C. Andrew Chapman

Effects of GABAA inhibition on the expression of long-term potentiation in CA1 pyramidal cells are dependent on tetanization parameters

Long‐term potentiation (LTP) of excitatory synaptic responses of principal neurons in the hippocampus is accompanied by changes in GABAergic inhibition mediated by interneurons. The impact of inhibition on LTP of excitatory postsynaptic responses in CA1 pyramidal cells was assessed by monitoring changes in field potentials evoked by Schaffer collateral stimulation in hippocampal slices in vitro. First, to determine the effect of inhibition on population EPSPs, slices were exposed to the GABAA receptor antagonist bicuculline (10 μM). Both the slope and amplitude of field EPSPs (fEPSPs) were significantly enhanced by bicuculline indicating that inhibition modulates excitatory postsynaptic responses of pyramidal cells. To assess if stimulation‐dependent changes in inhibition influence LTP of excitatory responses of pyramidal cells, LTP was examined in the presence and absence of bicuculline (20 μM) following either 100 Hz tetanization, or theta‐patterned stimulation (short bursts delivered at 5 Hz). In normal medium, 100 Hz stimulation produced marked short‐term potentiation that decayed 5–10 min post‐tetanus and both stimulation paradigms produced similar LTP at 30 min post‐tetanus. In comparison, LTP of the fEPSP slope and amplitude was significantly enhanced after theta‐patterned stimulation, but not after 100 Hz stimulation, in bicuculline. The greater potentiation of field responses following theta‐patterned stimulation in the presence of bicuculline indicates that a larger potentiation of excitatory responses was unmasked during suppression of inhibitory inputs. These results suggest that a long‐lasting enhancement of inhibition in pyramidal cells was also induced following theta‐patterned stimulation in normal ACSF. Since suppression of inhibition did not uncover a significantly larger potentiation following 100 Hz tetanization, the influence of inhibition on LTP of excitatory responses appears to be stimulation‐dependent. In conclusion, theta‐patterned stimulation appears to be more effective at inducing plasticity within inhibitory circuits, and this plasticity may partially offset concurrent increases in the excitability of the CA1 network. Hippocampus 1998;8:289–298.

GABAB receptor- and metabotropic glutamate receptor- dependent cooperative long-term potentiation of rat hippocampal GABAA synaptic transmission

Repetitive stimulation of Schaffer collaterals induces activity‐dependent changes in the strength of polysynaptic inhibitory postsynaptic potentials (IPSPs) in hippocampal CA1 pyramidal neurons that are dependent on stimulation parameters. In the present study, we investigated the effects of two stimulation patterns, theta‐burst stimulation (TBS) and 100 Hz tetani, on pharmacologically isolated monosynaptic GABAergic responses in adult CA1 pyramidal cells. Tetanization with 100 Hz trains transiently depressed both early and late IPSPs, whereas TBS induced long‐term potentiation (LTP) of early IPSPs that lasted at least 30 min. Mechanisms mediating this TBS‐induced potentiation were examined using whole‐cell recordings. The paired‐pulse ratio of monosynaptic inhibitory postsynaptic currents (IPSCs) was not affected during LTP, suggesting that presynaptic changes in GABA release are not involved in the potentiation. Bath application of the GABAB receptor antagonist CGP55845 or the group I/II metabotropic glutamate receptor antagonist E4‐CPG inhibited IPSC potentiation. Preventing postsynaptic G‐protein activation or Ca2+ rise by postsynaptic injection of GDP‐β‐S or BAPTA, respectively, abolished LTP, indicating a G‐protein‐ and Ca2+‐dependent induction in this LTP. Finally during paired‐recordings, activation of individual interneurons by intracellular TBS elicited solely short‐term increases in average unitary IPSCs in pyramidal cells. These results indicate that a stimulation paradigm mimicking the endogenous theta rhythm activates cooperative postsynaptic mechanisms dependent on GABABR, mGluR, G‐proteins and intracellular Ca2+, which lead to a sustained potentiation of GABAA synaptic transmission in pyramidal cells. GABAergic synapses may therefore contribute to functional synaptic plasticity in adult hippocampus.

Post-activation potentiation in the neocortex. IV. Multiple sessions required for induction of long-term potentiation in the chronic preparation

The neocortex in chronically prepared rats is very resistant to the induction of long-term potentiation (LTP). In the first of two experiments described in this paper, we tried unsuccessfully to induce neocortical LTP within one session by coactivating basal forebrain cholinergic and cortical inputs to our neocortical recording site. In the second experiment, we tested a new procedure which involved the application of repeated conditioning sessions over several days. This procedure was suggested by our finding that kindling-induced potentiation (KIP) of cortical field potentials could be reliably triggered but was slow to develop. We administered 30 high frequency trains per day to the corpus callosum for 25 days. LTP in callosal-neocortical field potentials became clear after about 5 days of stimulation and reached asymptotic levels by about 15 days. After the termination of treatment, LTP persisted for at least 4 weeks, the duration of our post-stimulation test period. As in previous experiments on kindling-induced potentiation, the potentiation effects were clear in both early population spike components and in a late (probably disynaptic) component. The monosynaptic EPSP component was often depressed, but this may have been due to competing field currents generated by the enhanced population spike activity. We discuss these results in the context of theories emphasizing slower but more permanent memory storage in neocortex compared to the hippocampus.

DCC Expression by Neurons Regulates Synaptic Plasticity in the Adult Brain

The transmembrane protein deleted in colorectal cancer (DCC) and its ligand, netrin-1, regulate synaptogenesis during development, but their function in the mature central nervous system is unknown. Given that DCC promotes cell-cell adhesion, is expressed by neurons, and activates proteins that signal at synapses, we hypothesized that DCC expression by neurons regulates synaptic function and plasticity in the adult brain. We report that DCC is enriched in dendritic spines of pyramidal neurons in wild-type mice, and we demonstrate that selective deletion of DCC from neurons in the adult forebrain results in the loss of long-term potentiation (LTP), intact long-term depression, shorter dendritic spines, and impaired spatial and recognition memory. LTP induction requires Src activation of NMDA receptor (NMDAR) function. DCC deletion severely reduced Src activation. We demonstrate that enhancing NMDAR function or activating Src rescues LTP in the absence of DCC. We conclude that DCC activation of Src is required for NMDAR-dependent LTP and certain forms of learning and memory.

Post-activation potentiation in the neocortex. III. Kindling-induced potentiation in the chronic preparation

Previous experiments have shown the neocortex to be very resistant to the induction of long-term potentiation in chronic preparations. We show here that kindling-induced potentiation effects can be reliably produced in the neocortex of awake, freely moving rats. These effects develop rather slowly. In sites contralateral to the stimulation electrode, potentiation effects did not become clear until the animals had received about 5 days or more of stimulation. Ipsilateral sites required even longer (approximately 10 days), and both sites required more than 13 days to reach asymptotic levels of potentiation. Both monosynaptic and polysynaptic components were present in the neocortical field potentials. When population spikes were absent, the surface negative monosynaptic EPSP component tended to show a potentiation effect. If population spikes were present, they were generally enhanced while the monosynaptic population EPSP tended to be depressed. Consequently, the apparent depression may have been due to competing field currents. The later polysynaptic components (15-28 ms latency to peak) always showed a potentiation effect with 5 or more kindling stimulations and is presumed to result from activation of cortico-cortical associational fibers. All of these effects were long-lasting, showing little decay over a period of several weeks.

Piriform cortex efferents to the entorhinal cortex in vivo: kindling-induced potentiation and the enhancement of long-term potentiation by low-frequency piriform cortex or medial septal stimulation.

The entorhinal cortex receives input from many cortical areas and mediates the flow of information between these sites and the hippocampal formation. Long‐term synaptic plasticity in cortical efferents to the entorhinal cortex may contribute to the transmission of neural activity to the hippocampus, as well as the storage of information, but little is known about plasticity in these pathways. We describe here the use of evoked field potential recordings from chronically implanted electrodes in the rat entorhinal cortex to investigate synaptic plasticity in the large piriform (olfactory) cortex projection to the superficial layers of the entorhinal cortex. Both kindling‐induced potentiation and long‐term potentiation (LTP) were tested. In addition, we attempted to modulate LTP induction by the co‐induction of frequency potentiation and by the co‐activation of the medial septum. Epileptogenic kindling stimulations of the piriform cortex (1‐s, 60‐Hz trains 3 times/day for 5 days) were found to result in a reliable potentiation of field responses evoked by piriform cortex test pulses. Non‐epileptogenic tetanization of the piriform cortex with 400‐Hz 16‐pulse trains reliably resulted in LTP effects. These effects could be augmented by embedding brief LTP induction stimuli within 11‐pulse, 15‐Hz trains that alone produce only frequency potentiation. Co‐activating the medial septum with 10‐Hz trains, just prior to tetanization of the piriform cortex, augmented LTP of piriform cortex inputs to the entorhinal cortex in an input‐specific manner. All potentiation effects were found to last for periods of weeks. These findings demonstrate that both epileptogenic and non‐epileptogenic piriform cortex stimulation induces lasting potentiation of population field responses in the entorhinal cortex of the awake rat. The LTP effects were inducible in a graded manner and were sensitive to the temporal context of stimulation. The finding that low‐frequency activation of the septum can enhance plasticity in the entorhinal cortex adds to a body of data indicating a role for the medial septum in contributing to theta activity and plasticity in both the entorhinal cortex and hippocampal formation. Hippocampus 7:257–270, 1997. © 1997 Wiley‐Liss, Inc.

Axons and synapses mediating startle-like responses evoked by electrical stimulation of the reticular formation in rats: symmetric and asymmetric collision effects

A new method for determining the locations, directions of transmission and transmission times of synapses mediating electrically evoked responses is proposed here. Electrical stimulation of pontine or medullary reticular formation with one 0.1-ms pulse evokes a short-latency startle-like response. Two pulses were delivered to single sites at various interpulse intervals and the currents required to evoke a criterion startle response were measured. The results suggest that the startle-evoking substrates have absolute refractory periods that range from 0.25-0.6 ms. When one pulse was delivered to a caudal pontine site and a second pulse was delivered to a an ipsilateral medulla site, decreases in required current were observed as interpulse interval increased from +0.4 to +0.8 ms or as interpulse interval decreased from -0.4 to -0.8 ms. These collision-like effects, being symmetric around an interpulse interval of 0, suggest that electrically evoked startle is mediated by fast axons that pass longitudinally through medulla. When one pulse was delivered to the rostral pons and a second pulse to the ipsilateral medulla, however, required currents decreased sharply as interpulse intervals increased from +0.4 to 1.0 ms and as interpulse intervals decreased from +0.2 to -0.2 ms. These asymmetric collision-like effects suggest that strong synapses in the caudal pons, transmitting from pons to medulla, mediate electrically evoked startle. The 0.3-ms asymmetry suggests that the transmission time (i.e., from presynaptic stimulus to postsynaptic action potential) averaged 0.3 ms via monosynaptic connections. The short duration of collision (0.7 ms) suggests that only one postsynaptic action potential was produced with high probability for each presynaptic action potential. From the localization of these effects and the short refractory periods, we estimate that < 60 giant cells on each side of the ventral pontine reticular formation mediate the startle reflex in the rat.

Receptor protein tyrosine phosphatase sigma regulates synapse structure, function and plasticity

J. Neurochem. (2012) 122, 147–161.

Dopaminergic Suppression of Synaptic Transmission in the Lateral Entorhinal Cortex

Dopaminergic projections to the superficial layers of the lateral entorhinal cortex can modulate the strength of olfactory inputs to the region. We have found that low concentrations of dopamine facilitate field EPSPs in the entorhinal cortex, and that higher concentrations of dopamine suppress synaptic responses. Here, we have used whole-cell current clamp recordings from layer II neurons to determine the mechanisms of the suppression. Dopamine (10 to 50 μM) hyperpolarized membrane potential and reversibly suppressed the amplitude of EPSPs evoked by layer I stimulation. Both AMPA- and NMDA-mediated components were suppressed, and paired-pulse facilitation was also enhanced indicating that the suppression is mediated largely by reduced glutamate release. Blockade of D2-like receptors greatly reduced the suppression of EPSPs. Dopamine also lowered input resistance, and reduced the number of action potentials evoked by depolarizing current steps. The drop in input resistance was mediated by activation of D1-like receptors, and was prevented by blocking K+ channels with TEA. The dopaminergic suppression of synaptic transmission is therefore mediated by a D2 receptor-dependent reduction in transmitter release, and a D1 receptor-dependent increase in a K+ conductance. This suppression of EPSPs may dampen the strength of sensory inputs during periods of elevated mesocortical dopamine activity.

Conductances mediating intrinsic theta-frequency membrane potential oscillations in layer II parasubicular neurons.

Ionic conductances that generate membrane potential oscillations in neurons of layer II of the parasubiculum were studied using whole cell current-clamp recordings in horizontal slices from the rat brain. Blockade of ionotropic glutamate and GABA synaptic transmission did not reduce the power of the oscillations, indicating that oscillations are not dependent on synaptic inputs. Oscillations were eliminated when cells were hyperpolarized 6-10 mV below spike threshold, indicating that they are mediated by voltage-dependent conductances. Application of TTX completely eliminated oscillations, suggesting that Na(+) currents are required for the generation of the oscillations. Oscillations were not reduced by blocking Ca(2+) currents with Cd(2+) or Ca(2+)-free artificial cerebrospinal fluid, or by blocking K(+) conductances with either 50 microM or 5 mM 4-aminopyridine (4-AP), 30 mM tetraethylammonium (TEA), or Ba(2+)(1-2 mM). Oscillations also persisted during blockade of the muscarinic-dependent K(+) current, I(M), using the selective antagonist XE-991 (10 microM). However, oscillations were significantly attenuated by blocking the hyperpolarization-activated cationic current I(h) with Cs(+) and were almost completely blocked by the more potent I(h) blocker ZD7288 (100 microM). Intrinsic membrane potential oscillations in neurons of layer II of the parasubiculum are therefore likely driven by an interaction between an inward persistent Na(+) current and time-dependent deactivation of I(h). These voltage-dependent conductances provide a mechanism for the generation of membrane potential oscillations that can help support rhythmic network activity within the parasubiculum during theta-related behaviors.