 rather than DPN or PPT in EW-mice could partially relieve the anxiety-like behaviors. The results indicate that postpartum E2 withdrawal causes dysfunction of GABAAR-mediated inhibition in the BLA through reducing GPR30 expression, which impairs LTD induction and causes anxiety-like behaviors.

Near-Perfect Synaptic Integration by Nav1.7 in Hypothalamic Neurons Regulates Body Weight

SummaryNeurons are well suited for computations on millisecond timescales, but some neuronal circuits set behavioral states over long time periods, such as those involved in energy homeostasis. We found that multiple types of hypothalamic neurons, including those that oppositely regulate body weight, are specialized as near-perfect synaptic integrators that summate inputs over extended timescales. Excitatory postsynaptic potentials (EPSPs) are greatly prolonged, outlasting the neuronal membrane time-constant up to 10-fold. This is due to the voltage-gated sodium channel Nav1.7 (Scn9a), previously associated with pain-sensation but not synaptic integration. Scn9a deletion in AGRP, POMC, or paraventricular hypothalamic neurons reduced EPSP duration, synaptic integration, and altered body weight in mice. In vivo whole-cell recordings in the hypothalamus confirmed near-perfect synaptic integration. These experiments show that integration of synaptic inputs over time by Nav1.7 is critical for body weight regulation and reveal a mechanism for synaptic control of circuits regulating long term homeostatic functions.

The role of hyperpolarization‐activated cationic current in spike‐time precision and intrinsic resonance in cortical neurons in vitro

Hyperpolarization-activated cyclic nucleotide modulated current (I(h)) sets resonance frequency within the θ-range (5–12 Hz) in pyramidal neurons. However, its precise contribution to the temporal fidelity of spike generation in response to stimulation of excitatory or inhibitory synapses remains unclear. In conditions where pharmacological blockade of I(h) does not affect synaptic transmission, we show that postsynaptic h-channels improve spike time precision in CA1 pyramidal neurons through two main mechanisms. I(h) enhances precision of excitatory postsynaptic potential (EPSP)--spike coupling because I(h) reduces peak EPSP duration. I(h) improves the precision of rebound spiking following inhibitory postsynaptic potentials (IPSPs) in CA1 pyramidal neurons and sets pacemaker activity in stratum oriens interneurons because I(h) accelerates the decay of both IPSPs and after-hyperpolarizing potentials (AHPs). The contribution of h-channels to intrinsic resonance and EPSP waveform was comparatively much smaller in CA3 pyramidal neurons. Our results indicate that the elementary mechanisms by which postsynaptic h-channels control fidelity of spike timing at the scale of individual neurons may account for the decreased theta-activity observed in hippocampal and neocortical networks when h-channel activity is pharmacologically reduced.

Respiratory drive to thoracic motoneurones

The paper by Saywell et al. (2007) in this issue of The Journal of Physiology provides a detailed study of the projection of the expiratory bulbospinal neurones to identified thoracic motoneurones in the anaesthetized cat. The importance of the paper lies first in its clarification of the debate regarding the strength of the monosynaptic excitation from this pathway and secondly, the deduction of the significance of the pathway in driving natural rhythmic motoneurone firing. The methods developed and the conclusions derived are relevant not only to the special case of respiration, but also to the more general consideration of the part played by particular sources of excitation in generating motoneurone firing patterns in other systems. It has long been known that both the inspiratory and the expiratory phases of breathing are dependent on activity in groups of cells in the hindbrain (Pitts et al. 1939). The most extensively studied group are in the nucleus retroambigualis and their output is carried to various motoneurones involved in respiration via crossed bulbospinal fibres. Previous studies have indicated that both phrenic and inspiratory intercostal motoneurones receive monosynaptic excitation from this source, but probably depend to a large degree on multisynaptic connections for their natural firing pattern (Davies et al. 1985). The relative contributions of mono- and multisynaptic connections to expiratory motoneurones, on the other hand, have not been clear. Using intracellular spike-triggered averaging (STA) from expiratory bulbospinal neurones (EBSNs) to internal intercostal motoneurones Merrill & Lipski (1987) found only very few and weak monosynaptic excitatory postsynaptic potentials (EPSPs), which could account for neither the rhythmic motoneurone firing nor the observed central respiratory drive potentials (CRDPs). Cross-correlation of EBSN spikes with expiratory nerve filaments also rarely showed the short duration peak expected for a monosynaptic connection. It was surprising therefore that when a spike correlation study was repeated by Kirkwood (1995) most EBSN neurones showed clear evidence of monosynaptic projection, which was estimated to be producing most of the depolarization required to drive the rhythmic firing of the expiratory motoneurones. A valuable review of this background was provided by Kirkwood et al. (1999) together with preliminary data now reported in detail. This new study has confirmed, by intracellular STA, the presence of a potent monosynaptic connection, especially to expiratory neurones with their axons in the internal intercostal nerves. Computations, taking account of directly measured EPSP duration and amplitude and reasonable estimates of numbers of EBSNs and of their firing frequencies, indicate that the sum of the unitary EPSPs could account for the observed CRDPs. Indeed the data imply a projection at least 10 times as strong as that found by Merrill & Lipski (1987). Of course the question arises as to how there can be such a disparity in data from basically similar experiments. Factors such as bias in selection of motoneurone types, rostral or caudal recording sites in a segment or variation according to the part of the thorax supplied were all considered but rejected. A final possibility arises from the observation of a correlation between EPSP size and CRDP amplitude, which suggests that some state-dependent modulation in EPSP amplitude may vary between different preparations, for example as a result of differing anaesthesia. Although the same agent (pentobarbitone) was employed in both cases, Saywell et al. (2007) appear to have controlled the dosage to give a lighter level. Nevertheless, this seems unlikely to be a very important factor and other causes should be considered. It is worth recalling the observations of Nelson et al. (1979) showing acute increases in Ia EPSP amplitudes following spinal transection. The mechanism of such state-dependent modulation is not considered, but two factors might be examined in future work. There could well be a presynaptic inhibitory mechanism involved (see Rudomin & Schmidt, 1999) which could vary due to small differences in the preparation. Also, the incidence of failures of transmission (Grimwood et al. 1992) could differ according to the condition of the animal. It is interesting to speculate as to the functional significance of a potentially strong monosynaptic EBSN projection to expiratory motoneurones. We have come to associate monosynaptic descending control with the need for precision, as in hand movements in primates. Perhaps similar precision may be required in some expiratory movements such as vocalization (Sears, 1977), though cats are not noted for their musical skills. The more serious message is the importance of detailed quantitative studies, such as reported by Saywell et al. (2007) in establishing the relative significance for normal function of various neural projections, which are generally only established qualitatively.

Dopaminergic Modulation of Short-Term Synaptic Plasticity in Fast-Spiking Interneurons of Primate Dorsolateral Prefrontal Cortex

Dopaminergic regulation of primate dorsolateral prefrontal cortex (PFC) activity is essential for cognitive functions such as working memory. However, the cellular mechanisms of dopamine neuromodulation in PFC are not well understood. We have studied the effects of dopamine receptor activation during persistent stimulation of excitatory inputs onto fast-spiking GABAergic interneurons in monkey PFC. Stimulation at 20 Hz induced short-term excitatory postsynaptic potential (EPSP) depression. The D1 receptor agonist SKF81297 (5 microM) significantly reduced the amplitude of the first EPSP but not of subsequent responses in EPSP trains, which still displayed significant depression. Dopamine (DA; 10 microM) effects were similar to those of SKF81297 and were abolished by the D1 antagonist SCH23390 (5 microM), indicating a D1 receptor-mediated effect. DA did not alter miniature excitatory postsynaptic currents, suggesting that its effects were activity dependent and presynaptic action potential dependent. In contrast to previous findings in pyramidal neurons, in fast-spiking cells, contribution of N-methyl-D-aspartate receptors to EPSPs at subthreshold potentials was not significant and fast-spiking cell depolarization decreased EPSP duration. In addition, DA had no significant effects on temporal summation. The selective decrease in the amplitude of the first EPSP in trains delivered every 10 s suggests that in fast-spiking neurons, DA reduces the amplitude of EPSPs evoked at low frequency but not of EPSPs evoked by repetitive stimulation. DA may therefore improve detection of EPSP bursts above background synaptic activity. EPSP bursts displaying short-term depression may transmit spike-timing-dependent temporal codes contained in presynaptic spike trains. Thus DA neuromodulation may increase the signal-to-noise ratio at fast-spiking cell inputs.

Electrophysiological alterations in subthalamic neurons after unilateral dopamine depletion in the rat

The present study examined the effects of unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc) on electrophysiological properties of subthalamic neurons (STN) in adult rats. Most neurons displayed regular spontaneous tonic firing patterns in both control and lesioned animals; however, the percentage of neurons with spontaneous burst firing at hyperpolarized membrane potentials was increased significantly in lesioned animals compared with controls (45% vs. 14% respectively). In the presence of bicuculline, a gamma-aminobutyric acid type A (GABAA) receptor antagonist, electrical stimulation of the internal capsule produced monosynaptic excitatory postsynaptic potentials (EPSPs) in almost all recorded neurons. DA (50 microM) increased the amplitude and/or duration of the EPSPs in neurons from both groups, whereas the DA D1 receptor agonist SKF 81297 (10 microM) produced a significant increase in amplitude and/or duration of EPSPs in neurons from the lesioned group only. This latter increase was blocked by pretreatment with the DA D1 antagonist SCH 23390 (10 microM). These data suggest that unilateral degeneration of DA neurons in the SNc changes firing properties and enhances electrophysiological responsiveness of STN neurons to activation of DA D1 receptors.

Asymmetric integration recorded from vestibular-only cells in response to position transients.

Angular and translational accelerations excite the semicircular canals and otolith organs, respectively. While canal afferents approximately encode head angular velocity due to the biomechanical integration performed by the canals, otolith signals have been found to approximate head translational acceleration. Because central vestibular pathways require velocity and position signals for their operation, the question has been raised as to how the integration of the otolith signals is accomplished. We recorded responses from 62 vestibular-only neurons in the vestibular nucleus of two monkeys to position transients in the naso-occipital and interaural orientations and varying directions in between. Responses to the transients were directionally asymmetric; one direction elicited a response that approximated the integral of the acceleration of the stimulus. In the opposite direction, the cells simply encoded the acceleration of the motion. We present a model that suggests that a neural integrator is not needed. Instead a neuron with a long membrane time constant and an excitatory postsynaptic potential duration that increases with the firing rate of the presynaptic cell can emulate the observed behavior.

Inhibitor of glutamate transport alters synaptic transmission at sensorimotor synapses in Aplysia.

Aplysia sensory neurons possess high-affinity glutamate uptake activity that is regulated by serotonin. To gain insight into the physiological role of glutamate uptake in sensory neurons, we examined whether blockade of glutamate transport altered synaptic transmission. We also examined whether glutamate transport affected homosynaptic depression and posttetanic potentiation (PTP). In the presence of DL-threo-beta-hydroxyaspartic acid (THA), previously shown to block glutamate uptake in Aplysia, the duration of unitary excitatory postsynaptic potentials (EPSPs) was significantly increased and their amplitude was significantly reduced. Similar effects were observed in the properties of summated EPSPs. However, no effect on the induction of homosynaptic depression or PTP was observed. Although it is unclear whether THA exerted its effect by modulating neuronal and/or glial mechanisms, at least one target of THA was neuronal, as the duration of unitary EPSPs measured in cultured sensorimotor synapses was also increased in the presence of THA. These results support the hypotheses that glutamate is the transmitter released by the sensory neurons and that glutamate transport plays an important role in regulating features of synaptic transmission in Aplysia.

Nicotine exposure during a postnatal critical period alters NR2A and NR2B mRNA expression in rat auditory forebrain

Chronic nicotine exposure (CNE) can alter brain development and is thought to produce deficits in auditory function. Previously, we found that CNE during the second postnatal week, but not before or after, increases the duration of excitatory postsynaptic potentials (EPSPs) mediated by N-methyl- d-aspartate receptors (NMDARs) in rat auditory cortex. It was proposed that a potential mechanism underlying increased EPSP duration could be over-stimulation of presynaptic nicotinic acetylcholine receptors, leading to prolonged glutamate release. Since glutamatergic activity regulates levels of postsynaptic NMDAR subunits, here we examine the effects of CNE on mRNA expression for the NR2A and NR2B subunits in auditory cortex and thalamus. Two days of CNE (postnatal days 8–9), produced no effects, but 5 days (postnatal days 8–12) enhanced cortical NR2A mRNA levels and reduced thalamic NR2B mRNA levels for up to 2 weeks. These effects are consistent with the hypothesis that CNE during a postnatal critical period disrupts auditory cortex development by over-stimulating glutamatergic synapses.

Cellular abnormalities and synaptic plasticity in seizure disorders of the immature nervous system.

The nervous system has an enhanced capacity to generate seizures during a restricted phase of postnatal development. Studies in animals and particularly in in vitro brain slices from hippocampus and neocortex have been instrumental in furthering an understanding of the underlying processes. Developmental alterations in glutaminergic excitatory synaptic transmission appear to play a key role in the enhanced seizure susceptible of rodents during the second and third week of life. Prior to this period, the number of excitatory synapses is relatively low. The scarcity of connections and the inability of the existing synapses to release glutamate when activated at high frequencies likely contribute importantly to the resistance of neonates to seizures. However, at the beginning of week 2, a dramatic outgrowth of excitatory synapses occurs, and these synapses are able to faithfully follow activation at high frequencies. These changes, coupled with the prolonged nature of synaptic potentials in early life, likely contribute to the ease of seizure generation. After this time, seizure susceptibility declines, patterns of local synaptic connectivity remodel, and some synapses are pruned. Concurrently, the duration of excitatory postsynaptic potentials shortens due at least in part to a switch in the subunit composition of postsynaptic receptors. Other studies have examined the mechanisms underlying chronic epilepsy initiated in early life. Models of both cortical dysplasia and recurrent early-life seizures suggest that alterations in the normal development of excitatory synaptic transmission can contribute importantly to chronic epileptic conditions. In the recurrent early-life seizure model, abnormal use-dependent selection of subpopulations of excitatory synapses may play a role. In experimental cortical dysplasia, alterations in the molecular composition of postsynaptic receptor are observed that favor subunit combinations characteristic of infancy.

Postsynaptic Glutamate Receptors and Integrative Properties of Fast-Spiking Interneurons in the Rat Neocortex

The glutamate-mediated synaptic responses of neocortical pyramidal cell to fast-spiking interneuron (pyramidal-FS) connections were studied by performing paired recordings at 30-33 degrees C in acute slices of 14- to 35-day-old rats (n = 39). Postsynaptic fast-spiking (FS) cells were recorded in whole cell configuration with a patch pipette, and presynaptic pyramidal cells were impaled with sharp intracellular electrodes. At a holding potential of -72 mV (near the resting membrane potential), unitary excitatory postsynaptic potentials (EPSPs) had a mean amplitude of 2.1 +/- 1.3 mV and a mean width at half-amplitude of 10.5 +/- 3.7 ms (n = 18). Bath application of the N-methyl-D-aspartate (NMDA) receptor antagonist D(-)2-amino-5-phosphonovaleric acid (D-AP5) had minor effects on both the amplitude and the duration of unitary EPSPs, whereas the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA)/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) almost completely blocked the synaptic responses. In voltage-clamp mode, the selective antagonist of AMPA receptors 1-(4-aminophenyl)-3-methylcarbamyl-4-methyl-7,8-methylenedioxy-3, 4-dihydro-5H-2,3-benzodiazepine (GYKI 53655; 40-66 microM) blocked 96 +/- 1.9% of D-AP5-insensitive unitary excitatory postsynaptic currents (EPSCs), confirming the predominance of AMPA receptors, as opposed to kainate receptors, at pyramidal-FS connections (n = 3). Unitary EPSCs mediated by AMPA receptors had fast rise times (0.29 +/- 0.04 ms) and amplitude-weighted decay time constants (2 +/- 0.8 ms; n = 16). In the presence of intracellular spermine, these currents showed the characteristic rectifying current-voltage (I-V) curve of calcium-permeable AMPA receptors. A slower component mediated by NMDA receptors was observed when unitary synaptic currents were recorded at a membrane potential more positive than -50 mV. In response to short trains of moderately high-frequency (67 Hz) presynaptic action potentials, we observed only a limited temporal summation of unitary EPSPs, probably because of the rapid kinetics of AMPA receptors and the absence of NMDA component in these subthreshold synaptic responses. By combining paired recordings with extracellular stimulations (n = 11), we demonstrated that EPSPs elicited by two different inputs were summed linearly by FS interneurons at membrane potentials below the action potential threshold. We estimated that, in our in vitro recording conditions, 8 +/- 5 pyramidal cells (n = 18) should be activated simultaneously to make FS interneurons fire an action potential from -72 mV. The low level of temporal summation and the linear summation of excitatory inputs in FS cells favor the role of coincidence detectors of these interneurons in neocortical circuits.

Long-term changes of ionotropic glutamate and GABA receptors after unilateral permanent focal cerebral ischemia in the mouse brain

Long-term hyperexcitability was found after unilateral, permanent middle cerebral artery occlusion in exofocal neocortical areas of the adult mouse [Mittmann et al. (1998) Neuroscience 85, 15–27]. The aim of the present study was to test the hypothesis in an identical paradigm of ischemia, whether alterations in the densities of both excitatory and inhibitory amino acid receptors may underlie these pathophysiological changes. Alterations in densities of [ 3H]dizocilpine, [ 3H] d, l- α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, [ 3H]kainate and [ 3H]muscimol binding sites were demonstrated with quantitative in vitro receptor autoradiography. All binding sites were severely reduced in the core of the ischemic lesion. A completely different reaction was found in the exofocal, histologically inconspicous parts of the somatosensory cortex and the more remote neocortical areas of both hemispheres. The [ 3H]muscimol binding sites were significantly reduced four weeks after ischemia in the motor cortex, hindlimb representation area and exofocal parts of the primary and secondary somatosensory cortices of both hemispheres. The focus of the reduction in [ 3H]muscimol binding sites was found in lower layer V and upper layer VI. Contrastingly, the densities of [ 3H]dizocilpine binding sites were found to be increased in these areas, whereas those of [ 3H] d, l- α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and [ 3H]kainate binding sites did not show significant changes. The [ 3H]dizocilpine binding site density increased predominantly in layers III and IV. All binding sites were also reduced in the retrogradely reacting, gliotic part of the ipsilateral ventroposterior thalamic nucleus, whereas the [ 3H] d, l- α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid binding sites were increased in the surround of the ipsilateral nucleus and no changes in binding sites were seen in the whole contralateral nucleus. We conclude that permanent local ischemia leads to a long-term and widespread impairment of the normal balance between binding sites of excitatory and inhibitory neurotransmitter receptors in neocortical areas far away from the focus of the post-ischemic tissue damage. The imbalance comprizes an up-regulation of the [ 3H]dizocilpine binding sites in the ion channels of N-methyl- d-aspartate receptors and a down-regulation of [ 3H]muscimol binding sites of the GABA A receptors in the ipsi- and contralateral neocortex. These changes at the receptor level explain the previously observed hyperexcitability with the appearance of epileptiform field potentials and the long duration of excitatory postsynaptic potentials four weeks after ischemia.

Physiological properties of anatomically identified basket and bistratified cells in the CA1 area of the rat hippocampus in vitro.

Basket and bistratified cells form two anatomically distinct classes of GABAergic local-circuit neurons in the CA1 region of the rat hippocampus. A physiological comparison was made of intracellularly recorded basket (n = 13) and bistratified neurons (n = 6), all of which had been anatomically defined by their efferent target profile (Halasy et al., 1996). Basket cells had an average resting membrane potential of -64.2 +/- 7.2 vs. -69.2 +/- 4.6 mV in bistratified cells. The latter had considerably higher mean input resistances (60.2 +/- 42.1 vs. 31.3 +/- 10.9 M Ohms) and longer membrane time constants (18.6 +/- 8.1 vs. 9.8 +/- 4.5 ms) than basket cells. Differences were also apparent in the duration of action potentials, those of basket cells being 364 +/- 77 and those of bistratified cells being 527 +/- 138 microseconds at half-amplitude. Action potentials were generally followed by prominent, fast after-hyperpolarizing potentials which in basket cells were 13.5 +/- 6.7 mV in amplitude vs. 10.5 +/- 5.1 in bistratified cells. The differences in membrane time constant, resting membrane potential, and action potential duration reached statistical significance (P < 0.05). Extracellular stimulation of Schaffer collateral/commissural afferents elicited short-latency excitatory postsynaptic potentials (EPSPs) in both cell types. The average 10-90% rise time and duration (at half-amplitude) of subthreshold EPSPs in basket cells were 1.9 +/- 0.5 and 10.7 +/- 5.6 ms, compared to 3.3 +/- 1.3 and 20.1 +/- 9.7 ms in bistratified cells, the difference in EPSP rise times being statistically significant. Basket and bistratified EPSPs were highly sensitive to a bath applied antagonist of non-N-methyl-D-aspartate (NMDA) receptors, whereas the remaining slow-rise EPSP could be abolished by an NMDA receptor antagonist. Increasing stimulation intensity elicited biphasic inhibitory postsynaptic potentials (IPSPs) in both basket and bistratified cells. In conclusion, basket and bistratified cells in the CA1 area show prominent differences in several of their membrane and firing properties. Both cell classes are activated by Schaffer collateral/commissural axons in a feedforward manner and receive inhibitory input from other, as yet unidentified, local-circuit neurons.

GABA B receptors modulate synaptically-evoked responses in the rat dentate gyrus, in vivo

We assessed the effects of systemically injected baclofen, a GABA B agonist, on single and paired-pulse responses in the dentate gyrus of urethane-anesthetized rats, in vivo. Baclofen (10 mg/kg) significantly increased the duration of single excitatory responses. This increase was blocked by the GABA B receptor antagonist, CGP 35348, indicating that baclofen was acting through GABA B receptors. To determine the mechanism underlying this increase in response duration, the NMDA antagonist, d-2-amino-5-phosphonopentanoic acid ( d-APV), was administered intracerebroventricularly (i.c.v.) after baclofen. d-APV by itself had no effect on the duration of the population excitatory post-synaptic potential (EPSP). However, when infused after baclofen, d-APV blocked the baclofen induced increase in EPSP duration. This indicates the prolonged EPSP duration caused by baclofen resulted from an enhancement of an NMDA receptor mediated component of the response. We then examined the effect of baclofen on population responses to paired stimuli. Baclofen attenuated paired-pulse inhibition of population spike amplitudes at a 25 ms interstimulus interval. CGP-35348 reduced the effect of baclofen on paired-pulse inhibition, indicating that baclofen suppressed paired-pulse inhibition by acting on GABA B receptors. In contrast to its disinhibitory effect at the 25 ms interval, baclofen had an inhibitory effect on responses evoked at a 150 ms interstimulus interval. Under control conditions, we observed that when stimuli were delivered 150 ms apart, both the EPSP duration and population spike amplitude evoked by the second stimulus were enhanced. Baclofen suppressed this enhancement. We conclude that GABA B receptor activation by baclofen reduces short interval inhibition and this reduction of inhibition leads to an enhanced NMDA-receptor mediated response. We also conclude that by reducing inhibition, baclofen occludes paired-pulse disinhibition found at longer interstimulus intervals. In contrast, CGP-35348 directly blocks paired-pulse disinhibition. Thus, GABA B receptor activation can regulate synaptic inhibition, in turn influencing NMDA receptor activation and synaptic transmission. Thus, pharmacologic manipulation of GABA B receptors may provide a powerful approach for regulating synaptic transmission in the hippocampus.

Excitatory synaptic transmission in neostriatal neurons: regulation by cyclic AMP-dependent mechanisms

The purpose of the present study was to examine whether cAMP-dependent mechanisms regulated excitatory synaptic transmission in the neostriatum. A brain slice preparation was utilized for intracellular recordings of the excitatory postsynaptic potentials (EPSPs) evoked by electrical stimulation. Bath application of forskolin, an activator of adenylate cyclase, enhanced the EPSP amplitude and duration. This potentiation was dose dependent and did not occur with the inactive analog 1,9-dideoxyforskolin. Forskolin potentiation was unaltered by treatment with the GABAA receptor antagonist bicuculline. Furthermore, two inhibitors of cAMP-dependent protein kinase (PKA), Rp-cAMPS and IP20-amide, attenuated forskolin's enhancement of the EPSP. In addition, the PKA activator Sp-cAMPS enhanced excitatory synaptic transmission. Interestingly, treatment with PKA inhibitors alone depressed while the phosphatase inhibitor okadaic acid enhanced the synaptic response. These results suggest a role for tonic kinase and phosphatase activity in regulating excitatory synaptic transmission in the neostriatum. Finally, forskolin was found to enhance the responses of neostriatal neurons to glutamate receptor agonists. This potentiation, which occurred in the presence of tetrodotoxin, provides at leas part of the explanation for the cAMP/PKA-dependent regulation of the EPSP. Overall, these results suggest a role for the adenylate cyclase cascade in the regulation of excitatory synaptic transmission in the neostriatum.

Cellular bases for the control of retinogeniculate signal transmission

The dorsal lateral geniculate nucleus (LGN) is the major thalamic relay for retinal signals en route to cortex. However, LGN cells operate as more than just a simple relay of their retinal inputs. Rather, they function as a variable gate, determining what, when, and how much retinal information gets passed to visual cortex. Two factors that are key to this control are the innervation patterns and electrophysiological membrane properties of geniculate cells. This paper discusses three active membrane properties and the manner in which they modulate the transfer of retinal signals to cortex. They are the low threshold calcium (Ca2+) conductance, a transient potassium (K+) conductance, and NMDA receptor-mediated excitatory postsynaptic potentials (EPSPs). The low-threshold Ca2+ conductance transforms a geniculate cell from a state of single spike activity to one of bursting discharge, the potassium current leads to a delay in membrane depolarization to reach spike threshold, and NMDA receptor activity modulates EPSP amplitude and duration near spike threshold. Additionally, we consider how nonretinal inputs, such as the ascending cholinergic pathway from the brainstem parabrachial region and the descending pathway from layer VI of visual cortex, influence the expression of these membrane properties through their control of membrane potential.

Alterations in the properties of hippocampal pyramidal neurons in the aged rat

The electrophysiological and pharmacological properties of CA1 hippocampal pyramidal neurons were studied in slices from young (three to four months) and aged (25–32 months) Sprague-Dawley rats having previously performed two behavioral tasks. About 20% of the aged rats were impaired in either the spontaneous alternation task or the water maze task. Electrophysiological parameters were measured and compared in young and aged animals using intracellular recordings. No age-related differences were observed in membrane potential, input resistance, amplitude of action potentials or amplitude of calcium spikes. The amplitude and duration of individual afterhyperpolarizations following a single spike were unchanged. In contrast, the neuronal excitability was significantly decreased and the spike duration significantly enhanced in aged rats as compared to young rats. The comparison of afterhyperpolarizations (which follow a burst of spikes) between young and aged rats was more complex. An increase in the amplitude and duration of afterhyperpolarizations generally occurred in aged animals. However, this increase was not consistent among animals and was dependent on the holding potential of the neuron and on the number of action potentials used to trigger the afterhyperpolarization. The depolarizing effect of bath-applied carbachol, as well as the associated increase in membrane resistance were reduced in neurons from aged rats. In contrast, the effects of carbachol on the depression of synaptic events and the blockade of the afterhyperpolarizations were similar in young and aged animals. In addition, the amplitude of the slow cholinergic excitatory postsynaptic potential induced by stimulation of cholinergic afferents in the presence of physostigmine was also decreased in aged rats. Excitatory postsynaptic potentials and inhibitory postsynaptic potentials following electrical stimulation of stratum radiatum were compared. The amplitude and duration of excitatory postsynaptic potentials were increased in aged rats. The amplitude and duration of the fast inhibitory postsynaptic potential were not significantly affected in aged animals. In contrast, the duration of the slow inhibitory postsynaptic potential was decreased in aged rats. Since the mean baclofen-induced hyperpolarization was only slightly reduced in aged rats, the most likely explanation is a decrease in the release of GABA rather than an alteration in the postsynaptic response mediated by GABA B receptors. A statistically significant correlation was found between the degree of impairment in the spontaneous alternation task and the amplitude of the carbachol-induced depolarization.

Excitatory transmission in the basolateral amygdala

1. Intracellular current-clamp recordings obtained from neurons of the basolateral nucleus of the amygdala (BLA) were used to characterize postsynaptic potentials elicited through stimulation of the stria terminalis (ST) or the lateral amygdala (LA). The contribution of glutamatergic receptor subtypes to excitatory postsynaptic potentials (EPSPs) were analyzed by the use of the non N-methyl-D-aspartate (non-NMDA) antagonist, 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX), and the NMDA antagonist, (DL)-2-amino-5-phosphonovaleric acid (APV). 2. Basic membrane properties of BLA neurons determined from membrane responses to transient current injection showed that at the mean resting membrane potential (RMP; -67.2 mV) the input resistance (RN) and time constant for membrane charging (tau) were near maximal, and that both values were reduced with membrane hyperpolarization, suggesting an intrinsic regulation of synaptic efficacy. 3. Responses to stimulation of the ST or LA consisted of an EPSP followed by either a fast inhibitory postsynaptic potential (f-IPSP) only, or by a fast- and subsequent slow-IPSP (s-IPSP). The EPSP was graded in nature, increasing in amplitude with increased stimulus intensity, and with membrane hyperpolarization after DC current injection. Spontaneous EPSPs were also observed either as discrete events or as EPSP/IPSP waveforms. 4. In physiological Mg2+ concentrations (1.2 mM), at the mean RMP, the EPSP consisted of dual, fast and slow, glutamatergic components. The fast-EPSP (f-EPSP) possessed characteristics of kainate/quisqualate receptor activation, namely, the EPSP increased in amplitude with membrane hyperpolarization, was insensitive to the NMDA receptor antagonist, APV (50 microM), and was blocked by the non-NMDA receptor antagonist, CNQX (10 microM). In contrast, the slow-EPSP (s-EPSP) decreased in amplitude with membrane hyperpolarization, was insensitive to CNQX (10 microM), and was blocked by APV (50 microM), indicating mediation by NMDA receptor activation. 5. In the presence of CNQX (10 microM), ST stimulation evoked an APV-sensitive s-EPSP. In contrast, LA stimulation evoked a f-IPSP, which when blocked by subsequent addition of bicuculline methiodide (BMI; 30 microM) revealed a temporally overlapping APV-sensitive s-EPSP. These data suggest that EPSP amplitude and duration are determined, in part, by the shunting of membrane conductance caused by a concomitant IPSP. 6. Superfusion of either CNQX or APV in BLA neurons caused membrane hyperpolarization and blockade of spontaneous EPSPs and IPSPs, suggesting that these compounds may act to block tonic excitatory amino acid (EAA) release within the nucleus, and that a degree of feed-forward inhibition occurs within the nucleus.(ABSTRACT TRUNCATED AT 400 WORDS)

Suppression of "fast" IPSP, superposed on "slow", as a possible cause of priming in murine hippocampus

Intra- and extracellular response in area CA1 to stimulation of two independent afferent inputs, one a priming or conditioned and the other a test or primed input (C1 and C2, respectively) were recorded in surviving murine hippocampal slices. Duration and amplitude of test field potentials (FP) and of excitatory postsynaptic potentials (EPSP), were measured, as well as amplitude of "fast" and "slow" components of inhibitory postsynaptic potentials or stimulation varying between 0 and 1 sec. Conditioning brought about an increase in the duration of FP, in duration and amplitude of EPSP, and suppression of IPSP at intervals of between 50 and 500 msec peaking at 200 msec (i.e., priming effect). These changes correlated with level of IPSPb in response to conditioned stimuli. The most pronounced effect could be seen in neurons manifesting hyperpolarizing IPSP in response to test stimuli. Suppression of test IPSPa after superposition on IPSPb is thought to bring about the increase in test FP and EPSP seen during priming.