Cholinergic modulation shifts the response of CA1 pyramidal cells to depolarizing ramps via TRPM4 channels with potential implications for place field firing.

A synergistic combination of in vitro electrophysiology and multicompartmental modeling of rat CA1 pyramidal neurons identified TRPM4 channels as major drivers of cholinergic modulation of the firing rate during a triangular current ramp, which emulates the bump in synaptic input received while traversing the place field. In control, fewer spikes at lower frequencies are elicited on the down-ramp compared to the up-ramp due to long-term inactivation of the NaV channel. The cholinergic agonist carbachol (CCh) removes or even reverses this spike rate adaptation, causing more spikes to be elicited on the down-ramp than the up-ramp. CCh application during Schaffer collateral stimulation designed to simulate a ramp produces similar shifts in the center of mass of firing to later in the ramp. The non-specific TRP antagonist flufenamic acid and the TRPM4-specific blockers CBA and 9-phenanthrol, but not the TRPC-specific antagonist SKF96365, reverse the effect of CCh; this implicates the Ca2+-activated nonspecific cation current, ICAN, carried by TRPM4 channels. The cholinergic shift of the center of mass of firing is prevented by strong intracellular Ca2+ buffering but not by antagonists for IP3 and ryanodine receptors, ruling out a role for known mechanisms of release from intracellular Ca2+ stores. Pharmacology combined with modeling suggest that [Ca2+] in a nanodomain near the TRPM4 channel is elevated through an unknown source that requires both muscarinic receptor activation and depolarization-induced Ca2+ influx during the ramp. Activation of the regenerative inward TRPM4 current in the model qualitatively replicates and provides putative underlying mechanisms for the experimental observations.

Interprofessional education as a potential foundation for future team-based prevention of alcohol use disorder.

BACKGROUND: Effective screening of alcohol use and prevention of alcohol use disorder (AUD) requires the continuous preparation of educated and confident providers across all health professions who will ideally work in close collaboration in their future practices. As one mechanism for achieving this goal, the development and provision of interprofessional education (IPE) training modules for health care students may cultivate beneficial interactions among future health providers early in their formative education. METHODS: In the present study, we assessed attitudes about alcohol and confidence in screening and AUD prevention in 459 students at our health sciences center. Students represented ten different health professions (audiology, cardiovascular sonography, dental hygiene, dentistry, medicine, nursing, physical therapy, public health, respiratory therapy, and speech language pathology programs). For purposes of this exercise, students were divided into small, professionally diverse teams. Responses to ten survey questions (Likert scale) were collected via a web-based platform. These assessments were collected before and after a case-based exercise that provided information to students on the risks of excessive alcohol use as well as the effective screening and team-based management of individuals susceptible to AUD. RESULTS: Wilcoxon signed-rank analyses revealed that the exercise led to significant decreases in stigma toward individuals engaging in at-risk alcohol use. We also discovered significant increases in self-reported knowledge and confidence in personal qualifications needed to initiate brief interventions to reduce alcohol use. Focused analyses of students from individual health programs uncovered unique improvements according to question theme and health profession. CONCLUSION: Our findings demonstrate the utility and effectiveness of single, focused IPE-based exercises to impact personal attitudes and confidence in young health professions learners. While additional longitudinal cohort follow-up studies are needed, these results may translate into more effective and collaborative AUD treatment in future clinical settings.

Long-Term Inactivation of Sodium Channels as a Mechanism of Adaptation in CA1 Pyramidal Neurons.

Many hippocampal CA1 pyramidal cells function as place cells, increasing their firing rate when a specific place field is traversed. The dependence of CA1 place cell firing on position within the place field is asymmetric. We investigated the source of this asymmetry by injecting triangular depolarizing current ramps to approximate the spatially tuned, temporally diffuse depolarizing synaptic input received by these neurons while traversing a place field. Ramps were applied to CA1 pyramidal neurons from male rats in vitro (slice electrophysiology) and in silico (multicompartmental NEURON model). Under control conditions, CA1 neurons fired more action potentials at higher frequencies on the up-ramp versus the down-ramp. This effect was more pronounced for dendritic compared with somatic ramps. We incorporated a four-state Markov scheme for NaV1.6 channels into our model and calibrated the spatial dependence of long-term inactivation according to the literature; this spatial dependence was sufficient to explain the difference in dendritic versus somatic ramps. Long-term inactivation reduced the firing frequency by decreasing open-state occupancy, and reduced spike amplitude during trains by decreasing occupancy in the closed state, which comprises the available pool. PKC activator phorbol-dibutyrate, known to reduce NaV long-term inactivation, removed spike amplitude attenuation in vitro more visibly in dendrites and greatly reduced adaptation, consistent with our hypothesized mechanism. Intracellular application of a peptide inducing long-term NaV inactivation elicited spike amplitude attenuation during spike trains in the soma and greatly enhanced adaptation. Our synergistic experimental/computational approach shows that long-term inactivation of NaV1.6 is a key mechanism of adaptation in CA1 pyramidal cells.SIGNIFICANCE STATEMENT The hippocampus plays an important role in certain types of memory, in part through context-specific firing of "place cells"; these cells were first identified in rodents as being particularly active when an animal is in a specific location in an environment, called the place field of that neuron. In this in vitro/in silico study, we found that long-term inactivation of sodium channels causes adaptation in the firing rate that could potentially skew the firing of CA1 hippocampal pyramidal neurons earlier within a place field. A computational model of the sodium channel revealed differential regulation of spike frequency and amplitude by long-term inactivation, which may be a general mechanism for spike frequency adaptation in the CNS.

Ih from synapses to networks: HCN channel functions and modulation in neurons.

Hyperpolarization-activated cyclic nucleotide gated (HCN) channels and the current they carry, Ih, are widely and diversely distributed in the central nervous system (CNS). The distribution of the four subunits of HCN channels is variable within the CNS, within brain regions, and often within subcellular compartments. The precise function of Ih can depend heavily on what other channels are co-expressed. In this review, we give an overview of HCN channel structure, distribution, and modulation by cyclic adenosine monophosphate (cAMP). We then discuss HCN channel and Ih functions, where we have parsed the roles into two main effects: a steady effect on maintaining the resting membrane potential at relatively depolarized values, and slow channel dynamics. Within this framework, we discuss Ih involvement in resonance, synaptic integration, transmitter release, plasticity, and point out a special case, where the effects of Ih on the membrane potential and its slow channel dynamics have dual roles in thalamic neurons.

Supporting health system transformation through an interprofessional education experience focused on population health.

The purpose of the study was to determine the impact of an interprofessional education (IPE) experience on first year students across all schools of a health sciences center on the topic of pediatric immunizations. The authors conducted a pre-/post-test at Louisiana State University Health Sciences Center-New Orleans with 731 first year students from 25 academic programs encompassing all six schools (Allied Health, Dentistry, Graduate Studies, Medicine, Nursing and Public Health). In the four questions related to the Interprofessional Education Collaborative (IPEC) sub-competencies and the three questions related to professional role regarding immunizations, there was a statistically significant difference in the pre-/post-test survey results (P < 0.0001). Student learning related to the collaboration needed to make a larger impact on patient outcomes was demonstrated through assessment of an open-ended question. IPE experiences can improve first-year students' perceptions of IPEC sub-competencies regarding the importance of population health and teamwork. By utilizing a population health focus with IPE activities, novice learners are equipped to learn and apply collaborative practice skills along with recognizing the importance of promoting overall health and well-being instead of just health care.

Intrinsic Mechanisms of Frequency Selectivity in the Proximal Dendrites of CA1 Pyramidal Neurons.

Gamma oscillations are thought to play a role in learning and memory. Two distinct bands, slow (25-50 Hz) and fast (65-100 Hz) gamma, have been identified in area CA1 of the rodent hippocampus. Slow gamma is phase locked to activity in area CA3 and presumably driven by the Schaffer collaterals (SCs). We used a combination of computational modeling and in vitro electrophysiology in hippocampal slices of male rats to test whether CA1 neurons responded to SC stimulation selectively at slow gamma frequencies and to identify the mechanisms involved. Both approaches demonstrated that, in response to temporally precise input at SCs, CA1 pyramidal neurons fire preferentially in the slow gamma range regardless of whether the input is at fast or slow gamma frequencies, suggesting frequency selectivity in CA1 output with respect to CA3 input. In addition, phase locking, assessed by the vector strength, was more precise for slow gamma than fast gamma input. This frequency selectivity was greatly attenuated when the slow Ca2+-dependent K+ (SK) current was removed from the model or blocked in vitro with apamin. Perfusion of slices with BaCl2 to block A-type K+ channels tightened this frequency selectivity. Both the broad-spectrum cholinergic agonist carbachol and the muscarinic agonist oxotremorine-M greatly attenuated the selectivity. The more precise firing at slower frequencies persisted throughout all of the pharmacological manipulations conducted. We propose that these intrinsic mechanisms provide a means by which CA1 phase locks to CA3 at different gamma frequencies preferentially in vivo as physiological conditions change with behavioral demands.SIGNIFICANCE STATEMENT Gamma frequency activity, one of multiple bands of synchronous activity, has been suggested to underlie various aspects of hippocampal function. Multisite recordings within the rat hippocampal formation indicate that different behavioral tasks are associated with synchronized activity between areas CA3 and CA1 at two different gamma bands: slow and fast gamma. In this study, we examine the intrinsic mechanisms that may allow CA1 to selectively "listen" to CA3 at slow compared with fast gamma and suggest mechanisms that gate this selectivity. Identifying the intrinsic mechanisms underlying differential gamma preference may help to explain the distinct types of CA3-CA1 synchronization observed in vivo under different behavioral conditions.

Differential Contribution of Ca2+-Dependent Mechanisms to Hyperexcitability in Layer V Neurons of the Medial Entorhinal Cortex.

Temporal lobe epilepsy is characterized by recurrent seizures in one or both temporal lobes of the brain; some in vitro models show that epileptiform discharges initiate in entorhinal layer V neurons and then spread into other areas of the temporal lobe. We previously found that, in the presence of GABAA receptor antagonists, stimulation of afferent fibers, terminating both at proximal and distal dendritic locations, initiated hyperexcitable bursts in layer V medial entorhinal neurons. We investigated the differential contribution of Ca2+-dependent mechanisms to the plateaus underlying these bursts at proximal and distal synapses. We found that the NMDA glutamatergic antagonist D,L-2-amino-5-phosphonovaleric acid (APV; 50 µM) reduced both the area and duration of the bursts at both proximal and distal synapses by about half. The L-type Ca2+ channel blocker nimodipine (10 µM) and the R- and T-type Ca2+ channel blocker NiCl2 (200 µM) decreased the area of the bursts to a lesser extent; none of these effects appeared to be location-dependent. Remarkably, the perfusion of flufenamic acid (FFA; 100 µM), to block Ca2+-activated non-selective cation currents (ICAN) mediated by transient receptor potential (TRP) channels, had a location-dependent effect, by abolishing burst firing and switching the suprathreshold response to a single action potential (AP) for proximal stimulation, but only minimally affecting the bursts evoked by distal stimulation. A similar outcome was found when FFA was pressure-applied locally around the proximal dendrite of the recorded neurons and in the presence of a selective blocker of melastatin TRP (TRPM) channels, 9-phenanthrol (100 µM), whereas a selective blocker of canonical TRP (TRPC) channels, SKF 96365, did not affect the bursts. These results indicate that different mechanisms might contribute to the initiation of hyperexcitability in layer V neurons at proximal and distal synapses and could shed light on the initiation of epileptiform activity in the entorhinal cortex.

Topological Regulation of Synaptic AMPA Receptor Expression by the RNA-Binding Protein CPEB3.

Synaptic receptors gate the neuronal response to incoming signals, but they are not homogeneously distributed on dendrites. A spatially defined receptor distribution can preferentially amplify certain synaptic inputs, resize receptive fields of neurons, and optimize information processing within a neuronal circuit. Thus, a longstanding question is how the spatial organization of synaptic receptors is achieved. Here, we find that action potentials provide local signals that influence the distribution of synaptic AMPA receptors along dendrites in mouse cerebellar stellate cells. Graded dendritic depolarizations elevate CPEB3 protein at proximal dendrites, where we suggest that CPEB3 binds to GluA2 mRNA, suppressing GluA2 protein synthesis leading to a distance-dependent increase in synaptic GluA2 AMPARs. The activity-induced expression of CPEB3 requires increased Ca(2+) and PKC activation. Our results suggest a cell-autonomous mechanism where sustained postsynaptic firing drives graded local protein synthesis, thus directing the spatial organization of synaptic AMPARs.

Effect of heterogeneity and noise on cross frequency phase-phase and phase-amplitude coupling.

Cross-frequency coupling is hypothesized to play a functional role in neural computation. We apply phase resetting theory to two types of cross-frequency coupling that can occur when a slower oscillator periodically forces one or more oscillators: phase-phase coupling, in which the two oscillations are phase-locked, and phase-amplitude coupling, in which the amplitude of the driven oscillation is modulated. Our first result is that the shape of the phase resetting curve predicts the tightness of locking to a pulsatile forcing periodic input at any ratio of forced to intrinsic period; the tightness of the locking decreases as the ratio increases. Theoretical expressions were obtained for the probability density of the phases for a population of heterogeneous oscillators or a noisy single oscillator. Results were confirmed using two types of simulated networks and experiments on hippocampal CA1 neurons. Theoretical expressions were also obtained and confirmed for the probability density of N spike times within a single cycle of low frequency forcing. The second result is a suggested mechanism for phase-amplitude coupling in which progressive desynchronization leads to decreasing amplitude during a low frequency forcing cycle. Network simulations confirmed the theoretical viability of this mechanism, and that it generalizes to more diffuse input.

Hippocampal CA1 pyramidal neurons exhibit type 1 phase-response curves and type 1 excitability.

Phase-resetting properties of neurons determine their functionality as integrators (type 1) vs. resonators (type 2), as well as their synchronization tendencies. We introduce a novel, bias-correction method to estimate the infinitesimal phase-resetting curve (iPRC) and confirm type 1 excitability in hippocampal pyramidal CA1 neurons in vitro by two independent methods. First, PRCs evoked using depolarizing pulses consisted only of advances, consistent with type 1. Second, the frequency/current (f/I) plots showed no minimum frequency, again consistent with type 1. Type 1 excitability was also confirmed by the absence of a resonant peak in the interspike interval histograms derived from the f/I data. The PRC bias correction assumed that the distribution of noisy phase resetting is truncated, because an input cannot advance a spike to a point in time before the input (the causal limit) and successfully removed the statistical bias for delays in the null PRC in response to zero-magnitude input by computing the phase resetting as the mean of the untruncated distribution. The PRC for depolarization peaked at late phases and decreased to zero by the end of the cycle, whereas delays observed in response to hyperpolarization increased monotonically. The bias correction did not affect this difference in shape, which was due instead to the causal limit obscuring the iPRC for depolarization but not hyperpolarization. Our results suggest that weak periodic hyperpolarizing drive can theoretically entrain CA1 pyramidal neurons at any phase but that strong excitation will preferentially phase-lock them with zero time lag.

Features of proximal and distal excitatory synaptic inputs to layer V neurons of the rat medial entorhinal cortex.

The entorhinal cortex (EC) has a fundamental function in transferring information between the hippocampus and the neocortex. EC layer V principal neurons are the main recipients of the hippocampal output and send processed information to the neocortex, likely playing an important role in memory processing and consolidation. Most of these neurons have apical dendrites that extend to the superficial layers and are rich in spines, which could be the targets of excitatory inputs from fibres innervating that region. We have used electrical stimulation of afferent fibres coupled with whole-cell patch-clamp somatic recordings to study the features of distal excitatory inputs and compare them with those of proximal ones. The amplitude of putative unitary excitatory responses was ∼1.5 times larger for distal compared with proximal inputs. The responses were purely glutamatergic, as they were abolished by a combination of AMPA and NMDA glutamatergic receptor antagonists. Blockade of I(h) by 4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride (ZD7288) increased temporal summation; the increase was comparable for proximal and distal inputs. Proximal inputs initiated a somatic spike more reliably than distal ones; in some instances, somatic action potentials triggered by distal stimulation were preceded by dendritic spikes that fully propagated to the soma. Altogether, our results show that medial layer V entorhinal neurons receive excitatory synapses at distal dendritic locations, which gives them access to information encoded by inputs to the superficial layers as well as the deep layers. These findings are fundamentally relevant to understanding the role of the EC in the formation and consolidation of episodic memory.

Distance- and activity-dependent modulation of spike back-propagation in layer V pyramidal neurons of the medial entorhinal cortex.

Layer V principal neurons of the medial entorhinal cortex receive the main hippocampal output and relay processed information to the neocortex. Despite the fundamental role hypothesized for these neurons in memory replay and consolidation, their dendritic features are largely unknown. High-speed confocal and two-photon Ca(2+) imaging coupled with somatic whole cell patch-clamp recordings were used to investigate spike back-propagation in these neurons. The Ca(2+) transient associated with a single back-propagating action potential was considerably smaller at distal dendritic locations (>200 µm from the soma) compared with proximal ones. Perfusion of Ba(2+) (150 µM) or 4-aminopyridine (2 mM) to block A-type K(+) currents significantly increased the amplitude of the distal, but not proximal, Ca(2+) transients, which is strong evidence for an increased density of these channels at distal dendritic locations. In addition, the Ca(2+) transients decreased with each subsequent spike in a 20-Hz train; this activity-dependent decrease was also more prominent at more distal locations and was attenuated by the perfusion of the protein kinase C activator phorbol-di-acetate. These data are consistent with a phosphorylation-dependent control of back-propagation during trains of action potentials, attributable mainly to an increase in the time constant of recovery from voltage-dependent inactivation of dendritic Na(+) channels. In summary, dendritic Na(+) and A-type K(+) channels control spike back-propagation in layer V entorhinal neurons. Because the activity of these channels is highly modulated, the extent of the dendritic Ca(2+) influx is as well, with important functional implications for dendritic integration and associative synaptic plasticity.

Local control of postinhibitory rebound spiking in CA1 pyramidal neuron dendrites.

Postinhibitory rebound spiking is characteristic of several neuron types and brain regions, where it sustains spontaneous activity and central pattern generation. However, rebound spikes are rarely observed in the principal cells of the hippocampus under physiological conditions. We report that CA1 pyramidal neurons support rebound spikes mediated by hyperpolarization-activated inward current (I(h)), and normally masked by A-type potassium channels (K(A)). In both experiments and computational models, K(A) blockage or reduction consistently resulted in a somatic action potential upon release from hyperpolarizing injections in the soma or main apical dendrite. Rebound spiking was systematically abolished by the additional blockage or reduction of I(h). Since the density of both K(A) and I(h) increases in these cells with the distance from the soma, such "latent" mechanism may be most effective in the distal dendrites, which are targeted by a variety of GABAergic interneurons. Detailed computer simulations, validated against the experimental data, demonstrate that rebound spiking can result from activation of distal inhibitory synapses. In particular, partial K(A) reduction confined to one or few branches of the apical tuft may be sufficient to elicit a local spike following a train of synaptic inhibition. Moreover, the spatial extent and amount of K(A) reduction determines whether the dendritic spike propagates to the soma. These data suggest that the plastic regulation of K(A) can provide a dynamic switch to unmask postinhibitory spiking in CA1 pyramidal neurons. This newly discovered local modulation of postinhibitory spiking further increases the signal processing power of the CA1 synaptic microcircuitry.

Associative pairing enhances action potential back-propagation in radial oblique branches of CA1 pyramidal neurons.

Back-propagating action potentials (bAPs) are involved in associative synaptic plasticity and the modulation of dendritic excitability. We have used high-speed confocal and two-photon imaging to measure calcium and voltage signals associated with action potential propagation into oblique branches of CA1 pyramidal neurons in adult hippocampal slices. The spatial profile of the bAP-associated Ca(2+) influx was biphasic, with an initial increase in the proximity of the branch point followed by a progressive decrease. Voltage imaging in the branches showed that bAP amplitude was initially constant and then steadily declined with distance from the soma. To determine the role of transient K(+) channels in this profile, we used external Ba(2+) (150 microm) as a channel blocker, after characterizing its effect on A-type K(+) channels in the apical trunk. Bath application of Ba(2+) significantly reduced the A-type K(+) current in outside-out patches and nearly eliminated the distance-dependent decrease in bAP amplitude and its associated Ca(2+) signal. Finally, small amplitude bAPs at more distal oblique branch locations could be boosted by simultaneous branch depolarization, such that the paired Ca(2+) signal became nearly the same for proximal and distal oblique dendrites. These data suggest that dendritic K(+) channels regulate the amplitude of bAPs to create a dendritic Ca(2+) signal whose magnitude is inversely related to the electrotonic distance from the soma when bAPs are not associated with a significant amount of localized synaptic input. This distance-dependent Ca(2+) signal from bAPs, however, can be amplified and a strong associative signal is produced once the proper correlation between synaptic activation and AP output is achieved. We hypothesize that these two signals may be involved in the regulation of the expression and activity of dendritic voltage- and ligand-gated ion channels.

State-dependent dendritic computation in hippocampal CA1 pyramidal neurons.

Depending on the behavioral state, hippocampal CA1 pyramidal neurons receive very distinct patterns of synaptic input and likewise produce very different output patterns. We have used simultaneous dendritic and somatic recordings and multisite glutamate uncaging to investigate the relationship between synaptic input pattern, the form of dendritic integration, and action potential output in CA1 neurons. We found that when synaptic input arrives asynchronously or highly distributed in space, the dendritic arbor performs a linear integration that allows the action potential rate and timing to vary as a function of the quantity of the input. In contrast, when synaptic input arrives synchronously and spatially clustered, the dendritic compartment receiving the clustered input produces a highly nonlinear integration that leads to an action potential output that is extraordinarily precise and invariant. We also present evidence that both of these forms of information processing may be independently engaged during the two distinct behavioral states of the hippocampus such that individual CA1 pyramidal neurons could perform two different state-dependent computations: input strength encoding during theta states and feature detection during sharp waves.

On the initiation and propagation of dendritic spikes in CA1 pyramidal neurons.

Under certain conditions, regenerative voltage spikes can be initiated locally in the dendrites of CA1 pyramidal neurons. These are interesting events that could potentially provide neurons with additional computational abilities. Using whole-cell dendritic recordings from the distal apical trunk and proximal tuft regions and realistic computer modeling, we have determined that highly synchronized and moderately clustered inputs are required for dendritic spike initiation: approximately 50 synaptic inputs spread over 100 mum of the apical trunk/tuft need to be activated within 3 msec. Dendritic spikes are characterized by a more depolarized voltage threshold than at the soma [-48 +/- 1 mV (n = 30) vs -56 +/- 1 mV (n = 7), respectively] and are mainly generated and shaped by dendritic Na+ and K+ currents. The relative contribution of AMPA and NMDA currents is also important in determining the actual spatiotemporal requirements for dendritic spike initiation. Once initiated, dendritic spikes can easily reach the soma, but their propagation is only moderately strong, so that it can be modulated by physiologically relevant factors such as changes in the V(m) and the ionic composition of the extracellular solution. With effective spike propagation, an extremely short-latency neuronal output is produced for greatly reduced input levels. Therefore, dendritic spikes function as efficient detectors of specific input patterns, ensuring that the neuronal response to high levels of input synchrony is a precisely timed action potential output.

Associative mossy fibre LTP induced by pairing presynaptic stimulation with postsynaptic hyperpolarization of CA3 neurons in rat hippocampal slice.

Whole cell recordings of excitatory postsynaptic potentials/currents (EPSPs/EPSCs) evoked by minimal stimulation of commissural-associative (CF) and mossy fibre (MF) inputs were performed in CA3 pyramidal neurons. Paired responses (at 50 ms intervals) were recorded before, during and after hyperpolarization of the postsynaptic membrane (20-30 mV for 15-35 min). Membrane hyperpolarization produced a supralinear increase of EPSPs/EPSCs amplitude in MF-inputs. Synaptic responses remained potentiated for the rest of the recording period (up to 40 min) after resetting the membrane potential to control level (221 +/- 60%, n = 15 and 219 +/- 61%, n = 11 for MF-EPSP and MF-EPSC, respectively). We shall refer to this effect as hyperpolarization-induced LTP (HI-LTP). In the absence of afferent stimulation, membrane hyperpolarization was unable to produce HI-LTP. In contrast to MF-EPSPs, the mean amplitude of CF-EPSPs did not increase significantly after hyperpolarization relative to controls (138 +/- 29%, n = 22). HI-LTP was associated with modifications of classical indices of presynaptic release: paired-pulse facilitation, failures rate, coefficient of variation of EPSP amplitudes and quantal content. The induction of HI-LTP was NMDA independent but was dependent on metabotropic glutamate receptors (mGluRs) activation and calcium release from inositol 1,4,5-triphosphate (IP3)-sensitive intracellular stores: it was prevented by mGluR antagonist, intracellular heparin and BAPTA. We conclude that while the induction of HI-LTP was postsynaptic, its expression was presynaptic.

Phosphorylation-dependent differences in the activation properties of distal and proximal dendritic Na+ channels in rat CA1 hippocampal neurons.

At distal dendritic locations, the threshold for action potential generation is higher and the amplitude of back-propagating spikes is decreased. To study whether these characteristics depend upon Na+ channels, their voltage-dependent properties at proximal and distal dendritic locations were compared in CA1 hippocampal neurons. Distal Na+ channels activated at more hyperpolarized voltages than proximal (half-activation voltages were -20.4 +/- 2.4 mV vs. -12.0 +/- 1.7 mV for distal and proximal patches, respectively, n = 16, P < 0.01), while inactivation curves were not significantly different. The resting membrane potential of distal regions also appeared to be slightly but consistently more hyperpolarized than their proximal counterpart. Staurosporine, a non-selective protein kinase inhibitor, shifted the activation curves for both proximal and distal Na+ channels to the left so that they overlapped and also caused the resting potentials to be comparable. Staurosporine affected neither the inactivation kinetics of Na+ currents nor the reversal potential for Na+. These results suggest that the difference in the voltage dependence of activation of distal and proximal Na+ channels can be attributed to a different phosphorylation state at the two locations.