REORGANIZATION OF BARREL CIRCUITS LEADS TO THALAMICALLY-EVOKED CORTICAL EPILEPTIFORM ACTIVITY

We studied circuit activities in layer IV of rat somatosensory barrel cortex containing microgyri induced by neonatal freeze lesions. Structural abnormalities in GABAergic interneurons are present in the epileptogenic paramicrogyral area (PMG) and we therefore tested the hypothesis that decreased postsynaptic inhibition within barrel microcircuits occurs in the PMG and contributes to epileptogenesis when thalamocortical afferents are activated. In thalamocortical (TC) slices from na?ve animals, single electrical stimuli within the thalamic ventrobasal (VB) nucleus evoked transient cortical multi-unit activity lasting 65±42 ms. Similar stimuli in TC slices from lesioned barrel cortex elicited prolonged 850 ±100 ms paroxysmal discharges that originated in the PMG and propagated laterally over several mm. Paroxysmal discharges were shortened in duration by ~70 % when APV was applied, and were totally abolished by CNQX. The cortical paroxysmal discharges did not evoke thalamic oscillations. Whole cell patch clamp recordings showed that there was a shift in the balance of TC evoked responses in the PMG that favored excitation over inhibition. Dual whole-cell recordings in layer IV of the PMG indicated that there was selective loss of inhibition from fast-spiking interneurons to spiny neurons in the barrel circuits that likely contributed to unconstrained cortical recurrent excitation with generation and spread of paroxysmal discharges.     

Characterization of thalamocortical responses of regular-spiking and fast-spiking neurons of the mouse auditory cortex in vitro and in silico

We use a combination of in vitro whole cell recordings and computer simulations to characterize the cellular and synaptic properties that contribute to processing of auditory stimuli. Using a mouse thalamocortical slice preparation, we record the intrinsic membrane properties and synaptic properties of layer 3/4 regular-spiking (RS) pyramidal neurons and fast-spiking (FS) interneurons in primary auditory cortex (AI). We find that postsynaptic potentials (PSPs) evoked in FS cells are significantly larger and depress more than those evoked in RS cells after thalamic stimulation. We use these data to construct a simple computational model of the auditory thalamocortical circuit and find that the differences between FS and RS cells observed in vitro generate model behavior similar to that observed in vivo. We examine how feedforward inhibition and synaptic depression affect cortical responses to time-varying inputs that mimic sinusoidal amplitude-modulated tones. In the model, the balance of cortical inhibition and thalamic excitation evolves in a manner that depends on modulation frequency (MF) of the stimulus and determines cortical response tuning.     

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

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

Synaptic proliferation in the auditory cortex of the young adult rat following callosal lesions

Summary The long-term effects of partial deafferentation in the neocortex of adult rats were studied in four-month old rats in which the corpus callosum had been completely sectioned when they were one-month old. Quantitative light microscopy was used to identify morphological changes in the auditory cortex resulting from the loss of established callosal connections. Particular attention was directed at those cortical layers known to receive the heaviest callosal projection (layers II and III) and at neurons known to be postsynaptic to callosal afferents (layer V pyramidal neurons). The comparative analysis of both semithin plastic sections and Golgi-impregnated material from long-term, callosally-lesioned rats and age-matched control animals reveals no differences in the overall cortical thickness, the thickness of cortical layers, the numbers of neurons or the density of spines along apical dendrites of layer V pyramidal neurons. However, as a result of the callosal lesion, large diameter apical dendrites are significantly thinner in the callosally deafferented cortex and there is a small increase in the number of neuroglial cells in the deeper cortical layers.To determine whether another system of afferents to the auditory cortex spreads into the deafferented callosal domain, geniculate lesions were made in long-term, callosally-lesioned animals and age-matched controls. The terminal projection patterns of thalamic afferents were compared using the Fink-Heimer technique and quantitative electron microscopy. Normally in the auditory cortex there is only a small region of overlap between the terminal projection fields of callosal afferents and thalamic afferents, the latter projecting chiefly to layer IV and low layer III. However, three months after callosal lesions, thalamic axons had proliferated superficially into part of the callosal domain. Furthermore, in the normal auditory cortex after geniculate lesions, there were three rostrocaudally oriented bands of relatively dense thalamocortical terminal degeneration separated by regions of less dense degeneration. In the doubly lesioned animals these bands of degeneration were less distinct due to a proliferation of thalamic axons into the regions characterized by sparse projections.Part of this study was done by SF in partial fulfillment of the requirements for the degree of Master of Arts, Boston University, Boston, MA, USA.     

Auditory thalamocortical transmission is reliable and temporally precise

We have used the auditory thalamocortical slice to characterize thalamocortical transmission in primary auditory cortex (ACx) of the juvenile mouse. "Minimal" stimulation was used to activate medial geniculate neurons during whole cell recordings from regular-spiking (RS cells; mostly pyramidal) and fast-spiking (FS, putative inhibitory) neurons in ACx layers 3 and 4. Excitatory postsynaptic potentials (EPSPs) were considered monosynaptic (thalamocortical) if they met three criteria: low onset latency variability (jitter), little change in latency with increased stimulus intensity, and little change in latency during a high-frequency tetanus. Thalamocortical EPSPs were reliable (probability of postsynaptic responses to stimulation was approximately 1.0) as well as temporally precise (low jitter). Both RS and FS neurons received thalamocortical input, but EPSPs in FS cells had faster rise times, shorter latencies to peak amplitude, and shorter durations than EPSPs in RS cells. Thalamocortical EPSPs depressed during repetitive stimulation at rates (2-300 Hz) consistent with thalamic spike rates in vivo, but at stimulation rates > or = 40 Hz, EPSPs also summed to activate N-methyl-D-aspartate receptors and trigger long-lasting polysynaptic activity. We conclude that thalamic inputs to excitatory and inhibitory neurons in ACx activate reliable and temporally precise monosynaptic EPSPs that in vivo may contribute to the precise timing of acoustic-evoked responses.     

Supralinear increase of recurrent inhibition during sparse activity in the somatosensory cortex

The balance between excitation and inhibition in the cortex is crucial in determining sensory processing. Because the amount of excitation varies, maintaining this balance is a dynamic process; yet the underlying mechanisms are poorly understood. We show here that the activity of even a single layer 2/3 pyramidal cell in the somatosensory cortex of the rat generates widespread inhibition that increases disproportionately with the number of active pyramidal neurons. This supralinear increase of inhibition results from the incremental recruitment of somatostatin-expressing inhibitory interneurons located in layers 2/3 and 5. The recruitment of these interneurons increases tenfold when they are excited by two pyramidal cells. A simple model demonstrates that the distribution of excitatory input amplitudes onto inhibitory neurons influences the sensitivity and dynamic range of the recurrent circuit. These data show that through a highly sensitive recurrent inhibitory circuit, cortical excitability can be modulated by one pyramidal cell.     

Physiological and morphological identification of ventrolateral fibers relaying cerebellar information to the cat motor cortex

In the cat motor cortex, recordings were obtained from thalamocortical fibers and then these fibers were intra-axonally injected with horseradish peroxidase. Each fiber was identified by both orthodromic activation from the ventrolateral nucleus of the thalamus and by monosynaptic activation from the brachium conjunctivum. In anesthetized cats, all ventrolateral thalamic fibers tested had bursts of spikes with an intraburst frequency of about 400 Hz. The bursts occurred spontaneously and in response to thalamic or brachium stimulation. Fast pyramidal tract cells had clusters of excitatory postsynaptic potentials with the same internal frequency as the bursting afferents, strongly suggesting that they arise from the ventrolateral afferents. The horseradish peroxidase-injected ventrolateral afferents were distributed to many zones within the motor area and had loose arborizations within cortical layers. Terminals were generally located in layer III and in the upper part of layer VI. None was observed in the more superficial layers.The ventrolateral thalamic afferents in the motor cortex establish a point to zones connectivity. This may provide a morphological basis for the central organization of certain movements that necessitate simultaneous contraction of many muscles.     

Organization of neurones in the cat cerebral cortex that are influenced from Group I muscle afferents

1. Neurones in the Group I projection area of the first sensori-motor cortex were investigated with extra- and intracellular technique.2. The majority of the neurones influenced by volleys in Group I afferents of contralateral forelimb nerves received exclusively excitation, but some received exclusively inhibition, and some mixed excitation and inhibition.3. The Group I influenced cells were usually found 500-1500 mu beneath the cortical surface.4. The EPSPs and IPSPs evoked from Group I afferents had a steep rising phase and a slow, approximately exponential decay. The duration was sometimes more than 50 msec. The EPSP evoked by a maximal Group I volley was often formed by a small number of large unitary EPSPs.5. Latency measurements indicate that the majority of the Group I activated neurones were monosynaptically excited from the thalamic fibres, and hence constitute the fourth-order neurones in the Group I projection system. The latencies of the IPSPs suggest a disynaptic linkage with thalamic fibres. Hence, the exclusively inhibited cells would constitute fifth-order neurones. It is suggested that most or all of the fourth-order neurones are inhibitory.6. The convergence of excitation and/or inhibition to individual cells was usually extensive and included effects not only from muscle groups working at different joints but also effects from antagonistic groups at the same joint. In addition cutaneous afferents contributed synaptic actions which had a longer latency than the synaptic actions from Group I afferents.7. The neurones influenced from Group I afferents were not antidromically activated on stimulation of the pyramidal tract.     

Commissural interneurons with input from group I and II muscle afferents in feline lumbar segments: neurotransmitters, projections and target cells

The aim of this study was to analyse neurotransmitter content, projection areas and target cells of commissural interneurons with input from group I and/or II muscle afferents in lumbar segments in the cat. Axonal projections of 15 intracellularly labelled commissural interneurons were reconstructed. Ten interneurons (nine located in laminae VI–VII, one in lamina VIII) were glutamatergic; only one interneuron (located in lamina VIII) was glycinergic. Contralateral terminal projections were found both in motor nuclei and within laminae VI–VIII. In order to identify target cells of commissural interneurons, effects of stimulation of contralateral group I and II muscle afferents were investigated on interneurons within these laminae. Three tests were used: intracellular records from individual interneurons, modulation of probability of activation of extracellularly recorded interneurons and modulation of their actions on motoneurons using disynaptic PSPs evoked in motoneurons as a measure. All these tests revealed much more frequent and/or stronger excitatory actions of contralateral afferents. The results indicate that commissural interneurons with input from contralateral group I and II afferents target premotor interneurons in disynaptic pathways from ipsilateral group I and II afferents and that excitatory disynaptic actions of contralateral afferents on these interneurons are mediated primarily by intermediate zone commissural interneurons. A second group of commissural interneurons activated by reticulospinal neurons, previously described, frequently had similar, but occasionally opposing, actions to the cells described here, thus indicating that these two subpopulations may act on the same premotor interneurons and either mutually enhance or counteract each other's actions.     

Hyperpolarizing responses to application of glutamate in hippocampal CA1 pyramidal neurons

Micropressure injection of glutamate onto the apical dendrites of hippocampal CA1 pyramidal cells usually produces a fast rising, brief depolarization. However, hyperpolarizing responses with longer durations (300-500 ms) can be produced over a range of drug electrode locations. These hyperpolarizations can be reversed with intracellular injection of hyperpolarizing current. Localized application of glutamate in the stratum radiatum produces a depolarizing response in intracellularly recorded CA1 interneurons. Previous studies have shown that the dendrites of GABA-ergic basket cell interneurons extend into the stratum radiatum and are involved in mediating feedforward inhibition of pyramidal neurons. The glutamate-induced hyperpolarizations observed in pyramidal neurons are probably due to direct excitation of dendrites of interneurons, which in turn produce a synaptic inhibition in pyramidal cells.     

Afferent connexions to Group I activated cells in the main cuneate nucleus of the cat

1. Extracellular recordings were made from a total of 240 group I activated cells in the main cuneate nucleus. Cuneothalamic relay neurones (128) were identified by antidromic stimulation of the medial lemniscus in the ventrobasal thalamic complex.2. A majority of the relay neurones were activated by afferents in only one of six dissected forelimb nerves innervating muscle groups at various joints. Even among afferents from adjacent synergistic muscles, convergence to individual neurones was infrequent.3. Some of the relay neurones received excitation from group II muscle afferents in the same nerve that provided group I excitation. Excitation from group II muscle afferents in other nerves was uncommon. Some neurones were weakly excited by cutaneous volleys.4. Inhibition of group I relay cells was produced from cutaneous afferents and group II muscle afferents. Weak inhibition was sometimes observed from group I afferents. The relay cells were also inhibited by stimulation of the cerebral cortex with a focus around the lateral end of the cruciate sulcus. A good correspondence was found between the inhibition and the depolarization of group I afferent terminals in the cuneate nucleus.5. A majority of the group I activated cells not antidromically activated from the ventrobasal complex (;non-relay cells') were excited by cortical stimulation. Excitation from cutaneous afferents and group II muscle afferents was frequently found among these cells.6. The group I activated cells were found almost exclusively in the ventral part of the nucleus.7. The pattern of convergence found in eleven group I activated cells in the dorsal horn of the spinal cord from C 2 to C 4 is described.     

Excitatory inputs to CA1 interneurons show selective synaptic dynamics

The dynamic properties of synapses between neurons in the hippocampal CA1 area are important for the frequency-dependent signal transfer of the network. We have examined the synaptic dynamics of excitatory inputs to CA1 interneurons and pyramidal cells using whole cell voltage-clamp recordings. The CA1 network was activated using extracellular stimulation electrodes at the Schaffer collaterals (feedforward activation) or at the Alveus (activation of the feedback loop). The dynamic properties of input from the Schaffer collaterals to CA1 interneurons (basket and bistratified cells) were different from the synaptic dynamics of input from the Alveus. Synaptic input from the Schaffer collaterals to CA1 interneurons showed facilitation for most frequencies. After 10 stimuli the synaptic response reached a plateau level that was approximately 150% of the first response in the train. In contrast, the plateau levels of Alveus inputs to interneurons were not different from the first responses for frequencies 相似文献   

Selective blockade of Ca2+ permeable AMPA receptors in CA1 area of rat hippocampus

Using whole cell patch-clamp recording from pyramidal cells and interneurons in the CA1 area of hippocampal slices, the effect of IEM-1460, a selective channel blocker of Ca2+ permeable AMPA receptors (AMPARs), on postsynaptic currents (PSCs) was studied. Excitatory postsynaptic currents (EPSCs) were evoked by stimulation of Schaffer collaterals (SCs) in the presence of APV and bicuculline to pharmacologically isolate the EPSCs mediated by AMPAR activation. IEM-1460 (50 microM) did not affect the amplitude of EPSCs in CA1 pyramidal cells but reversibly decreased their amplitude in interneurons of pyramidal layer (15 cells), radiatum (37 cells) and border radiatum-lacunosum-moleculare (R-LM) (55 cells) layers. The ability of IEM-1460 to decrease EPSC amplitude correlated with EPSC rectification properties in CA1 interneurons, providing evidence for synaptic localization of Ca2+ permeable AMPARs at the SC synaptic input. Independent of their localization, the majority of interneurons studied exhibited only modest sensitivity to IEM-1460 (EPSC amplitude decreased by less than 30%), while in 15% of interneurons IEM-1460 induced more than 50% reduction in EPSC amplitude. To reveal possible afferent-specific localization of Ca2+ permeable AMPARs on R-LM interneurons, the effect of IEM-1460 on EPSCs evoked by stimulation of SC was compared with that of perforant path (PP). Although average sensitivities did not differ significantly, in 61% of R-LM layer interneurons, the SC-evoked EPSCs exhibited higher sensitivity to IEM-1460 than the PP-evoked EPSCs. Moreover, in 54% of R-LM layer interneurons the EPSCs evoked by SC stimulation were complex, having an initial peak followed by one or several late components. Kinetics, latency distribution and reversal potential of late components suggest di- and polysynaptic origin of the late components. Late EPSCs were strongly and reversibly inhibited by IEM-1460 indicating that Ca2+ permeable AMPARs are involved in the indirect excitation of R-LM layer interneurons. Despite the ability to decrease the excitatory synaptic input to interneurons, IEM-1460 did not affect interneuron-mediated inhibitory postsynaptic currents (IPSCs) evoked in pyramidal neurons by SC stimulation. These data suggest that interneurons with a synaptic input highly sensitive to IEM-1460 do not contribute specifically to the feed-forward inhibition of hippocampal pyramidal neurons.     

Blockade of different muscarinic receptor subtypes changes the equilibrium between excitation and inhibition in rat visual cortex

We have shown that cortical acetylcholine modulates the balance between excitation and inhibition evoked in layer 5 pyramidal neurons of rat visual cortex [Lucas-Meunier E, Monier C, Amar M, Baux G, Frégnac Y, Fossier P (2009) Cereb Cortex 19:2411–2427]. Our aim is now to establish a functional basis for the role of the different types of muscarinic receptors (MRs) on glutamate fibers and on GABAergic interneurons and to analyse their contribution to the modulation of excitation-inhibition balance in the rat visual cortex. To ascertain that there was a basis for our functional study, we first checked for the presence of the various MR subtypes by single cell RT-PCR and immunolabeling experiments. Then, recording the composite responses in layer 5 pyramidal neurons to layer 1–2 stimulation (which also recruits cholinergic fibers) in the presence of specific antagonists of the different types of MR allowed us to determine their modulatory role. We show that the specific blockade of the widely distributed M1R (with the mamba toxin, MT7) induced a significant increase in the excitatory conductance without modifying the inhibitory conductance, pointing to a localization of M1R on glutamatergic neurons where their activation would decrease the release of glutamate. From our functional results, M2/M4Rs appear to be located on glutamatergic neurons afferent to the recorded layer 5 pyramidal neuron and they decrease glutamate release. The extended distribution of M4Rs in the cortex compared to the restricted distribution of M2R (layers 3–5) is in favour of a major role as a modulator of M4R. The selective antagonist of M3Rs, 4-DAMP, decreased the inhibitory conductance, showing that activated M3Rs increase the release of GABA and thus are located on GABAergic interneurons. The activation of the different types of MRs located either on glutamatergic neurons or on GABAergic interneurons converges to reinforce the dominance of inhibitory inputs thus decreasing the excitability of layer 5 pyramidal neurons.     

Spinal interneurons that receive input from muscle afferents are differentially modulated by dorsolateral descending systems

The possibility that descending systems have differential actions on the spinal interneurons that receive input from muscle afferents was investigated. Prolonged, physiological inputs were generated by stretch of the triceps surae muscles. The resulting firing patterns of 25 lumbosacral interneurons were recorded before and during a reversible cold block of the dorsolateral white matter at the thoracic level in nonparalyzed, decerebrate preparations. The strength of group I muscle afferent input was assessed from the response to sinusoidal tendon vibration, which activated muscle spindle Ia afferents directly and tendon organ Ib afferents via the resulting reflex force. The stretch-evoked responses of interneurons with strong responses to vibration were markedly suppressed by dorsal cold block, whereas the stretch-evoked responses of interneurons with weak vibration input were enhanced. The cells most strongly activated by vibration received their primary input from Ia afferents and all of these cells were inhibited by the cold block. These results suggest that a disruption of the descending system, such as occurs in spinal cord injury, will lead to a suppression of the interneuronal pathways with group Ia input while enhancing excitability within interneuronal pathways transmitting actions from higher threshold afferents. One possible consequence of this suppression would be a decreased activity among the Ia inhibitory interneurons that mediate reciprocal inhibition, resulting in abnormal reciprocal relations between antagonists and promoting anomalous muscle cocontraction.     

Patterns of spontaneous activity and morphology of interneuron types in organotypic cortex and thalamus-cortex cultures.

The physiological and morphological properties of interneurons in infragranular layers of rat visual cortex have been studied in organotypic cortex monocultures and thalamus-cortex co-cultures using intracellular recordings and biocytin injections. Cultures were prepared at the day of birth and maintained for up to 20 weeks. Twenty-nine interneurons of different types were characterized, in addition to 170 pyramidal neurons. The cultures developed a considerable degree of synaptically driven "spontaneous" bioelectric activity without epileptiform activity. Interneurons in cortex monocultures and thalamus-cortex co-cultures had the same physiological and morphological properties, and also pyramidal cell properties were not different in the two culture conditions. All interneurons and the majority of pyramidal cells displayed synaptically driven action potentials. The physiological group of fast-spiking interneurons included large basket cells, columnar basket cells (two cells with an arcade axon) and horizontally bitufted cells. The physiological group of slow-spiking interneurons included Martinotti cells and a "long-axon" cell. Analyses of the temporal patterns of activity revealed that fast-spiking interneurons have higher rates of spontaneous activity than slow-spiking interneurons and pyramidal cells. Furthermore, fast-spiking interneurons fired spontaneous bursts of action potentials in the gamma frequency range. We conclude from these findings that physiological and morphological properties of interneurons in organotypic mono- and co-cultures match those of interneurons characterized in vivo or in acute slice preparations, and they maintain in long-term cultures a well-balanced state of excitation and inhibition. This suggests that cortex-intrinsic or cell-autonomous mechanisms are sufficient for the expression of cell type-specific electrophysiological properties in the absence of afferents or sensory input.     

Synaptic potentials of primary afferent fibers and motoneurons evoked by single intermediate nucleus interneurons in the cat spinal cord

Spike-triggered averaging of dorsal and ventral root potentials was used in anesthetized cats to disclose possible synaptic connections of spinal interneurons in the intermediate nucleus with afferent fibers and/or motoneurons. With this method we have been able to document the existence of a distinct group of interneurons whose activity was associated with the recording of inhibitory potentials in the ventral roots (iVRPs), but not with negative dorsal root potentials (nDRPs). The iVRPs had mean durations of 60.8 +/- 22.1 ms and latencies between 1.7 and 5.1 ms relative to the onset of the interneuronal spikes. Within this group of neurons it was possible to characterize two categories depending on their responses to segmental inputs. Most type A interneurons were mono- or disynaptically activated by group I muscle afferents and polysynaptically by low threshold (1.08-1.69 X T) cutaneous fibers. Type B interneurons were instead polysynaptically activated by group II muscle and by cutaneous fibers with thresholds ranging from 1.02 to 3.1 X T. Whenever tested, both type A and B interneurons could be antidromically activated from Clarke's columns. There was a second group of interneurons whose activity was associated with the generation of both iVRPs and nDRPs. These potentials had mean durations of 107.5 +/- 35.6 and 131.5 +/- 32 ms, respectively, and onset latencies between 1.7 and 6.1 ms. The interneurons belonging to this group, which appear not to send axonal projections to Clarke's column, could be classified in three categories depending on their responses to peripheral inputs. Type C interneurons responded mono- or disynaptically to group I muscle volleys and polysynaptically to intermediate threshold (1.22-2.7 X T) cutaneous afferents. Type D interneurons were polysynaptically activated by group II muscle afferents (2.3-8.5 X T) and by intermediate threshold (1.4-3 X T) cutaneous fibers and type E interneurons only by group I muscle afferents with mono- or disynaptic latencies. A third group of interneurons produced nDRPs without iVRPs. The nDRPs had onset latencies varying from 1.9 to 6.2 ms and mean durations of 130.0 +/- 34.6 ms. These neurons (type F) showed spontaneous and evoked bursts of activity and were not antidromically activated from Clarke's column. They responded to stimulation of low- and intermediate-threshold cutaneous fibers (1.04-2.9 X T) with mono- and polysynaptic latencies, but not by group I muscle fibers. Type F interneurons appear to be located in more superficial layers than all the other interneurons.(ABSTRACT TRUNCATED AT 400 WORDS)     

Sequential activation of microcircuits underlying somatosensory-evoked potentials in rat neocortex

Evoked cortical field potentials are widely used in neurophysiological studies into cortical functioning, but insight in the underlying neural mechanisms is severely hampered by ambiguities in the interpretation of the field potentials. The present study aimed at identifying the precise relationships between the primary evoked cortical field potential (the positive-negative [P1-N1]response) and the temporal and spatial sequence in which different local cortical micro-circuits are recruited. We electrically stimulated the median nerve and recorded field potentials using a 12-channel depth probe in somatosensory cortex of ketamine anesthetized rats. Current source density analysis was used and a grand average was constructed based on all individual animals taking into account individual differences in cortical layering. Manipulation of stimulus strength, selective averaging of single trial responses, and double-pulse stimulation, were used to help disentangle overlapping dipoles and to determine the sequence of neuronal events. We discriminated three phases in the generation of the P1-N1 wave. In the first phase, specific thalamic afferents depolarize both layer III and layer V pyramidal cells. In the second phase, superficial pyramidal cells are depolarized via supragranular intracortical projections. In the third phase, population spikes are generated in layer Vb pyramidal cells, associated with a distinct fast (approximately 1 ms) sink/source configuration. Axon-collaterals of layer Vb pyramidal cells produce an enhanced activation of the supragranular pyramidal cells in layer I-II, which generates N1.     

AMPA receptor modulators have different impact on hippocampal pyramidal cells and interneurons

Positive modulators of AMPA receptors enhance synaptic plasticity and memory encoding. Facilitation of AMPA receptor currents not only results in enhanced activation of excitatory neurons but also increases the activity of inhibitory interneurons by up-modulating their excitatory input. However, little is known about the effects of these modulators on cells other than pyramidal neurons and about their impact on local microcircuits. This study examined the effects of members from three subfamilies of modulators (mainly CX516, CX546 and cyclothiazide) on excitatory synaptic responses in four classes of hippocampal CA1 neurons and on excitatory and disynaptically induced inhibitory field potentials in hippocampal slices. Effects on excitatory postsynaptic currents (EPSCs) were examined in pyramidal cells, in two types of inhibitory interneurons located in stratum radiatum and oriens, and in stratum radiatum giant cells, a novel type of excitatory neuron. With CX516, increases in EPSC amplitude in pyramidal cells were two to three times larger than in interneurons and six times larger than in radiatum giant cells. The effects of CX546 on response duration similarly were largest in pyramidal cells. However, this drug also strongly differentiated between stratum oriens and radiatum interneurons with increases being four times larger in the latter. In contrast, cyclothiazide had similar effects on response duration in all cell types. In field recordings, CX516 was several times more potent in enhancing excitatory postsynaptic potentials (EPSPs) than feedback or feedforward circuits, as expected from its larger influence on pyramidal cells. In contrast, BDP-20, a CX546 analog, was more potent in enhancing feedforward inhibition than either EPSPs or feedback inhibition. This preference for feedforward over feedback circuits is probably related to its higher potency in stratum radiatum versus oriens interneurons. Taken together, AMPA receptor modulators differ substantially in their potency and/or efficacy across major classes of neurons which is likely to have consequences with regard to their impact on circuits and behavior.