Frequency dependence of synaptic transmission in nucleus of the solitary tract in vitro

Afferent fibers from visceral sensory receptors enter the medulla oblongata, form the solitary tract, and synapse with neurons in the nucleus of the solitary tract. In the present study longitudinal slices were prepared from guinea pig medulla in order to examine the properties of transmission at these synapses in vitro. Synaptic responses to selective stimulation of solitary tract fibers were recorded intracellularly from neurons in an area, close to the obex and immediately medial and lateral to the tract, where arterial baroreceptor fibers are known to terminate. The amplitude of maximally evoked postsynaptic potentials (PSPs) in solitary tract neurons was strongly dependent on stimulus frequency. On increasing frequency from 0.5 to 20 Hz, a PSP depression of 80% was reached in 4-8 s. The mean depression was 35% at 5 Hz and 60% at 10 Hz. Sufficient local connections were retained in vitro that solitary tract stimulation evoked disynaptic inhibitory potentials and long latency, possibly polysynaptic, excitatory potentials in some neurons. The possibility that frequency-dependent changes in the efficacy of these local synaptic circuits contributed to PSP depression was examined. The role of postsynaptic inhibition in synaptic depression was tested by examining the frequency dependence of PSPs at membrane potentials close to the reversal of their excitatory component. The resulting hyperpolarizing PSPs were also depressed suggesting that a facilitation of postsynaptic inhibition at high frequency does not underlie the depression. The contribution of depression in multisynaptic excitatory pathways to PSP depression was assessed by exclusion. At low stimulus intensities, excitatory synaptic events with no long latency components were evoked. These events exhibited a similar frequency dependence to that of maximal PSPs. These results suggest that mechanisms operating at synapses made by solitary tract fibers are responsible for the frequency dependence of PSPs recorded in solitary tract neurons. Such mechanisms might contribute to the adaptation of some cardiovascular reflexes initiated by baroreceptors.     

Presynaptic GABA(B) receptors modulate organum vasculosum lamina terminalis-evoked postsynaptic currents in rat hypothalamic supraoptic neurons

Whole-cell patch-clamp recordings obtained from 36 hypothalamic supraoptic nucleus neurons in explant preparations evaluated a role for GABA(B) receptors in modulating postsynaptic inhibitory and excitatory currents evoked by electrical stimulation in the organum vasculosum of the lamina terminalis. At a holding current of -65 mV, application of baclofen (1-10 microM) induced a dose-dependent reduction in the amplitude of pharmacologically isolated inhibitory and excitatory postsynaptic currents, converted paired-pulse depression in inhibitory postsynaptic currents to paired-pulse facilitation, and enhanced paired-pulse ratios for excitatory postsynaptic currents. In media containing 2-hydroxysaclofen (200-400 microM), baclofen-associated events were blocked and paired-pulse depression in evoked inhibitory postsynaptic currents was abolished. In addition, a progressive increase in the amplitude of inhibitory postsynaptic currents implied that GABA was endogenously active at presynaptic GABA(B) receptors. In contrast, no paired-pulse depression was observed for inhibitory postsynaptic currents evoked in six non-magnocellular neurons. Neither baclofen nor 2-hydroxysaclofen altered holding currents or input resistances in supraoptic neurons, or altered the kinetics of the evoked responses.These observations imply that the terminals of both inhibitory (GABAergic) and excitatory (glutamatergic) afferents to supraoptic nucleus neurons from organum vasculosum lamina terminalis neurons are subject to modulation by presynaptic GABA(B) receptors, and that this modulation is preferentially directed to the inhibitory inputs.     

Synaptic integrative properties at hyperbaric pressure

1. Because hyperbaric pressure profoundly depresses excitatory synaptic transmission, it has proved difficult to account for its excitatory effects in the CNS. We tested the hypothesis that hyperbaric pressure might increase excitation by enhancing facilitation and potentiation during repetitive synaptic activation, and/or by selectively depressing inhibitory synaptic transmission. Intracellular microelectrode recordings were obtained from crustacean muscle fibers innervated by single identifiable excitor and inhibitor motor neurons; the preparations were exposed to pressures of 0.1-10.1 MPa. 2. Hyperbaric pressure reduced the amplitude of the singly evoked excitatory junctional potential (EJP), enhanced paired-pulse facilitation, and increased the potentiation elicited by trains of stimuli. The potentiated EJP at 10.1 MPa approached the comparable response evoked at normobaric pressure. 3. Hyperbaric pressure also depressed inhibitory synaptic transmission, measured as depression of the EJP by the inhibitor motor neuron. However, pressure depressed excitatory and inhibitory synaptic transmission to the same extent. Thus there appears to be no selective effect of pressure on the GABA-activated chloride channel. The amplitude of the inhibited EJP at 10.1 MPa remained below that at normobaric pressure, even during repetitive stimulation. 4. The results do not support the hypothesis that pressure increases central excitation by selectively depressing inhibitory transmission per se; enhancement of potentiation, however, probably plays an important role. In this preparation, in which inhibitory transmission also displays facilitation, pressure did not increase overall excitation or alter the balance between excitation and inhibition. 5. These results predict that a pressure-excitable network should encompass excitatory synaptic connections which exhibit pronounced facilitation and inhibitory synapses with little or no facilitation.     

Short-term dynamics of thalamocortical and intracortical synapses onto layer 6 neurons in neocortex

Layer 6 is the main source of neocortical connections back to specific thalamic nuclei. Corticothalamic (CT) systems play an important role in shaping sensory input, but little is known about the functional circuitry that generates CT activity. We recorded from the two main types of neurons in layer 6, regular-spiking (RS; pyramidal neurons) and fast-spiking (FS; inhibitory interneurons) cells and compared the physiological properties of different excitatory inputs. Thalamic stimulation evoked two monosynaptic inputs with distinct properties: suspected thalamocortical (TC) synaptic events had short latencies, short-term synaptic depression, and paired-pulse responses that suggested subnormal axonal conduction. A second group of synaptic responses likely originated from intracortical collaterals of CT cells that were antidromically activated from the thalamus. These intracortical responses had longer latencies, short-term synaptic facilitation, and were transmitted by axons with supernormal conduction. Suspected TC inputs to FS cells had significantly larger amplitudes than those onto RS cells. Dual recordings from neighboring neurons in layer 6 revealed both facilitating and depressing synaptic connections; the depressing synapses were probably formed by layer 6 cells that do not project to the thalamus, and thus were not sampled by thalamic stimulation. We conclude that layer 6 neurons integrate a variety of inputs with distinct temporal dynamics that are determined by the presynaptic cell type.     

Group II and group III metabotropic glutamate receptor agonists depress synaptic transmission in the rat spinal cord dorsal horn

The effects of group II and group III metabotropic glutamate receptor agonists on synaptic responses evoked by primary afferent stimulation in the dorsal horn, but mostly substantia gelatinosa, neurons were studied in the spinal cord slice preparation using conventional intracellular recording technique. Bath application of a potent metabotropic glutamate receptor 2- and 3-selective agonist (2S,1'R,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl) glycine reversibly suppressed monosynaptic and polysynaptic excitatory postsynaptic potentials evoked by A primary afferent fibers stimulation, the effect likely mediated by mGlu3 receptor subtype. This suppressing effect of (2S,1'R,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl) glycine on primary afferent neurotransmission was dose dependent and reduced by (S)-alpha-ethylglutamate, a group II metabotropic glutamate receptor antagonist. (2S,1'R,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl) glycine suppressed excitatory postsynaptic potentials without inducing detectable changes of postsynaptic membrane potential and neuronal input resistance in dorsal horn neurons. The paired-pulse depression at excitatory synapses between primary afferent fibers and dorsal horn neurons was reduced by (2S,1'R,2'R,3'R)-2-(2', 3'-dicarboxycyclopropyl) glycine application, suggesting a presynaptic site of action. The selective group III metabotropic glutamate receptor agonist (S)-2-amino-4-phosphonobutanoate also depressed A afferent fibers-evoked monosynaptic and polysynaptic excitatory postsynaptic potentials in a dose-dependent and reversible manner. The concentration-dependence of (S)-2-amino-4-phosphonobutanoate-mediated depression was most consistent with activation of mGlu receptor subtypes 4 and 7. However, on the basis of anatomical distribution of mGlu 4 and 7 subtypes, it is also possible that the (S)-2-amino-4-phosphonobatanoate effect is due to interaction with mGlu 7 receptor alone. (RS)-alpha-cyclopropyl-4-phosphonophenylglycine a preferential antagonist at group III metabotropic glutamate receptors, completely reversed the depressant effects of (S)-2-amino-4-phosphonobutanoate on both monosynaptic and polysynaptic responses. (S)-2-amino-4-phosphonobutanoate reduced the paired-pulse depression at excitatory synapses between primary afferent fibers and dorsal horn neurons, but did not alter their postsynaptic membrane potential and input resistance. A clear facilitation of the (S)-2-amino-4-phosphonobutanoate-induced depression of monosynaptic and polysynaptic excitatory postsynaptic potentials in the absence of gamma-aminobutyric acid-subtype A receptor- and glycine-mediated synaptic inhibition was shown. Besides the depressant effect on excitatory synaptic transmission, inhibitory actions of group II and III metabotropic glutamate receptor agonists on the inhibitory postsynaptic potentials evoked by primary afferent stimulation in dorsal horn neurons were observed.These results suggest that group II and group III metabotropic glutamate receptors are expressed at primary afferent synapses in the dorsal horn region, and activation of the receptors suppresses synaptic transmission by an action on the presynaptic site.     

Differential changes of synaptic transmission in spiny neurons of rat neostriatum following transient forebrain ischemia

Spiny neurons in neostriatum are vulnerable to cerebral ischemia. To reveal the mechanisms underlying the postischemic neuronal damage, the spontaneous activities, evoked postsynaptic potentials and membrane properties of spiny neurons in rat neostriatum were compared before and after transient forebrain ischemia using intracellular recording and staining techniques in vivo. In control animals the membrane properties of spiny neurons were about the same between the left and right neostriatum but the inhibitory synaptic transmission was stronger in the left striatum. After severe ischemia, the spontaneous firing and membrane potential fluctuation of spiny neurons dramatically reduced. The cortically evoked initial excitatory postsynaptic potentials were suppressed after ischemia indicated by the increase of stimulus threshold and the rise time of these components. The paired-pulse facilitation test indicated that such suppression might involve presynaptic mechanisms. The inhibitory postsynaptic potentials in spiny neurons were completely abolished after ischemia and never returned to the control levels. A late depolarizing postsynaptic potential that was elicited from approximately 5% of the control neurons by cortical stimulation could be evoked from approximately 30% of the neurons in the left striatum and approximately 50% in the right striatum after ischemia. The late depolarizing postsynaptic potential could not be induced after acute thalamic transection. The intrinsic excitability of spiny neurons was suppressed after ischemia evidenced by the significant increase of spike threshold and rheobase as well as the decrease of repetitive firing rate following ischemia. The membrane input resistance and time constant increased within 6 h following ischemia and the amplitude of fast afterhyperpolarization significantly increased after ischemia. These results indicate the depression of excitatory monosynaptic transmission, inhibitory synaptic transmission and excitability of spiny neurons after transient forebrain ischemia whereas the excitatory polysynaptic transmission in neostriatum was potentiated. The facilitation of excitatory polysynaptic transmission is stronger in the right neostriatum than in the left neostriatum after ischemia. The suppression of inhibitory component and the facilitation of excitatory polysynaptic transmission may contribute to the pathogenesis of neuronal injury in neostriatum after transient cerebral ischemia.     

Differences in amplitude-voltage relations between minimal and composite mossy fibre responses of rat CA3 hippocampal neurons support the existence of intrasynaptic ephaptic feedback in large synapses

Computer simulations and electrophysiological experiments have been performed to test the hypothesis on the existence of an ephaptic interaction in purely chemical synapses. According to this hypothesis, the excitatory postsynaptic current would depolarize the presynaptic release site and further increase transmitter release, thus creating an intrasynaptic positive feedback. For synapses with the ephaptic feedback, computer simulations predicted non-linear amplitude-voltage relations and voltage dependence of paired-pulse facilitation. The deviation from linearity depended on the strength of the feedback determined by the value of the synaptic cleft resistance. The simulations showed that, in the presence of the intrasynaptic feedback, recruitment of imperfectly clamped synapses and synapses with linear amplitude-voltage relations tended to reduce the non-linearity and voltage dependence of paired-pulse facilitation. Therefore, the simulations predicted that the intrasynaptic feedback would particularly affect small excitatory postsynaptic currents induced by activation of electrotonically close synapses with long synaptic clefts. In electrophysiological experiments performed on hippocampal slices, the whole-cell configuration of the patch-clamp technique was used to record excitatory postsynaptic currents evoked in CA3 pyramidal cells by activation of large mossy fibre synapses. In accordance with the simulation results, minimal excitatory postsynaptic currents exhibited "supralinear" amplitude-voltage relations at hyperpolarized membrane potentials, decreases in the failure rate and voltage-dependent paired-pulse facilitation. Composite excitatory postsynaptic currents evoked by activation of a large amount of presynaptic fibres typically bear linear amplitude-voltage relationships and voltage-independent paired-pulse facilitation. These data are consistent with the hypothesis on a strong ephaptic feedback in large mossy fibre synapses. The feedback would provide a mechanism whereby signals from large synapses would be amplified. The ephaptic feedback would be more effective on synapses activated in isolation or together with electrotonically remote inputs. During synchronous activation of a large number of neighbouring inputs, suppression of the positive intrasynaptic feedback would prevent abnormal boosting of potent signals.     

CB1 modulation of temporally distinct synaptic facilitation among local circuit interneurons mediated by N-type calcium channels in CA1

One of the critical factors in determining network behavior of neurons is the influence of local circuit connections among interneurons. The short-term synaptic plasticity and the subtype of presynaptic calcium channels used at local circuit connections of inhibitory interneurons in CA1 were investigated using dual whole-cell recordings combined with biocytin and double immunofluorescence labeling in acute slices of P18- to 21-day-old rat stratum radiatum (SR) and stratum lacunosum molecular (SLM). Two forms of temporally distinct synaptic facilitation were observed among interneuron connections involving presynaptic cholecystokinin (CCK)-positive cells in SR, frequency-dependent facilitation, and a delayed onset of release (45-80 ms) with subsequent facilitation (DORF). Inhibition at both these synapses was under tonic cannabinoid-type 1 (CB1) receptor activity. DORF synapses did not display conventional release-dependent properties; however, blocking CB1 receptors with antagonist AM-251 (10 μM) altered the synaptic transmission to frequency-dependent depression with a fast onset of release (2-4 ms). Presynaptic CCK-negative interneurons in SLM elicited inhibitory postsynaptic potentials (IPSPs) insensitive to CB1 receptor pharmacology displayed frequency-dependent depression. Release of GABA at facilitating synapses was solely mediated via N-type presynaptic calcium channels, whereas depressing synapses utilized P/Q-type channels. These data reveal two distinct models of neurotransmitter release patterns among interneuron circuits that correlate with the subtype of presynaptic calcium channel. These data suggest that endocannabinoids act via CB1 receptors to selectively modulate N-type calcium channels to alter signal transmission.     

Synaptic origin of the respiratory-modulated activity of laryngeal motoneurons

To determine the synaptic source of the respiratory-related activity of laryngeal motoneurons, spike-triggered averaging of the membrane potentials of laryngeal motoneurons was conducted using spikes of respiratory neurons located between the Bötzinger complex and the rostral ventral respiratory group as triggers in decerebrate, paralyzed cats. We identified one excitatory and two inhibitory sources for inspiratory laryngeal motoneurons, and two inhibitory sources for expiratory laryngeal motoneurons. In inspiratory laryngeal motoneurons, monosynaptic excitatory postsynaptic potentials were evoked by spikes of inspiratory neurons with augmenting firing patterns, and monosynaptic inhibitory postsynaptic potentials (IPSPs) were evoked by spikes of expiratory neurons with decrementing firing patterns and by spikes of inspiratory neurons with decrementing firing patterns. In expiratory laryngeal motoneurons, monosynaptic IPSPs were evoked by spikes of inspiratory neurons with decrementing firing patterns and by spikes of expiratory neurons with augmenting firing patterns. We conclude that various synaptic inputs from respiratory neurons contribute to shaping the respiratory-related trajectory of membrane potential of laryngeal motoneurons.     

Photolysis of postsynaptic caged Ca2+ can potentiate and depress mossy fiber synaptic responses in rat hippocampal CA3 pyramidal neurons

The induction of mossy fiber-CA3 long-term potentiation (LTP) and depression (LTD) has been variously described as being dependent on either pre- or postsynaptic factors. Some of the postsynaptic factors for LTP induction include ephrin-B receptor tyrosine kinases and a rise in postsynaptic Ca2+ ([Ca2+]i). Ca2+ is also believed to be involved in the induction of the various forms of LTD at this synapse. We used photolysis of caged Ca2+ compounds to test whether a postsynaptic rise in [Ca2+]i is sufficient to induce changes in synaptic transmission at mossy fiber synapses onto rat hippocampal CA3 pyramidal neurons. We were able to elevate postsynaptic [Ca2+]i to approximately 1 microm for a few seconds in pyramidal cell somata and dendrites. We estimate that CA3 pyramidal neurons have approximately fivefold greater endogenous Ca2+ buffer capacity than CA1 neurons, limiting the rise in [Ca2+]i achievable by photolysis. This [Ca2+]i rise induced either a potentiation or a depression at mossy fiber synapses in different preparations. Neither the potentiation nor the depression was accompanied by consistent changes in paired-pulse facilitation, suggesting that these forms of plasticity may be distinct from synaptically induced LTP and LTD at this synapse. Our results are consistent with a postsynaptic locus for the induction of at least some forms of synaptic plasticity at mossy fiber synapses.     

Cortically and lingually induced postsynaptic potentials in trigeminal motoneurons after axotomy

Summary The membrane properties and the efficacy of excitatory and inhibitory synapses were studied in cat masseteric motoneurons (Mass Mns) after axotomy. In axotomized Mass Mns the slope of the primary range in the frequency-current relationship showed a higher gain than that of normal Mass Mns. The safety of antidromic invasion was increased and the initial segment component of antidromic action potentials could not be separated from the somadendritic component. In normal Mass Mns a single shock delivered to the orbital gyrus or the lingual nerve induced long-lasting inhibitory postsynaptic potentials (IPSPs). In two-thirds of Mass Mns explored 30 days after axotomy, a single shock delivered to the orbital gyrus or the lingual nerve evoked a mixture of inhibitory and excitatory synaptic potentials. In Mass Mns 50 days after axotomy, we have demonstrated that the major fraction of the total sample of explored Mass Mns showed long-lasting excitatory postsynaptic potentials followed by IPSPs. The results suggest that in Mass Mns, axotomy is followed by the decline of synaptic efficacy of inhibitory rather than of excitatory synapses.     

Rat hippocampal neurons in culture: responses to electrical and chemical stimuli

Intracellular activity was recorded from dissociated rat hippocampal neurons maintained in tissue culture conditions for 4-6 wk. The cells developed dense interconnections and had typical morphological characteristics similar to hippocampal neurons in situ. The recorded neurons possessed similar electrophysiological properties to those observed in situ or in a slice preparation. Their input resistance (42 M omega), resting membrane potential (-60 mV), membrane time constant (16.2 ms), total electrotonic length (0.92), and spike size (68.3 mV) were similar to values obtained in hippocampal cells in a slice. The connections among adjacent neurons were largely inhibitory. The inhibitory postsynaptic potentials (IPSPs) had longer durations than excitatory postsynaptic potentials (EPSPs) when these were detected. Synaptic delay varied between 0.3 and 3.0 ms. There were no electrotonic connections among neurons. Reciprocal connections were common. Most neurons reacted to acetylcholine (ACh) by an increase in frequency of spontaneous EPSPs, action-potential discharges, and IPSPs. Concurrently, there was a marked reduction in the magnitude of the evoked PSPs tested in pairs of cells. This effect is probably presynaptic to the recorded neurons. A statistical analysis of quantal properties of the synaptic interactions among neurons revealed that ACh causes a reduction of magnitude of PSPs by reducing the number of releasing elements (m). This effect is different from the reduction of evoked PSPs caused by postsynaptic depolarization.     

Synaptic responses of neurons controlling the parotid and von Ebner salivary glands in rats to stimulation of the solitary nucleus and tract

Salivary secretion results from reflex stimulation of autonomic neurons via afferent sensory information relayed to neurons in the rostral nucleus of the solitary tract (rNST), which synapse with autonomic neurons of the salivatory nuclei. We investigated the synaptic properties of the afferent sensory connection to neurons in the inferior salivatory nucleus (ISN) controlling the parotid and von Ebner salivary glands. Mean synaptic latency recorded from parotid gland neurons was significantly shorter than von Ebner gland neurons. Superfusion of GABA and glycine resulted in a concentration-dependent membrane hyperpolarization. Use of glutamate receptor antagonists indicated that both AMPA and N-methyl-D-aspartate (NMDA) receptors are involved in the evoked excitatory postsynaptic potentials (EPSPs). Inhibitory postsynaptic potential (IPSP) amplitude increased with higher intensity ST stimulation. Addition of the glycine antagonist strychnine did not affect the amplitude of the IPSPs significantly. The GABA(A) receptor antagonist, bicuculline (BMI) or mixture of strychnine and BMI abolished the IPSPs in all neurons. IPSP latency was longer than EPSP latency, suggesting that more than one synapse is involved in the inhibitory pathway. Results show that ISN neurons receive both excitatory and inhibitory afferent input mediated by glutamate and GABA respectively. The ISN neuron response to glycine probably derives from descending connections. Difference in the synaptic characteristics of ISN neurons controlling the parotid and von Ebner glands may relate to the different function of these two glands.     

Enhancement of excitatory synaptic transmission in spiny neurons after transient forebrain ischemia

Spiny neurons in the neostriatum are highly vulnerable to ischemia. Enhancement of excitatory synaptic transmissions has been implicated in ischemia-induced excitotoxic neuronal death. Here we report that evoked excitatory postsynaptic currents in spiny neurons were potentiated after transient forebrain ischemia. The ischemia-induced potentiation in synaptic efficacy was associated with an enhancement of presynaptic release as demonstrated by an increase in the frequency of miniature excitatory postsynaptic currents (mEPSCs) and a decrease in the paired-pulse ratio. The amplitude of inward currents evoked by exogenous application of glutamate did not show significant changes after ischemia, suggesting that postsynaptic mechanism is not involved. The ischemia-induced increase in mEPSCs frequency was not affected by blockade of voltage-gated calcium channels, but it was eliminated in the absence of extracellular calcium. Bath application of ATP P2X receptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) significantly reduced mEPSC frequency in ischemic neurons but had no effects on the control ones. Furthermore, the inhibitory effect of PPADS on ischemic neurons was abolished in Ca2+-free external solution. These results indicate that excitatory synaptic transmissions in spiny neurons are potentiated after ischemia via presynaptic mechanisms. Activation of P2X receptors and the consequent Ca2+ influx might contribute to the ischemia-induced facilitation of glutamate release.     

Short-term dynamics of synaptic transmission within the excitatory neuronal network of rat layer 4 barrel cortex

The short-term plasticity of synaptic transmission between excitatory neurons within a barrel of layer 4 rat somatosensory neocortex was investigated. Action potentials in presynaptic neurons at frequencies ranging from 1 to 100 Hz evoked depressing postsynaptic excitatory postsynaptic potentials (EPSPs). Recovery from synaptic depression followed an exponential time course with best-fit parameters that differed greatly between individual synaptic connections. The average maximal short-term depression was close to 0.5 with a recovery time constant of around 500 ms. Analysis of each individual sweep showed that there was a correlation between the amplitude of the response to the first and second action potentials such that large first EPSPs were followed by smaller than average second EPSPs and vice versa. Short-term depression between excitatory layer 4 neurons can thus be termed use dependent. A simple model describing use-dependent short-term plasticity was able to closely simulate the experimentally observed dynamic behavior of these synapses for regular spike trains. More complex irregular trains of 10 action potentials occurring within 500 ms were initially well described, but during the train errors increased. Thus for short periods of time the dynamic behavior of these synapses can be predicted accurately. In conjunction with data describing the connectivity, this forms a first step toward computational modeling of the excitatory neuronal network of layer 4 barrel cortex. Simulation of whisking-evoked activity suggests that short-term depression may provide a mechanism for enhancing the detection of objects within the whisker space.     

Activity-dependent depression of local excitatory connections in the CA1 region of mouse hippocampus

The existence of recurrent excitatory synapses between pyramidal cells in the hippocampal CA1 region has been known for some time yet little is known about activity-dependent forms of plasticity at these synapses. Here we demonstrate that under certain experimental conditions, Schaffer collateral/commissural fiber stimulation can elicit robust polysynaptic excitatory postsynaptic potentials due to recurrent synaptic inputs onto CA1 pyramidal cells. In contrast to CA3 pyramidal cell inputs, recurrent synapses onto CA1 pyramidal cells exhibited robust paired-pulse depression and a sustained, but rapidly reversible, depression in response to low-frequency trains of Schaffer collateral fiber stimulation. Blocking GABA(B) receptors abolished paired-pulse depression but had little effect on low-frequency stimulation (LFS)-induced depression. Instead, LFS-induced depression was significantly attenuated by an inhibitor of A1 type adenosine receptors. Blocking the postsynaptic effects of GABA(B) and A1 receptor activation on CA1 pyramidal cell excitability with an inhibitor of G-protein-activated inwardly rectifying potassium channels had no effect on either paired-pulse depression or LFS-induced depression. Thus activation of presynaptic GABA(B) and adenosine receptors appears to have an important role in activity-dependent depression at recurrent synapses. Together, our results indicate that CA3-CA1 and CA1-CA1 synapses exhibit strikingly different forms of short-term synaptic plasticity and suggest that activity-dependent changes in recurrent synaptic transmission can transform the CA1 region from a sparsely connected recurrent network into a predominantly feedforward circuit.     

Brain-derived neurotrophic factor modulates GABAergic synaptic transmission by enhancing presynaptic glutamic acid decarboxylase 65 levels, promoting asynchronous release and reducing the number of activated postsynaptic receptors

Brain-derived neurotrophic factor is known to modulate the function of GABAergic synapses, but the site of brain-derived neurotrophic factor action is still a matter of controversy. This study was aimed at further dissecting the functional alterations produced by brain-derived neurotrophic factor treatment of GABAergic synaptic connections in cultures of the murine superior colliculus. The functional consequences of long-term brain-derived neurotrophic factor treatment were assessed by analysis of unitary evoked and delayed inhibitory postsynaptic currents in response to high frequency stimulation of single axons. It was found that brain-derived neurotrophic factor facilitated the asynchronous release, but had no effect on the probability of evoked release, the size of the readily releasable pool, and the paired-pulse behavior of evoked inhibitory postsynaptic currents. However, the amplitudes of evoked inhibitory postsynaptic currents, delayed inhibitory postsynaptic currents and miniature inhibitory postsynaptic currents were significantly reduced. Non-stationary fluctuation analysis revealed a decrease in the open channel number at the miniature/evoked inhibitory postsynaptic current peak, but no effect on the mean GABA(A) receptor single channel conductance. Quantitative immunocytochemistry uncovered a significant elevation of presynaptic levels of glutamic acid decarboxylase 65. Together, these findings indicate that brain-derived neurotrophic factor treatment induces pre- as well as postsynaptic changes. What effect predominates will depend on the presynaptic activity pattern: at low activation rates brain-derived neurotrophic factor-treated synapses display a pronounced postsynaptic depression, but at high frequencies this depression is fully compensated by an enhancement of asynchronous release.     

Do premotor interneurons act in parallel on spinal motoneurons and on dorsal horn spinocerebellar and spinocervical tract neurons in the cat?

It has previously been established that ventral spinocerebellar tract (VSCT) neurons and dorsal spinocerebellar tract neurons located in Clarke's column (CC DSCT neurons) forward information on actions of premotor interneurons in reflex pathways from muscle afferents on α-motoneurons. Whether DSCT neurons located in the dorsal horn (dh DSCT neurons) and spinocervical tract (SCT) neurons are involved in forwarding similar feedback information has not yet been investigated. The aim of the present study was therefore to examine the input from premotor interneurons to these neurons. Electrical stimuli were applied within major hindlimb motor nuclei to activate axon-collaterals of interneurons projecting to these nuclei, and intracellular records were obtained from dh DSCT and SCT neurons. Direct actions of the stimulated interneurons were differentiated from indirect actions by latencies of postsynaptic potentials evoked by intraspinal stimuli and by the absence or presence of temporal facilitation. Direct actions of premotor interneurons were found in a smaller proportion of dh DSCT than of CC DSCT neurons. However, they were evoked by both excitatory and inhibitory interneurons, whereas only inhibitory premotor interneurons were previously found to affect CC DSCT neurons [as indicated by monosynaptic excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) in dh DSCT and only IPSPs in CC DSCT neurons]. No effects of premotor interneurons were found in SCT neurons, since monosynaptic EPSPs or IPSPs were only evoked in them by stimuli applied outside motor nuclei. The study thus reveals a considerable differentiation of feedback information provided by different populations of ascending tract neurons.     

Presynaptic GABA(B) receptors inhibit synaptic inputs to rat subthalamic neurons.

Effects of baclofen on synaptic transmission were studied in rat subthalamic neurons using whole-cell patch clamp recording from brain slices. Focal electrical stimulation of the brain slice evoked GABAergic inhibitory postsynaptic currents and glutamatergic excitatory postsynaptic currents. Baclofen reduced the amplitude of evoked inhibitory postsynaptic currents in a concentration-dependent manner with an IC(50) of 0.6+/-0.2 microM. Evoked excitatory postsynaptic currents were also reduced by baclofen concentration-dependently (IC(50) of 1.6+/-0.2 microM), but baclofen was more potent at reducing the GABA(A) receptor inhibitory postsynaptic currents. The GABA(B) receptor antagonist CGP 35348 blocked these inhibitory effects of baclofen on evoked inhibitory and excitatory postsynaptic currents. Baclofen increased the paired-pulse ratios of evoked inhibitory and excitatory postsynaptic currents. Furthermore, baclofen reduced the frequency of spontaneous miniature excitatory postsynaptic currents, but had no effect on their amplitude.These results provide evidence for presence of presynaptic GABA(B) receptors that modulate both GABA and glutamate release from afferent terminals in the subthalamus.     

Two dynamically distinct inhibitory networks in layer 4 of the neocortex

Normal operations of the neocortex depend critically on several types of inhibitory interneurons, but the specific function of each type is unknown. One possibility is that interneurons are differentially engaged by patterns of activity that vary in frequency and timing. To explore this, we studied the strength and short-term dynamics of chemical synapses interconnecting local excitatory neurons (regular-spiking, or RS, cells) with two types of inhibitory interneurons: fast-spiking (FS) cells, and low-threshold spiking (LTS) cells of layer 4 in the rat barrel cortex. We also tested two other pathways onto the interneurons: thalamocortical connections and recurrent collaterals from corticothalamic projection neurons of layer 6. The excitatory and inhibitory synapses interconnecting RS cells and FS cells were highly reliable in response to single stimuli and displayed strong short-term depression. In contrast, excitatory and inhibitory synapses interconnecting the RS and LTS cells were less reliable when initially activated. Excitatory synapses from RS cells onto LTS cells showed dramatic short-term facilitation, whereas inhibitory synapses made by LTS cells onto RS cells facilitated modestly or slightly depressed. Thalamocortical inputs strongly excited both RS and FS cells but rarely and only weakly contacted LTS cells. Both types of interneurons were strongly excited by facilitating synapses from axon collaterals of corticothalamic neurons. We conclude that there are two parallel but dynamically distinct systems of synaptic inhibition in layer 4 of neocortex, each defined by its intrinsic spiking properties, the short-term plasticity of its chemical synapses, and (as shown previously) an exclusive set of electrical synapses. Because of their unique dynamic properties, each inhibitory network will be recruited by different temporal patterns of cortical activity.