Sensorimotor Neocortex Research Articles

Prolonged prophylactic effects of gabapentin on status epilepticus-induced neocortical injury

Long-term consequences of status epilepticus (SE) occur in a significant proportion of those who survive the acute episode. We developed an in vivo model of acute focal neocortical SE (FSE) to study long-term effects on local cortical structure and function and potential strategies to mitigate adverse consequences of SE. An acute 2 h episode of FSE was induced in anesthetized mice by epidural application of gabazine +4-aminopyridine over sensorimotor neocortex. Ten and 30 days later, the morphological and functional consequences of this single episode of FSE were studied using immunocytochemical and electrophysiological techniques. Results, focused on cortical layer V, showed astrogliosis, microgliosis, decreased neuronal density, and increased excitatory synapses, along with increased immunoreactivity for thrombospondin 2 (TSP2) and α2δ-1 proteins. In addition, neocortical slices, obtained from the area of prior focal seizure activity, showed abnormal epileptiform burst discharges along with increases in the frequency of miniature and spontaneous excitatory postsynaptic currents in layer V pyramidal cells, together with decreases in both parvalbumin immunoreactivity (PV-IR) and the frequency of miniature inhibitory postsynaptic currents in layer V pyramidal cells. Treatment with an approved drug, gabapentin (GBP) (ip 100 mg/kg/day 3×/day for 7 days following the FSE episode), prevented the gliosis, the enhanced TSP2- and α2δ-1- IR and the increased excitatory synaptic density in the affected neocortex. This model provides an approach for assessing adverse effects of FSE on neocortical structure and function and potential prophylactic treatments.

Architectonics of GABAergic inhibitory network in the sensorimotor area of the rat neocortex in the early postnatal period under normal conditions and after acute perinatal hypoxia

The distribution of GABAergic interneurons as well as terminal and synaptic networks in different layers of the rat sensorimotor neocortex were studied at different stages of the postnatal period under normal conditions and after exposure to perinatal hypoxia. In control animals, the architectonics of the inhibitory network in different layers of the sensorimotor neocortex was shown to display distinctive features at different stages of the postnatal development. At early postnatal stages, a significant portion of neurons in layers II–V are immunopositive for GAD-67, indicative of a high level of GABA expression, however, GABA transmission is extremely weak, thus supporting the presence in the neuropil of only sporadic GABAergic terminals and synapses. By the juvenile age, a dramatic drop in the number of GABAergic neurons and an increase in the density of the network of GABA-immunopositive processes and synaptic structures occur in the neuropil, suggesting a considerable increase in GABA transmission. A higher level of GABA transmission is revealed in layers IV and V, persisting over the prepubertal period. Our results demonstrate that acute perinatal hypoxia affects the state of the inhibitory GABAergic network in the rat sensorimotor neocortex during the postnatal period. GABA expression and transmission were shown to change virtually in all layers.

Persistent enhancement of functional MRI responsiveness to sensory stimulation following repeated seizures

Neural reorganization and interictal behavioral anomalies have been documented in people with epilepsy and in animal seizure models. Alterations in behavior could be due to somatosensory dysfunction. This study was designed to determine whether seizures can lead to changes in somatosensory representations and whether those changes are persistent. Twice-daily seizures were elicited by delivering 1 s of electrical stimulation through carbon fiber electrodes implanted in both the corpus callosum and sensorimotor neocortex of young adult male Long-Evans rats until a total of 20 seizures were elicited. Either 1-3 days or 3-5 weeks following the last seizure, functional magnetic resonance imaging (MRI) was used to image the brain during electrical stimulation of each forepaw independently. Forepaw stimulation in control rats resulted in a focused and contralateral fMRI signal in the somatosensory neocortex. Rats that had repeated seizures had a 151% increase in the number of voxels activated in the contralateral hemisphere 1-3 days after the last seizure and a 166% increase at 3-5 weeks after the last seizure. The number of voxels activated in response to forepaw stimulation was positively correlated with the duration of the longest seizure experienced by each rat. The intensity of the activated voxels was not significantly increased at either time interval from the last seizure. The increased area of activation in somatosensory cortex, which is persistent at 3-5 weeks, is consistent with previous observations of larger motor maps following seizures. Seizure-induced changes in the functioning of sensory cortex may also contribute to interictal behavioral anomalies.

A prolonged experimental febrile seizure results in motor map reorganization in adulthood

Introduction Clinical studies have suggested that children experiencing a febrile seizure (FS) before the age of 1 year have persistent deficits, but it is unknown whether these seizures lead to permanent cortical reorganization and alterations in function. A FS on the background of increased genetic seizure susceptibility may also lead to negative long-term consequences. Alterations in neocortical motor map expression provide a measure of neocortical reorganization and have been reported in both adults with frontal lobe epilepsy and following seizure induction in experimental models. The objectives of the present study were to determine whether 1) an infantile FS leads to changes to motor map expression in adulthood; 2) long-term cortical reorganization is a function of the age at FS or genetic seizure susceptibility; and 3) different levels of GABA A or glutamate receptor subunits or cation-chloride-co-transporters (CCCs) at the time of FS correlate with alterations to motor map expression. Materials and methods FSs were induced in postnatal day 10 (P10) or P14 Long–Evans (LE) rats or in P14 seizure-prone FAST rats by the administration of the bacterial endotoxin lipopolysaccharide (LPS) and a subconvulsant dose of kainic acid. Ten weeks later intracortical microstimulation was performed to generate motor maps of forelimb movement representations. Sensorimotor neocortex samples were also dissected from naïve P10 FAST and P10 and P14 LE pups for western blotting with antibodies against various GABA A, NMDA, and AMPA receptor subunits and for CCCs. Results Adult FAST rats had larger motor maps with lower stimulation thresholds after a FS at P14, while adult LE rats had significantly lower map stimulation thresholds but similar sized maps after a FS at P10 compared to controls. There were no differences in neocortical motor map size or stimulation thresholds in adult LE rats after a FS at P14. Both P10 LE and P14 FAST rats had significantly lower levels of the GABA A receptor α1 subunit, higher levels of the α2 subunit, and a higher NKCC1/KCC2 ratio in the sensorimotor cortex compared with the P14 LE rat. In addition, the P14 FAST rats had lower levels of the GluR2 and NR2A receptor subunits in the sensorimotor cortex compared with the P14 LE rats. Conclusions A single infantile FS can have long-term effects on neocortical reorganization in younger individuals and those with underlying seizure susceptibility. These changes may be related to an increased level of excitability in the neocortex of younger or genetically seizure-prone rats, as suggested by immaturity of their GABAergic and CCC systems. Given the high incidence of FSs in children, it will be important to gain a better understanding of how age and genetic seizure predisposition may contribute to the long-term sequelae of these events.

Seizures, but not lowered seizure thresholds, results in larger neocortical motor maps and concomitant disruptions in skilled motor behaviour

Kindling of the sensorimotor neocortex has been found to result in reorganization of the somatotopic map of movement representations as well as disruptions of skilled forelimb behaviours. It has been suggested that the repeated seizures induced during kindling altered motor maps, thereby disrupting the motor engram necessary for the production of skilled movements. However, kindling leads to neural changes other than those associated with repeated seizures, and the role of these comorbid effects is often overlooked. Our lab has developed a stimulation paradigm, which allows for the dissociation of the two main effects of kindling; repeated seizures and the reduction of afterdischarge (seizure) threshold. In the current study, we have utilized this paradigm to examine the effects of electrical stimulation on motor maps and skilled forelimb behaviour. We found that repeated seizures with no concomitant reduction of afterdischarge threshold resulted in large motor maps, as well as task specific deficits in skilled forelimb use and deficiencies in task acquisition. Rats that had reduced seizure thresholds and few seizures did not show alterations in map size or skilled forelimb use. These results suggest that movement disturbances following kindling are the result of repeated seizures, and not other stimulation-induced effects such as reduction of afterdischarge threshold. These results also corroborate the relationship between the integrity of movement representations and the ability to perform skilled motor tasks.

Neocortical movement representations are reduced and reorganized following bilateral intrastriatal 6-hydroxydopamine infusion and dopamine type-2 receptor antagonism

The neurophysiologic model of Parkinson's disease predicts nigrostriatal dopamine depletion leads to increased inhibitory basal ganglia output resulting in frontal neocortical hypoactivity. The nature of this hypoactivation is not well understood and modeled predominantly by a unilateral representation. Intracortical microstimulation (ICMS) was used to probe topographic movement representations of the left forelimb motor area 2 weeks following sham, unilateral left hemisphere or bilateral intrastriatal 6-hydroxydopamine (6-OHDA) infusion and under acute dopamine receptor antagonism with haloperidol in non-lesioned rats. 6-OHDA infusions induced a significant loss of substantia nigra pars compacta (SNc) dopamine neurons. Bilateral SNc lesions and haloperidol significantly reduced map area which was preserved in unilateral lesions. All lesion conditions and haloperidol induced significant map reorganization, characterized by increased representation of distal forelimb movements. Results suggest basal ganglia dopamine deficiency can affect the topographic organization of sensorimotor neocortex and lead to significant reduction in the size of motor representations. We conclude that the neurophysiologic model is supported but that bilateral loss of dopamine is required to see a reduction in the size of motor maps.

One hertz stimulation to the corpus callosum quenches seizure development and attenuates motor map expansion

Low-frequency stimulation applied through indwelling electrodes has been used to depress or depotentiate synaptic efficacy. Moreover it has been reported to inhibit seizure expression and progression when started either during or after seizures. We have recently shown that low-frequency stimulation can also reduce the size of seizure-enlarged movement representations (motor maps) when delivered after 30 afterdischarges that had propagated from the hippocampus to the neocortex. This study was designed to examine the effects of low-frequency stimulation delivered to the corpus callosum on motor map topography when applied during or after each elicited seizure. Specifically, 15 min of 1 Hz stimulation was applied to the corpus callosum either concurrent with or immediately following a neocortical afterdischarge that had propagated from the hippocampus. Long-Evans hooded rats were electrically stimulated twice daily in the right ventral hippocampus until the first neocortical afterdischarge was elicited. Rats then received low-frequency stimulation which began either with the afterdischarge or following each afterdischarge for 20 additional kindling sessions; a sham low-frequency stimulation group was also included. Afterdischarges were recorded from both hippocampal and neocortical sites, and seizure expression was documented. One to six days following the last stimulation session, forelimb movement representations were derived using high-resolution intracortical microstimulation in the left sensorimotor neocortex. Low-frequency stimulation following each kindled seizure, suppressed behavioral seizure severity and hippocampal afterdischarge duration, as well as attenuated kindling-induced motor map expansion.

Repeated seizures lead to altered skilled behaviour and are associated with more highly efficacious excitatory synapses

People with epilepsy have a high incidence of interictal behavioural problems that appear to be related to the location of their seizure focus. This study investigated a novel test of the hypotheses that repeated seizures result in behavioural deficits and altered performance during the interictal state, and that those behaviours are related to the presence of more highly efficacious excitatory synapses. We tested these hypotheses by first repeatedly eliciting seizures with electric current through indwelling electrodes in the corpus callosum at the level of the caudal forelimb area of sensorimotor neocortex in the rat. We then assessed learned skilled behaviours that primarily utilize the forelimbs on tasks that are sensitive to the functional integrity of that structure. We observed both behavioural deficits and altered kinematic performance in rats that experienced repeated neocortical seizures relative to an electrode-implanted control group. From a separate set of rats, tissue was prepared for quantification of thickness and excitatory synaptic subtypes from neocortical layer V. We observed significantly increased numbers of perforated synapses that make their connections directly onto the dendritic shaft at 3 weeks following the last seizure. Altered reaching behaviours are likely due to neural reorganization in the neocortex including more efficacious synapses.

Low-frequency stimulation reverses kindling-induced neocortical motor map expansion

Repeated application of low-frequency stimulation can interrupt the development and progression of seizures. Low-frequency stimulation applied to the corpus callosum can also induce long-term depression in the neocortex of awake freely moving rats as well as reduce the size of neocortical movement representations (motor maps). We have previously shown that seizures induced through electrical stimulation of the corpus callosum, amygdala or hippocampus can expand the topographical expression of neocortical motor maps. The purpose of the present study was to determine if low-frequency stimulation administered to the corpus callosum could reverse the expansion of neocortical motor maps induced by seizures propagating from the hippocampus. Adult Long-Evans hooded rats were electrically stimulated in the right ventral hippocampus, twice daily until 30 neocortical seizures were recorded. Subsequently, low-frequency stimulation was administered to the corpus callosum once daily for 20 sessions. High-resolution intracortical microstimulation was then utilized to derive forelimb-movement representations in the left (un-implanted) sensorimotor neocortex. Our results show that hippocampal seizures result in expanded motor maps and that subsequent low-frequency application can reduce the size of the expanded motor maps. Low-frequency stimulation may be an effective treatment for reversing seizure-induced reorganization of brain function.

Hippocampal Kindling Leads to Motor Map Expansion

To determine whether seizure activity, repeatedly elicited in the hippocampus, could alter the functional organization of neocortical movement representations (motor maps) and whether a relation exists between the number of afterdischarges recorded in the sensorimotor neocortex and the size of the motor maps. We electrically kindled the right ventral hippocampus of Long-Evans hooded rats, twice daily, for 40 sessions and recorded the afterdischarges in the stimulated hippocampus and right sensorimotor neocortex. Between 3 and 7 days after the last seizure, we used high-resolution intracortical microstimulation to derive the forelimb-movement representations in the left (un-implanted) sensorimotor neocortex. In the hippocampal kindled rats, we observed a dramatic expansion of the area of neocortex that would elicit forelimb movements compared with sham-kindled controls. The number of afterdischarges recorded in the neocortex was significantly and positively correlated with the size of the motor maps. Seizures propagating from the hippocampus have long-distance effects on the functional organization of motor maps.

Induction of Neocortical Long-Term Depression Results in Smaller Movement Representations, Fewer Excitatory Perforated Synapses, and More Inhibitory Synapses

Long-term depression (LTD) is one of the most widely investigated models of the synaptic mechanisms underlying learning and memory. Previous research has shown that induction of LTD in the neocortex decreases measures of pyramidal cell dendritic morphology in both layers III and V. Here, we investigated the effects of LTD induction on 1) the time course of recovery of synaptic efficacy, 2) movement representations, 3) cortical thickness and layer V neuron density, and 4) the density of excitatory and inhibitory synapses in layer V of sensorimotor neocortex. Rats carried a stimulating electrode in the midline corpus callosum and a recording electrode in the right sensorimotor neocortex. Each rat received either low-frequency stimulation composed of 900 pulses at 1 Hz or handling daily for a total of 20-25 days. Callosal-neocortical evoked potentials were recorded in the right hemisphere before and after stimulation or handling. Our results show that LTD induction lasts for 3 weeks and results in smaller motor maps of the caudal forelimb area. We did not observe any reduction in neocortical thickness or neuron density. There was a reduction in the density of excitatory perforated synapses and an increase in the density of inhibitory synapses in layer V of the sensorimotor neocortex, thereby providing a general mechanism for the reduction in motor map size. This study sheds light on the interaction between an artificial model of learning, receptive field characteristics, and synaptic number in the sensorimotor cortex.

Long-term potentiation induces expanded movement representations and dendritic hypertrophy in layer V of rat sensorimotor neocortex.

While long-term potentiation (LTP) is currently the most widely investigated model of the synaptic mechanisms underlying learning, there is a paucity of reports on the direct effects of LTP on cortical organization. Here we show that strengthening polysynaptic potentiation correlates with an expanded neocortical area that responds to intracortical microstimulation-induced movements of rat forelimb and increased dendritic material in layer V pyramidal cells. Rats carried a stimulating electrode in the corpus callosum (midline), and a recording electrode in the right caudal forelimb area (CFA). Each rat received 15 days of either high frequency stimulation (HFS) or handling. Evoked potentials of the transcallosal pathway were recorded in the right hemisphere before and after 15 days of stimulation or handling. Following the last stimulation, movement representations were determined in the left CFA using high-resolution intracortical microstimulation (ICMS) and then the brains were processed for Golgi-Cox staining. Our results show that synaptic modification results in a recruitment of more neocortical area into movement representations and increases in several measures of dendritic morphology in layers III and V. This study sheds light on the interaction between artificial models of learning, receptive field characteristics and dendritic morphology in the sensorimotor cortex.

Ampakines reduce methamphetamine-driven rotation and activate neocortex in a regionally selective fashion

It has been proposed that glutamatergic and dopaminergic systems are functionally opposed in their regulation of striatal output. The present study tested the effects of drugs that enhance AMPA-receptor-mediated glutamatergic transmission (ampakines) for their effects on dopamine-related alterations in cortical activity and locomotor behavior. Rats with unilateral 6-hydroxydopamine lesions of the ascending nigro-striatal dopamine system were sensitized to methamphetamine and then tested for methamphetamine-induced circling behavior in the presence and absence of ampakines CX546 and CX614. Both ampakines produced rapid, dose-dependent reductions in circling that were evident within 15 min and sustained through 1 h of behavioral testing. In situ hybridization maps of c-fos mRNA expression showed that in the intact hemisphere, ampakine cotreatment markedly increased c- fos expression in parietal, sensori-motor neocortex above that found in rats treated with methamphetamine alone. Ampakine cotreatment did not augment c- fos expression in frontal, sensori-motor cortex or striatum. Still larger ampakine-elicited effects were obtained in parietal cortex of the dopamine-depleted hemisphere where labeling densities were increased by approximately 60% above values found in methamphetamine-alone rats. With these effects, the hemispheric asymmetry of cortical activation was less pronounced in the ampakine-cotreatment group as compared with the methamphetamine-alone group. These results indicate that positive modulation of AMPA-type glutamate receptors 1) can offset behavioral disturbances arising from sensitized dopamine receptors and 2) increases aggregate neuronal activity in a regionally selective manner that is probably dependent upon behavioral demands.

Synaptic Reorganization in an Experimental Model of Posttraumatic Epilepsy.

Synaptic Activity in Chronically Injured, Epileptogenic Sensorimotor Neocortex Li H, Prince D J Neurophysiol 2002;88:2–12 We recorded spontaneous and evoked synaptic currents in pyramidal neurons of layer V in chronically injured, epileptogenic neocortex to assess changes in the efficacy of excitatory and inhibitory neurotransmission that might promote cortical hyperexcitability. Partial sensory-motor neocortical isolations with intact blood supply (“undercuts”) were made in 20 rats on postnatal day 21–25 and examined 2–6 weeks later in standard brain slice preparations by using whole-cell patch-clamp techniques. Age-matched, uninjured naive rats (n = 20) were used as controls. Spontaneous and miniature excitatory and inhibitory postsynaptic currents (s- and mEPSCs; s- and mIPSCs) were recorded by using patch-clamp techniques. The average frequency of s- and mEPSCs was significantly higher, whereas that of s- and mIPSCs was significantly lower in neurons of undercuts versus controls. The increased frequency of excitatory events was due to an increase in both s- and mEPSC frequency, suggesting an increased number of excitatory contacts and/or increased release probability at excitatory terminals. No significant difference was observed in 10–90% rise time of these events. The input-output slopes of fast, short-latency, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate (AMPA/KA) receptor-mediated components of evoked EPSCs were steeper in undercuts than in controls. The peak amplitude of the AMPA/KA component of EPSCs evoked by suprathreshold stimuli was significantly greater in the partially isolated neocortex. In contrast, the N-methyl-d-aspartate receptor-mediated component of evoked EPSCs was not significantly different in neurons of injured versus control cortex, suggesting that the increased AMPA/KA component was due to postsynaptic alterations. Results support the conclusion that layer V pyramidal neurons receive increased AMPA/KA receptor-mediated excitatory synaptic drive and decreased γ-aminobutyric acid type A (GABAA) receptor-mediated inhibition in this chronically injured, epileptogenic cortex. This shift in the balance of excitatory and inhibitory synaptic activation of layer V pyramidal cells toward excitation might be maladaptive and play a critical role in epileptogenesis.

Damage, reorganization, and abnormal neocortical hyperexcitability in the pilocarpine model of temporal lobe epilepsy.

Clinical, neuropathological, and electrophysiological data have shown that limbic structures are involved in the pathogenesis of temporal lobe epilepsy (TLE). In most cases, limbic-originated seizures frequently spread to extrahippocampal areas. It is unclear whether such distant circuitries, especially the neocortex, exhibit abnormal electrophysiology as consequences of a chronic epileptogenic process. The present research studied neuropathological abnormalities and in vitro electrophysiological properties of sensorimotor neocortex in pilocarpine-treated epileptic rats. Adult epileptic animals showing six to seven seizures/week and saline-injected rats were selected for neurohistology. Coronal sections were sampled throughout the anteroposterior extent of the diencephalon and stained with cresyl violet (Nissl). Immunocytochemistry (ICC) was performed using anti-neurofilament (SMI-311) antibody. Extracellular (layer II/III) and intracellular (layer V) recordings were performed in coronal sensorimotor neocortical slices. Several electrophysiological aspects were examined such as evoked responses, intrinsic properties, and firing patterns of layer V pyramidal cells. Nissl staining showed a significant decrease of cortical thickness in epileptic rats when compared with controls, particularly in superficial layers (II-IV). Such abnormalities were also revealed by SMI-311 staining. SMI-311-labeled dendrite arborizations were more complex in layers I-II of epileptic rats. Epileptic rats manifested several abnormalities in extracellular field responses including hyperresponsiveness and presence of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-mediated polysynaptic activity. Although no significant changes were observed concerning passive intrinsic properties, it was possible to detect a higher proportion of bursting neurons distributed in layer V (60%) of epileptic rats compared with 22% in control slices. Taken together, our findings indicate damage, reorganization, and chronic hyperexcitability of sensorimotor neocortex in experimental TLE.

Diffusion-weighted MRI of infarct growth in a rat photochemical stroke model: effect of lubeluzole

We studied the neuroprotective effect of lubeluzole, a NOS (nitric oxide synthase) pathway modulator, on the development of ischemic damage within the first six hours after a photochemically induced neocortical infarct in rats using diffusion-weighted MRI and Apparent Diffusion Coefficient (ADC) maps. A unilateral photochemical infarct was induced in the hindlimb sensorimotor neocortex of Wistar rats. One hour after infarction, rats received either vehicle ( n=10) or lubeluzole ( n=11; a 0.31 mg/kg i.v. bolus followed by a one-hour 0.31 mg/kg i.v. infusion). During the first six hours after infarct induction, multislice T 2- and Diffusion-Weighted magnetic resonance images (MRI) were obtained to measure percent change of volume of ischemic damage, whereas regional ADC maps were used to measure time-dependent density of ischemic damage. Lubeluzole reduced the percent increase of volume of ischemic damage relative to baseline (at 1 h after infarct induction just before drug treatment), by 18% at 5 and 6 hrs after infarct induction. Lubeluzole attenuated the ADC decreases in the peripheral rim of the infarct, but left the ADC values in the core unaffected. In conclusion, the neuroprotectant lubeluzole attenuates growth of ischemic damage as well as its density in the periphery of a photochemically induced neocortical infarct in rats.

Early Activation of inhibitory neurons in the thalamic reticular nucleus during focal neocortical seizures

The neurons of the thalamic reticular nucleus are among the main targets of corticothalamic projections and their vulnerability in pathological conditions is well established. The present experiments aimed at the description and immunocytochemical characterization of the neurons of the thalamic reticular nucleus activated in neocortical seizures. Focal seizures were induced by the topical application of isotonic, isohydric 4-aminopyridine solution to the sensorimotor neocortex of adult, anesthetized Wistar rats. The animals were perfused with fixative after 1 and 2 h of recorded seizure activity. Coronal plane vibratome sections were incubated with cocktails of polyclonal c-fos and monoclonal parvalbumin antisera. Labeled cells in the thalamic reticular nucleus were counted and related to total cell counts. Neurons and neuropil showed strong parvalbumin immunoreactivity. Double-stained sections revealed that 55.32% of the parvalbumin-positive cell population expressed c-fos protein in their cell nuclei at the end of the 1 h seizure period. This ratio decreased to 43.5% following 2 h seizure. Labeled cells, although less in number were also observed in the contralateral thalamic reticular nucleus. Since parvalbumin labels GABAergic cells, it is tempting to speculate that this activation of intrathalamic inhibiton might exert an important anticonvulsant protection on other thalamic nuclei.

Cellular Mechanisms of the Augmenting Response: Short-Term Plasticity in a Thalamocortical Pathway

Some thalamocortical pathways display an "augmenting response" when stimuli are delivered at frequencies between 7 and 14 Hz. Cortical responses to the first three stimuli of a series increase progressively in amplitude and are relatively stable thereafter. We have investigated the cellular mechanisms of the augmenting response using extracellular and intracellular recordings in vivo and in slices of the sensorimotor neocortex of the rat. Single stimuli to the ventrolateral (VL) nucleus of the thalamus generate EPSPs followed by feedforward IPSPs that hyperpolarize cells in layer V. A long-latency depolarization interrupts the IPSP with a peak at approximately 200 msec. A second VL stimulus delivered during the hyperpolarization and before the peak of the long-latency depolarization yields an augmenting response. The shortest latency for augmenting responses occurs in cells of layer V, and they appear in dendrites and somata recorded in upper layers approximately 5 msec later. Recordings in vitro show that some layer V cells have hyperpolarization-activated and deinactivated conductances that may serve to increase their excitability after IPSPs. Also in vitro, cells from layer V, but not from layer III, generated augmenting responses at the same stimulation frequencies that were effective in vivo. Control experiments indicated that neither paired-pulse depression of IPSPs nor presynaptically mediated facilitation can account for the augmenting response. Active dendritic conductances contribute to the spread of augmenting responses into upper layers by way of back-propagating fast spikes, which attenuate with repetition, and long-lasting spikes, which enhance in parallel with the augmenting response. In conclusion, we propose that the initiation of augmenting responses depends on an interaction between inhibition, intrinsic membrane properties, and synaptic interconnections of layer V pyramidal neurons.

Cerebellar neuronal activity correlates with spike and wave EEG patterns in the rat

In this study we investigated the involvement of the cerebellum in high voltage spike-and-wave spindles, a rodent model of petit mal epilepsy. High voltage spindles, recorded epidurally from the sensorimotor neocortex, were correlated with single or multiple unit activity in the cerebellar cortex and deep cerebellar nuclei. The majority of neurons or neuronal groups in the cerebellum (77.9%) fired rhythmically and phase-locked with the high voltage spindles, either during the spike (43.2%; n = 41) or during the wave (34.7%; n = 33) component of the high voltage spindle. Tremor of the head and neck musculature, recorded with an accelero-meter, occurred during the high voltage spindle in approximately half of the rats. When present, rhythmic movement occurred predominantly during the wave phase of the high voltage spindle. The remaining half of the rats did not show tremor during high voltage spindles but, nevertheless, had cerebellar units that burst during the spike or wave phase of the high voltage spindle. These latter results demonstrate that phase-locked bursting of cerebellar units during high voltage spindle is independent of rhythmic movement. The findings suggest that rhythmic output from the cerebellum may contribute to the maintenance of generalized petit mal seizures.

Investigation of β-adrenergic modulation of synaptic transmission and postsynaptic induction of associative LTP in layer V neurones in slices of rat sensorimotor cortex

Long-term potentiation (LTP) of synaptic transmission is considered to be a neuronal model of learning. Recently, the probability of induction of associative LTP in layer V cells in sensorimotor neocortex was shown to be much higher in the awake cat than in the slice preparation. We hypothesised that the loss of extrinsic noradrenergic activity in the slice might account for this difference, particularly since a β-adrenergic enhancement of field potentials has been seen in this preparation. We therefore bath-applied noradrenaline (NA) or the β 1-adrenergic agonist, isoprenaline (ISO) to elucidate the cellular basis of the enhancement of field potentials, and to see if the drugs increased the probability of induction of associative LTP in slices. We found that NA and ISO produced a dose-dependent, reversible reduction of spike accommodation and an increase in excitability but had no effect on the depolarizing slope or peak amplitude of sub-threshold EPSPs, and that drug application did not increase the probability of induction of LTP. We conclude that: (1) the enhancement of field potentials and late components of EPSPs (7) can be explained by the known actions of β-adrenergic drugs on membrane currents in layer V cells, and (2) the lower probability of induction of associative LTP in slices cf. the awake cat cannot be due solely to the loss of noradrenergic activity.