Long-term Changes In Excitability Research Articles

Multiscale effects of excitatory-inhibitory homeostasis in lesioned cortical networks: A computational study.

Stroke-related disruptions in functional connectivity (FC) often spread beyond lesioned areas and, given the localized nature of lesions, it is unclear how the recovery of FC is orchestrated on a global scale. Since recovery is accompanied by long-term changes in excitability, we propose excitatory-inhibitory (E-I) homeostasis as a driving mechanism. We present a large-scale model of the neocortex, with synaptic scaling of local inhibition, showing how E-I homeostasis can drive the post-lesion restoration of FC and linking it to changes in excitability. We show that functional networks could reorganize to recover disrupted modularity and small-worldness, but not network dynamics, suggesting the need to consider forms of plasticity beyond synaptic scaling of inhibition. On average, we observed widespread increases in excitability, with the emergence of complex lesion-dependent patterns related to biomarkers of relevant side effects of stroke, such as epilepsy, depression and chronic pain. In summary, our results show that the effects of E-I homeostasis extend beyond local E-I balance, driving the restoration of global properties of FC, and relating to post-stroke symptomatology. Therefore, we suggest the framework of E-I homeostasis as a relevant theoretical foundation for the study of stroke recovery and for understanding the emergence of meaningful features of FC from local dynamics.

Multiscale interactions between chemical and electric signaling in LTP induction, LTP reversal and dendritic excitability

Synaptic plasticity leads to long-term changes in excitability, whereas cellular homeostasis maintains excitability. Both these processes involve interactions between molecular events, electrical events, and network activity. Here I explore these intersections with a multilevel model that embeds molecular events following synaptic calcium influx into a multicompartmental electrical model of a CA1 hippocampal neuron. I model synaptic plasticity using a two-state (bistable) molecular switch that controls glutamate receptor insertion into the post-synaptic density. I also model dendritic activation of the MAPK signaling pathway, which in turn phosphorylates and inactivates A-type potassium channels. I find that LTP-inducing stimuli turn on individual spines and raise dendritic excitability. This increases the amount of calcium that enters due to synaptic input triggered by network activity. As a result, LTD is now induced in some synapses. Overall, this suggests a mechanism for cellular homeostasis where strengthening of some synapses eventually balances out through weakening of a possibly overlapping set of other synapses. Even in this very narrow slice of cellular events, interesting system properties arise at the interface between multiple scales of cellular function.

Transcranial magnetic stimulation primes the effects of exercise therapy in multiple sclerosis

Exercise therapy (ET) can be beneficial in disabled multiple sclerosis (MS) patients. Intermittent transcranial magnetic theta burst stimulation (iTBS) induces long-term excitability changes of the cerebral cortex and may ameliorate spasticity in MS. We investigated whether the combination of iTBS and a program of ET can improve motor disability in MS patients. In a double-blind, sham-controlled trial, 30 participants were randomized to three different interventions: iTBS plus ET, sham stimulation plus ET, and iTBS alone. Before and after 2 weeks of treatment, measures of spasticity through the modified Ashworth scale (MAS) and the 88 items Multiple Sclerosis Spasticity Score questionnaire (MSSS-88), fatigue through the Fatigue Severity Scale (FSS), daily living activities (ADL) through the Barthel index and health-related quality of life (HRQoL) through the 54 items Multiple Sclerosis Quality of life inventory (MSQoL-54) were collected. iTBS plus ET reduced MAS, MSSS-88, FSS scores, while in the Barthel index and MSQoL-54, physical composite scores were increased. iTBS alone caused a reduction of the MAS score, while none of the measured scales showed significant changes after sham iTBS plus ET. iTBS associated with ET is a promising tool for motor rehabilitation of MS patients.

Induction of Cortical Plastic Changes in Wrist Muscles by Paired Associative Stimulation in the Recovery Phase of Stroke Patients

Background. Paired associative stimulation (PAS) combining peripheral nerve and transcranial magnetic stimulation (TMS) have been proposed to induce long-term changes in excitability of the cerebral cortex and potentially optimize motor recovery in stroke patients. Objective. This pilot study examined whether short-lasting changes in cortical excitability could be induced by a single session of PAS within the first months after stroke. Methods. Six hemiparetic patients with a subcortical stroke were included. The single session PAS protocol was applied at 1, 5, and 12 months after stroke. During the follow-up, the clinical recovery of wrist function was assessed in parallel to the PAS study by the Fugl-Meyer motor scale and dynamometry of wrist extension. Results. The PAS protocol induced a significant extensor carpi radialis motor evoked potential facilitation (mean +78.5%) on the paretic side 5 months after stroke. The facilitation was still present 12 months after stroke but on average smaller (+30 %). Conclusions. These electrophysiological findings suggest that patients with subcortical infarcts may respond to PAS in an earlier than later period after stroke. If the clinical efficacy of interventions such as PAS is confirmed, it could be proposed early as add-on therapy to optimize training-induced plasticity processes.

Cholera Toxin Induces Sustained Hyperexcitability in Submucosal Secretomotor Neurons in Guinea Pig Jejunum

Neural mechanisms underlying cholera toxin (CT)-induced intestinal hypersecretion remain unclear. We investigated long-term excitability changes in vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY) secretomotor neurons after prolonged luminal exposure to CT. Isolated segments of guinea pig jejunum were incubated with saline or CT +/- neurotransmitter antagonist in the lumen; the submucosal plexus was then dissected clear, circumferentially adjacent to intact mucosa. Synaptic inputs and firing properties of S neurons in ganglia next to the mucosa in control saline were studied using intracellular recording. Neurons were processed for VIP and NPY immunoreactivity. Thirty S neurons (20 VIP(+), 7 NPY(+), 3 VIP(-)/NPY(-)) from CT-treated preparations and 27 control S neurons (19 VIP(+), 4 NPY(+), 4 VIP(-)/NPY(-)) in ganglia adjacent to intact mucosa were analyzed. VIP(+) and NPY(+) neurons in CT-treated preparations fired significantly more action potentials and for longer periods during injected depolarizing current pulses (50-350 pA) than control neurons. Addition of tetrodotoxin, hexamethonium, granisetron, or the neurokinin-1 (NK1) antagonist SR140333 during the CT incubation blocked CT-induced effects in both neuron types. The NK3 antagonist SR142801 blocked CT-induced effects in NPY(+) neurons and reduced the number of action potentials in VIP(+) neurons. Synaptic activity was unaffected by CT. CT induces specific and sustained hyperexcitability of secretomotor neurons in enteric pathways. CT acts in the mucosa. Its effect is neurally mediated and depends on 5-hydroxytryptamine-3, nicotinic, and NK1 receptors. This system represents a unique model to understand the neural mechanisms of action of CT and to identify therapeutic targets.

Focusing Effect of Acetylcholine on Neuroplasticity in the Human Motor Cortex

Cholinergic neuromodulation is pivotal for arousal, attention, and cognitive processes. Loss or dysregulation of cholinergic inputs leads to cognitive impairments like those manifested in Alzheimer's disease. Such dysfunction can be at least partially restored by an increase of acetylcholine (ACh). In animal studies, ACh selectively facilitates long-term excitability changes induced by feed-forward afferent input. Consequently, it has been hypothesized that ACh enhances the signal-to-noise ratio of input processing. However, the neurophysiological foundation for its ability to enhance cognition in humans is not well documented. In this study we explore the effects of rivastigmine, a cholinesterase inhibitor, on global and synapse-specific forms of cortical plasticity induced by transcranial direct current stimulation (tDCS) and paired associative stimulation (PAS) on 10-12 healthy subjects, respectively. Rivastigmine essentially blocked the induction of the global excitability enhancement elicited by anodal tDCS and revealed a tendency to first reduce and then stabilize cathodal tDCS-induced inhibitory aftereffects. However, ACh enhanced the synapse-specific excitability enhancement produced by facilitatory PAS and consolidated the inhibitory PAS-induced excitability diminution. These findings are in line with a cholinergic focusing effect that optimizes the detection of relevant signals during information processing in humans.

Does brain stimulation after stroke have a future?

Transcranial methods of cortical stimulation can induce long-term changes in excitability of the cerebral cortex in humans and may be useful as therapeutic interventions in stroke rehabilitation. Two approaches have been tested: (1) increasing excitability of the cortex in the stroke hemisphere and (2) suppression of the non-stroke hemisphere to reduce potential interference with function of the stroke hemisphere. The interventions have been transcranial direct current stimulation, transcranial magnetic stimulation and implanted epidural stimulation. All have been reported to give 10-20% functional improvement in small numbers of patients in single-session studies as well as in a small number of longer-term therapeutic trials. Preliminary experiments in aphasic patients using transcranial magnetic stimulation in an interference design show, however, that stimulation of the nonstroke hemisphere can in some patients reduce verbal fluency, questioning the general applicability of the second approach. Cortical stimulation appears to be a safe and promising intervention for stroke patients. More studies are needed to assess its long-term benefits on substantial numbers of patients. We need to know what type of intervention is best, which patients are likely to benefit, the optimum time to intervene and the duration of any benefits.

Ionic Mechanism Underlying Recovery of Rhythmic Activity in Adult Isolated Neurons

Neurons exhibit long-term excitability changes necessary for maintaining proper cell and network activity in response to various inputs and perturbations. For instance, the adult crustacean pyloric network can spontaneously recover rhythmic activity after complete shutdown resulting from permanent removal of neuromodulatory inputs. Dissociated lobster stomatogastric ganglion (STG) neurons have been shown to spontaneously develop oscillatory activity via excitability changes. Rhythmic electrical stimulation can eliminate these oscillatory patterns in some cells. The ionic mechanisms underlying these changes are only partially understood. We used dissociated crab STG neurons to study the ionic mechanisms underlying spontaneous recovery of rhythmic activity and stimulation-induced activity changes. Similar to lobster neurons, rhythmic activity spontaneously develops in crab STG neurons. Rhythmic hyperpolarizing stimulation can eliminate, but more commonly accelerate, the emergence of stable oscillatory activity depending on Ca(2+) influx at hyperpolarized voltages. Our main finding is that upregulation of a Ca(2+) current and downregulation of a high-threshold K(+) current underlies the spontaneous homeostatic development of oscillatory activity. However, because of a nonlinear dependence on stimulus frequency, hyperpolarization-induced oscillations appear to be inconsistent with a homeostatic regulation of activity. We find no difference in the activity patterns or the underlying ionic currents involved between neurons of the fast pyloric and the slow gastric mill networks during the first 10 days in isolation. Dynamic-clamp experiments confirm that these conductance modifications can explain the observed activity changes. We conclude that spontaneous and stimulation-induced excitability changes in STG neurons can both result in intrinsic oscillatory activity via regulation of the same two conductances.

Correlation of electrophysiology, shape and synaptic properties of myenteric AH neurons of the guinea pig distal colon

Well-defined correlations between morphology, electrophysiological properties and the types of synaptic inputs received are established for myenteric neurons in the guinea pig ileum. However, in the distal colon, the correlations between AH electrophysiological properties, presence of fast excitatory post-synaptic potentials (EPSPs) and neuronal shape have been inadequately resolved and it is unknown whether any colon neurons receive synaptic inputs that generate sustained excitation. In this work, we have used intracellular recording, dye filling via the recording electrode, and immunohistochemistry to classify distal colon neurons. Neurons (24 of 168) had Dogiel type II morphology and 42% of these were dendritic type II neurons, compared to about 10% in the ileum. All Dogiel type II neurons had AH electrophysiological properties, including a prolonged post-spike after-hyperpolarization (AHP). None of these received fast excitatory post-synaptic potentials, 11 of 22 tested exhibited sustained slow post-synaptic excitation (SSPE) in response to 1 Hz pre-synaptic stimulation and 13 of 15 tested were immunoreactive for calbindin. Neurons (127) had Dogiel type I, filamentous or other uniaxonal cell shape and S type electrophysiology. Neurons of this group had fast excitatory post-synaptic responses to stimulation of synaptic inputs, but did not exhibit a prolonged post-spike after-hyperpolarization or sustained slow post-synaptic excitation. Another group of neurons (17) had both AH electrophysiological characteristics and fast excitatory post-synaptic potentials. These neurons had Dogiel type I, filamentous or other uniaxonal shapes, but none had Dogiel type II morphology and none showed sustained slow post-synaptic excitation. It is concluded that Dogiel type II neurons are all AH neurons and are probably intrinsic sensory neurons that could be involved in long-term changes in excitability in the colon. All other neurons are monoaxonal; these are motor neurons and interneurons, and most are S neurons, electrophysiologically. A small number of monoaxonal neurons display AH electrophysiology and also receive fast excitatory synaptic inputs. These include motor and interneurons, but not sensory neurons.

Dynamic regulation of K+ channel gene expression in differentiated cells.

Recent studies have determined that K+ channel gene expression is dynamically controlled in endocrine, cardiac, and neuronal cells. This regulation is induced by physiological stimuli (e.g., hormones, transmitters, depolarization), drugs (e.g., opiates) and with pathophysiological conditions (e.g., seizures, hypertension). In many cases, alterations in subunit expression are driven by transcriptional changes. Furthermore, resultant changes in excitability can be produced within hours because of the rapid turnover of Kv-channel proteins. Finally, the consequences of altering K+-channel subunit are complex because a single gene product can participate in forming functionally distinct homomeric and heteromeric channels in the same cell. Thus, regulating K+-channel genes constitutes a novel mechanism for producing intricate long-term changes in excitability.

Differential expression of the metabotropic glutamate receptor mGluR1alpha by neurons and axons in the cochlear nucleus: in situ hybridization and immunohistochemistry.

mGluR1alpha is a metabotropic glutamate receptor involved in synaptic modifiability. A differential expression in specific neuronal types could reflect their different connections and response properties in central auditory processing. Using in situ hybridization and immunohistochemistry, we studied mGluR1alpha receptor expression throughout the cochlear nucleus. Robust labeling occurred in the dorsal cochlear nucleus and small cell shell, with less in the ventral cochlear nucleus. Among the most intensely labeled were the granule cells of the small cell shell. In the dorsal cochlear nucleus, most cell types expressed message and receptor protein, except granule cells. High levels of receptor were expressed by corn cells and cartwheel cells. The terminal dendrites and synaptic spines of cartwheel and fusiform cells contained receptor protein in the molecular layer, where they could synapse with parallel fibers. Fusiform dendrites also expressed mRNA for mGluR1alpha. The basal dendrites of fusiform cells contained receptor protein in the region where they receive cochlear nerve synapses. Immunostaining of terminal axons was prominent in the molecular layer and the small cell shell, where they were associated with synaptic nests, structures thought to provide long-term changes in excitability. Differential expression levels may reflect different functional requirements of specific cell types, including inhibitory interneurons, like corn cells and cartwheel cells, and excitatory interneurons, like granule cells in the small cell shell, which may participate in local circuits involved in modulatory or gating functions, such as stimulus enhancement or suppression. In presynaptic axons, mGluR1alpha may relate to the long-term signaling requirements of their modulatory functions.

Long-term changes in excitability induced by protein kinase C activation in Aplysia sensory neurons.

Protein kinases A (PKA) and C (PKC) play a central role as intracellular transducers during simple forms of learning in Aplysia. These two proteins seem to cooperate in mediating the different forms of plasticity underlying behavioral modifications of defensive reflexes in a state- and time-dependent manner. Although short- and long-term changes in the synaptic efficacy of the connections between mechanosensory neurons and motoneurons of the reflex have been well characterized, there is also a distinct intermediate phase of plasticity that is not as well understood. Biochemical and physiological experiments have suggested a role for PKC in the induction and expression of this form of facilitation. In this report, we demonstrate that PKC activation can induce both intermediate- and long-term changes in the excitability of sensory neurons (SNs). Short application of 4beta-phorbol ester 12,13-dibutyrate (PDBU), a potent activator of PKC, produced a long-lasting increase in the number of spikes fired by SNs in response to depolarizing current pulses. This effect was observed in isolated cell culture and in the intact ganglion; it was blocked by a selective PKC inhibitor (chelerythrine). Interestingly, the increase in excitability measured at an intermediate-term time point (3 h) after treatment was independent of protein synthesis, while it was disrupted at the long-term (24 h) time point by the general protein synthesis inhibitor, anisomycin. In addition to suggesting that PKC as well as PKA are involved in long-lasting excitability changes, these findings support the idea that memory formation involves multiple stages that are mechanistically distinct at the biochemical level.

Short-term and long-term excitability changes of the insular cortical neurons after the acquisition of taste aversion learning in behaving rats

Conditioned taste aversion, a long-lasting type of learning established after a single pairing of a novel taste and subsequent internal malaise, [2, 17]is an adaptive behavior to prevent animals from repeated intakes of poisonous substances. The present study was designed to identify the time-dependent excitability changes of cortical neurons to gustatory stimuli after the acquisition of conditioned taste aversion in freely behaving rats. Conditioned taste aversion to saccharin was established by an intraperitoneal injection of lithium chloride, a sickness-inducing agent, soon after an intraoral infusion of saccharin. Twenty minutes after the pairing, 25 (29%) of 86 rats showed aversive taste reactivities to saccharin, and 30 min after the pairing, all of the rats showed aversive behaviors to saccharin; these behavioral changes lasted throughout the test session (over 360 min). When unit activities were recorded from the insular cortex simultaneously with the behavioral test, 14 (11%) of 122 neurons showed a significant enhancement of excitability in response to saccharin, but not to other taste stimuli, after the acquisition of taste aversion. Eight of these 14 neurons showed a short-term enhancement: significant effects were detected only 30 min after the pairing. The remaining six neurons exhibited a long-term enhancement: the effects lasted over 360 min after the pairing. The existence of such short-term and long-term excitability changes suggests that the gustatory insular cortex is involved in different aspects of taste aversion learning.

Activity-dependent induction of functional secretory properties at cultured neuromuscular synapses of Helisoma.

1. The role of activity-dependent mechanisms in target-mediated induction of secretory properties was investigated at regenerating neuromuscular synapses of the American pond snail, Helisoma trivolvis, in cell culture. 2. Identified motoneurons were isolated into cell culture conditions that promoted neurite outgrowth. Buccal neurons 19 (B19) were cultured alone for 2 days, at which time dissociated muscle fibers were manipulated into contact with newly formed neurites. 3. Immediately before the plating of muscle fibers, the sodium channel blocker, tetrodotoxin (TTX), or the acetylcholine receptor antagonist, d-tubocurarine chloride (curare), was added to the culture dish. After 48 h of exposure, the inhibitors were removed by repeated dilution of the culture medium and electrophysiological analyses were performed. 4. Cholinoceptive assay cells were manipulated into contact with the presynaptic neurons to assess secretory properties along neuronal processes. Assay cells were used to control for variations in postsynaptic sensitivity that could result from long-term exposure to activity inhibitors. 5. These analyses demonstrated that inhibition of TTX-sensitive presynaptic activity and inhibition of curare-sensitive postsynaptic activation both blocked the induction of excitation-secretion coupling typically induced in these motoneurons by appropriate target contact. Neuron B5, which rapidly acquires functional synaptic properties in vitro, was unaffected in its secretory function by 48 h of activity inhibition. 6. Acquisition of secretory competence was not suppressed due to a reduction in the viability or long-term changes in excitability of the activity-inhibited neurons, as indicated by analyses of electrophysiological properties. 7. Although target-contact and activity both participated in the induction of secretory modifications in neuron B19, target-mediated changes did not involve retrograde effects on presynaptic neuronal excitability. 8. We hypothesize that contact-mediated mechanisms govern the initiation of presynaptic modifications in B19, however, our data indicate that the acquisition of functional excitation-secretion coupling also involves activity-dependent mechanisms. Although the mechanistic role of activity remains undefined, our results suggest that the activation of the target muscle plays a critical role in a retrograde signaling pathway underlying maturation of a functional secretory apparatus in target-contacted neuronal processes.

Time‐Dependent Increase in Protein Phosphorylation Following One‐Trial Enhancement in Hermissenda

One-trial conditioning of the nudibranch mollusk Hermissenda produces short- and long-term changes in excitability (enhancement) of identified sensory neurons. To investigate the biochemical mechanisms underlying this example of plasticity, we have examined changes in protein phosphorylation at different times following the in vitro conditioning trial. Changes in the incorporation of 32 PO4 into proteins were determined using two-dimensional polyacrylamide gel electrophoresis, autoradiography, and densitometry. Conditioning resulted in increases in levels of several phosphoproteins, five of which, ranging in apparent molecular mass from 22 to 55 kDa, were chosen for analysis. The increased phosphorylation of the 46- and 55-kDa phosphoproteins, detected 2 h postconditioning was significantly greater than the level of phosphorylation detected in an unpaired control group, indicating that long-term enhancement is pairing specific. Statistically significant increases in phosphorylation as compared with the control group that received only light were detected immediately after conditioning (5 min) for the 55-, 46-, and 22-kDa phosphoproteins, at 1 h for the 55- and 46-kDa phosphoproteins, and at 2 h for the 55-, 46-, and 22-kDa phosphoproteins. The 46- and 55-kDa phosphoproteins are putative structural proteins, and the 22-kDa phosphoprotein is proposed to be a protein kinase C substrate previously identified in Hermissenda following multitrial classical conditioning. Time-dependent increases in protein phosphorylation may contribute to the induction and maintenance of different memory stages expressed in sensory neurons after one-trial conditioning.

Hyperalgesia following noxious thermal, mechanical, or chemical stimulation involves overlapping spinal mechanisms and interactive participation of excitatory amino acids and neuropeptides

H yperalgesia is an increased response to a stimulus that is normally painful. Clinical observations and basic science data indicate a primary hyperalgesia that is associated with an area of tissue damage and is attributed to altered sensitivity of peripheral afferent fibers, and a secondary hyperalgesia that radiates from the original affected tissue and is attributed to a change in function of central pain processing mechanisms. 2'29, 3o,58,61,64 Hyperalgesia is one of a number of terms given to relatively long-term changes in excitability of nociceptive mechanisms; other terms include allodynia, windup, and sensitization. All of these changes seem to involve an increased excitability or facilitation of nociceptive mechanisms and, at least among those attributed to a CNS or a spinal mechanism, NMDA receptors have been implicated by a number of reports. In his focus article, Stephen Mellet has made an attempt to describe the mechanisms at the spinal level that bring about thermal and mechanical hyperalgesia. While we agree with some of his interpretations of the literature, we also have marked differences. He presents the hypothesis that thermal and mechanical hyperalgesia are brought about by different mechanisms, thermal hyperalgesia

Presynaptic long-term changes in excitability of the corticostriatal pathway.

We employed measurements of striatal terminal excitability to monitor the presynaptic effects of tetanic stimulation of corticostriatal fibers. Cortical tetanic stimulation (CTS) initiated a long-lasting decrease in terminal excitability. With higher current CTS, a transient increase in excitability preceded the decrease. However, a long-term increase was induced (1) by a second tetanus applied during the brief elevation in excitability initiated by a previous CTS or (2) when dopamine and GABA transmission were disrupted. A long-term increase also occurred following tetanic stimulation of the striatal terminal field (STS). The direction of the long-lasting change in excitability may depend on the level of polarization of the membrane. These presynaptic mechanisms could be important for the long-term selective modification of striatal synaptic transmission.

Multiple ionic mechanisms are activated by the potent agonist quisqualate in cultured cerebellar Purkinje neurons

Current clamp recordings were used to analyze responses of cultured cerebellar Purkinje neurons to quisqualate and several other selectivenon- N-methyl- d-aspertate (NMDA) agonists. Quisqualate, a potent agonist in the cerebellar Purkinje neuron, evoked both short- and long-term changes in excitability, that activated within seconds and lasted for several minutes. Two components of the response were activated differentially by subtype selective agonists, and differed in their mechanism of expression and time course. The initial component of the response was activated by ionotropic agonists ((RS)-d-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) domoate), and by quisqualate and glutamate which are effective at both the ionotropic and metabotropic quisqualate receptor subtypes, but not by the metabotropic agonist trans(±)-1amino-1,3-cyclopentanedicarboxylic acid (ACPD). This component was dependent on extracellular Na +, and characterized by a rapid depolarization with a short latency (<1–2 s) and a decrease in membrane resistance as expected for an ionotropic response. The rapid depolarization extended into an agonist-dependent plateau phase, which could not be evoked by depolarization alone. The second (‘late’) phase of the response was a slowly-activating, long-lasting change in membrane excitability, accompanied by little or no change in the membrane potential. The late phase, marked by an increase in voltage-dependent bursting spike activity, was induced by the metabotropic agonist, ACPD, and by quisqualate and glutamate, but not by ionotropic selective agonists such as AMPA. Little or no bursting was evoked by AMPA, domoate, kainate or homocysteate. This late phase was also accompanied by increases in the magnitude and duration of the complex spikes and in the afterhyperpolarization following brief current-driven depolarizations. The slower time course of the late component is consistent with a pathway involving second messenger systems. Our results support the hypothesis that coregulation of both ionotropic and metabotropic mechanisms produces the complex and prolonged excitatory response characteristic of the Purkinje neuron.

Long-term increases in excitability in the CA1 region of rat hippocampus induced by beta-adrenergic stimulation: possible mediation by cAMP

The cellular mechanisms underlying beta-adrenergic potentiation in the CA1 region of the rat hippocampus were examined. A 10 min treatment with isoproterenol (ISO) induced a long-term depolarization of the pyramidal neurons that persisted for at least 30 min of washout; the ISO-induced decrease in the calcium-activated potassium conductance (afterhyperpolarization, or AHP) was similarly prolonged. The long-term excitability changes induced by ISO did not depend upon the calcium concentration of the medium and could be elicited in medium containing as little as 240 microM calcium. The persistent increase in population spike induced by ISO was mimicked by superfusion with several cAMP analogs and by forskolin (which directly activates adenylate cyclase), but not by the inactive dideoxyforskolin. Forskolin and cAMP analogs also induced decreases in AHPs that could be quite prolonged, but did not depolarize pyramidal neurons as consistently as did ISO. We hypothesize that activation of beta-adrenergic receptors in the CA1 region of hippocampus may induce an alteration of the hippocampal "state" that can persist for as long as several hours, during which the induction of other forms of plasticity may be enhanced.

An iontophoretic study of single somatosensory neurons in rat granular cortex serving the limbs: a laminar analysis of glutamate and acetylcholine effects on receptive-field properties.

1. Glutamate, acetylcholine (ACh), and bicuculline were delivered by iontophoretic pipettes to the 545 neurons described in the preceding paper. Their response properties were examined to determine the effect of these compounds on the behavior of neurons in rat somatosensory cortex. 2. The responses to glutamate covered a broad range. Some cells were completely depolarized by small amounts of this excitatory amino acid, whereas others were extremely insensitive requiring in excess of 100 nA to be excited. This range of sensitivities was seen throughout all cortical layers. 3. Glutamate was most effective in uncovering new receptive fields or in enhancing preexisting somatic responses in the bottom of layer II/III and in layer IV. Receptive fields uncovered by glutamate had properties comparable to receptive fields observed without drugs. Overall, glutamate enhanced the ability of afferent inputs to drive 39% of the neurons tested. 4. In 61% of the cells tested with glutamate there was no evidence of somatic input even during excitation with glutamate. Of 50 cells displaying receptive fields, only two were enlarged by treatment with glutamate. For 36 other cells receptive fields of normal dimensions were uncovered during glutamate administration. 5. Bicuculline uncovered more somatic inputs than either glutamate or ACh, leaving only 37% of 86 cells tested without evidence of excitatory inputs from the skin. Bicuculline produced an average receptive-field enlargement of 8.7 times in 11 of 56 cells tested. This drug acted uniformly throughout the cortical layers. 6. ACh excited 36.9% of the 360 cells tested. Those excited tended to be located in laminae Vb and VIb. The effects of ACh on afferent response properties could not be predicted from its ability to excite a cell. The magnitude of the response to 100 nA of ACh varied with the laminar position of the cell being tested, being weakest in layer II/III and greatest in layer Vb. 7. Overall, 34.2% of 263 cells showed changes in afferent drive during ACh treatment. ACh enhanced the responses to somatic stimulation most frequently in laminae IV and V. 8. Of the 90 neurons tested for long-term effects, 27% displayed effects of ACh that significantly outlasted the duration of the ACh administration. In 18% of these, changes lasted for greater than 5 min, sometimes remaining altered for the duration of the time that the cell was studied. These long-term changes in excitability were generally produced by administration of ACh during the time that the cell was excited by glutamate or by somatic stimulation.