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PubMed2006

Modular propagation of epileptiform activity: evidence for an inhibitory veto in neocortex.

What regulates the spread of activity through cortical circuits? We present here data indicating a pivotal role for a vetoing inhibition restraining modules of pyramidal neurons. We combined fast calcium imaging of network activity with whole-cell recordings to examine epileptiform propagation in mouse neocortical slices. Epileptiform activity was induced by washing Mg2+ ions out of the slice. Pyramidal cells receive barrages of inhibitory inputs in advance of the epileptiform wave. The inhibitory barrages are effectively nullified at low doses of picrotoxin (2.5-5 microM). When present, however, these inhibitory barrages occlude an intense excitatory synaptic drive that would normally exceed action potential threshold by approximately a factor of 10. Despite this level of excitation, the inhibitory barrages suppress firing, thereby limiting further neuronal recruitment to the ictal event. Pyramidal neurons are recruited to the epileptiform event once the inhibitory restraint fails and are recruited in spatially clustered populations (150-250 microm diameter). The recruitment of the cells within a given module is virtually simultaneous, and thus epileptiform events progress in intermittent (0.5-1 Hz) steps across the cortical network. We propose that the interneurons that supply the vetoing inhibition define these modular circuit territories.

Action Potentials↗
PubMed2004

Postsynaptic calcium influx at single synaptic contacts between pyramidal neurons and bitufted interneurons in layer 2/3 of rat neocortex is enhanced by backpropagating action potentials.

Pyramidal neurons in layer 2/3 (L2/3) of the rat somatosensory cortex excite somatostatin-positive inhibitory bitufted interneurons located in the same cortical layer via glutamatergic synapses. A rise in volume-averaged dendritic [Ca2+]i evoked by backpropagating action potentials (APs) reduces glutamatergic excitation via a retrograde signal, presumably dendritic GABA. To measure the rise in local [Ca2+]i at synaptic contacts during suprathreshold excitation, we identified single synaptic contacts in the acute slice preparation in pairs of pyramidal and bitufted cells each loaded with a Ca2+ indicator dye. Repetitive APs (10-15 APs at 50 Hz) evoked in a L2/3 pyramidal neuron gave rise to facilitating unitary EPSPs in the bitufted cell. Subthreshold EPSPs evoked a transient rise in [Ca2+]i of 80-250 nM peak amplitude at the postsynaptic dendritic site. The local postsynaptic [Ca2+]i transient was restricted to 10 microm of dendritic length, lasted for 200 msec, and was mediated predominantly by NMDA receptor channels. When EPSPs were suprathreshold, the evoked AP backpropagated into the apical and basal dendritic arbor and increased the local [Ca2+]i transient at active contacts by approximately twofold, with a peak amplitude reaching 130-450 nM. This value is in the range of the half-maximal dendritic [Ca2+]i, evoking retrograde inhibition of glutamate release from boutons of pyramids. The localized enhancement of dendritic Ca2+ influx at synaptic contacts by synaptically evoked backpropagating APs could represent one mechanism by which a retrograde signal can limit the excitation of bitufted interneurons by L2/3 pyramids when these are repetitively active.

Action Potentials↗
PubMed2004

Early expression of sodium channel transcripts and sodium current by cajal-retzius cells in the preplate of the embryonic mouse neocortex.

In mouse, the first neurons are generated at embryonic day (E) 12 and form the preplate (PP), which contains a mix of future marginal zone cells, including Cajal-Retzius cells, and subplate cells. To detect developmental changes in channel populations in these earliest-generated neurons of the cerebral cortex, we studied the electrophysiological properties of proliferative cells of the ventricular zone and postmitotic neurons of the PP at E12 and E13, using whole-cell patch-clamp recordings. We found an inward sodium current in 55% of PP cells. To determine whether sodium currents occur in a specific cell type, we stained recorded cells with an antibody for calretinin, a calcium-binding protein found specifically in Cajal-Retzius cells. All calretinin-positive cells had sodium currents, although so did some calretinin-negative cells. To correlate the Na current expression to Na channel gene expression with the Cajal-Retzius cell phenotype, we performed single-cell reverse transcription-PCR on patch-clamp recorded cells to detect expression of the Cajal-Retzius cell marker reelin and the Na channel isoforms SCN 1, 2, and 3. These results showed that virtually all Cajal-Retzius cells (97%), as judged by reelin expression, express the SCN transcript identified as the SCN3 isoform. Of these, 41% presented a functional Na current. There is, however, a substantial SCN-positive population in the PP (27% of SCN-positive cells) that does not express reelin. These results raise the possibility that populations of pioneer neurons of the PP, including Cajal-Retzius cells, gain neuronal physiological properties early in development via expression of the Na(v)1.3 (SCN3) Na channel isoform.

Animals↗
PubMed2005

Target-specific regulation of synaptic amplitudes in the neocortex.

In layers 2/3 in the rat visual cortex, glutamatergic synapses, between pyramidal neurons and GABAergic interneurons, show target-specific depression or facilitation. To study the mechanisms regulating these short-term synaptic modifications, we recorded from synaptically connected pyramidal neurons (presynaptic) and multipolar or bitufted interneurons (postsynaptic). Evoked AMPA receptor (AMPAR)- or NMDA receptor (NMDAR)-mediated EPSCs were pharmacologically isolated at these pyramidal-to-interneuron synapses while altering release probability (P(r)) by changing the extracellular Ca2+ concentration ([Ca2+]o). At the pyramidal-to-multipolar synapse, which shows paired-pulse depression, elevation of [Ca2+]o from physiological concentrations (2 mm) to 3 mm increased the amplitude of the initial AMPAR-mediated EPSC and enhanced paired-pulse depression. In contrast, the initial NMDAR-mediated EPSC did not change in amplitude with raised P(r) nor was paired-pulse depression altered. This lack of an increase of NMDAR-mediated currents is not a result of Ca2+-dependent effects on the NMDAR. Rather, at the pyramidal-to-multipolar synapse, raised P(r) increases the transient glutamate concentration at individual release sites, possibly reflecting multivesicular release. In contrast, at the pyramidal-to-bitufted synapse, which shows facilitation, AMPAR- and NMDAR-meditated EPSCs showed parallel increases in response to raised P(r). Thus, our results reveal differential recruitment of AMPA and NMDARs at depressing and facilitating synapses in layers 2/3 of the cortex and suggest that the mechanisms regulating dynamic aspects of synaptic transmission are target specific.

Animals↗
PubMed1999

Electro-oscillographic correlation between dorsal raphe nucleus, neocortex and hippocampus during wakefulness before and after serotoninergic inactivation.

Theta rhythm in many brain structures characterizes wakefulness and desynchronized sleep in most subprimate mammalian brains. In close relation to behaviors, theta frequency and voltage undergo a fine modulation which may involve mobilization of dorsal raphe nucleus efferent pathways. In the present study we analyzed frequency modulation (through instantaneous frequency variation) of theta waves occurring in three cortical areas, in hippocampal CA1 and in the dorsal raphe nucleus of Wistar rats during normal wakefulness and after injection of the 5-HT1a receptor agonist 8-OH-DPAT into the dorsal raphe. We demonstrated that in attentive states the variation of theta frequency among the above structures is highly congruent, whereas after 8-OH-DPAT injection, although regular signals are present, the variation is much more complex and shows no relation to behaviors. Such functional uncoupling after blockade demonstrates the influence of dorsal raphe nucleus efferent serotoninergic fibers on the organization of alertness, as evaluated by electro-oscillographic analysis.

Animals↗
PubMed2006

Acute microelectrode array implantation into human neocortex: preliminary technique and histological considerations.

OBJECT: Researchers at The Center for Neural Interfaces at the University of Utah have designed and produced a silicon-based high-density microelectrode array that has been used successfully in mammalian models. The authors investigate the ability to transfer array insertion techniques to humans and examine the acute response of human cortical tissue to array implantation. METHODS: Six patients who were scheduled to undergo temporal lobectomy surgery were enrolled in an Institutional Review Board-approved protocol. Before the patients underwent lateral temporal cortical resection, one or two high-density microelectrode arrays were implanted in each individual by using a pneumatic insertion device. Cortical tissue was then excised and preserved in formalin. The specimens were sectioned and stained for histological examination. Pneumatic insertion of a microelectrode array into human cortex in the operating room was feasible. There were no clinical complications associated with implantation and no evidence of significant insertion-related hemorrhage. Tissue responses ranged from mild cortical deformity to small focal hemorrhages several millimeters below the electrode tines. Based on initial results, the insertion device was modified. A footplate that mechanically isolates a small area of cortex and a calibrated micromanipulator were added to improve the reproducibility of insertion. CONCLUSIONS: A high-density microelectrode array designed to function as a direct cortical interface device can be implanted into human cortical tissue without acute clinical complications. Further modifications to the insertion device and array design are ongoing and future work will assess the functional significance of the tissue reactions observed.

Electrodes, Implanted↗
PubMed1999

Lack of correlation between neuronal hyperexcitability and electrocorticographic responsiveness in epileptogenic human neocortex.

OBJECT: The purpose of this study was to determine whether intrinsic neuronal properties and synaptic responses differed between interictally active and inactive tissue removed in neocortical resections from patients undergoing surgical treatment for epilepsy. METHODS: Whole-cell patch recordings were performed in layer 2 or 3 and layer 5 pyramidal cells in neocortical slices obtained from tissue surgically removed from patients for the treatment of medically intractable seizures. Synaptic responses to stimulation at the layer 6-white matter border were used to classify cells as nonbursting if they responded with only a single action potential for all above-threshold stimuli (80%). These responses were usually followed by biphasic inhibitory postsynaptic potentials (IPSPs). Cells were classified as bursting if they fired at least three action potentials in response to synaptic stimulation (20%). These cells typically showed no IPSPs and responded in either an all-or-nothing or graded fashion. Approximately twice as many cells at layer 2 or 3 (29%) than cells at layer 5 (14%) fired synaptic bursts. Synaptic bursting was not associated with an alteration in a cell's response properties to gamma-aminobutyric acid. It was notable that, in tissue samples determined by electrocorticography (ECoG) to be either interictally active or not active, the proportion of cells that burst was exactly the same in both groups (24%). We found no cells with intrinsic burst firing. CONCLUSIONS: We conclude that synaptic bursting was characteristic of a small proportion of cells from epileptic tissue; however, this did not correlate with interictal spikes on ECoG.

Electric Conductivity↗
PubMed2000

Ischemic tolerance in the rat neocortex following hypothermic preconditioning.

OBJECT: Ischemic neuronal damage associated with neurological and other types of surgery can have severe consequences for functional recovery after surgery. Hypothermia administered during and/or after ischemia has proved to be clinically beneficial and its effects often rival or exceed those of other therapeutic strategies. In the present study the authors examined whether transient hypothermia is an effective preconditioning stimulus for inducing ischemic tolerance in the brain. METHODS: Adult rats were subjected to a 20-minute period of hypothermic preconditioning followed by an interval ranging from 6 hours to 7 days. At the end of this interval, the animals were subjected to transient focal ischemia induced by clamping one middle cerebral artery and both carotid arteries for 1 hour. The volume of cerebral infarction was assessed 1 or 7 days postischemia. In the first series of experiments, hypothermic preconditioning (28.5 degrees C) with a postconditioning interval of 1 day reduced the extent of cerebral infarction measured 1 and 7 days postischemia. In the second series, hypothermic preconditioning (31.5 degrees C) with postconditioning intervals of 6 hours, 1 day, or 2 days (but not 7 days) reduced the extent of cerebral infarction measured 1 day postischemia. Treatment with the protein synthesis inhibitor anisomycin blocked the protective effect of hypothermic preconditioning. In a final series of experiments, in vitro brain slices prepared from hypothermia-preconditioned (nonischemic) animals were shown to tolerate a hypoxic challenge better than slices prepared from unconditioned animals. CONCLUSIONS: These findings indicate that hypothermic preconditioning induces a form of delayed tolerance to focal ischemic damage. The time course over which tolerance occurs and the ability of a protein synthesis inhibitor to block tolerance suggest that increased expression of one or more gene products is necessary to establish tissue tolerance following hypothermia. The attenuation of hypoxic injury in vitro following in vivo preconditioning indicates that tolerance is due, at least in part, to direct effects on the brain neuropil. Hypothermic preconditioning could provide a relatively low-risk approach for improving surgical outcome after invasive surgery, including high-risk neurological and cardiovascular procedures.

Animals↗
PubMed2000

Spontaneous spike-wave discharges in rat neocortex and their relation to behaviour.

A certain proportion of laboratory rats of various strains show spontaneous nonconvulsive ECoG seizures in the form of bursts of spike-and-wave discharges (SWD). Since in the majority of behavioural experiments the EEG is not controlled, the experimenter is usually unaware of this fact. The purpose of the present work was to find out whether the SWD trait is related to the rats behavioural performance in selected test situations. The experiment was performed on two groups of male Wistar rats, outbreds, aged six (group 6M, n = 17) and 24 months (group 24M, n = 14). First, in both groups the following forms of behaviour were assessed: (1) seeking water reward in an 8-arm radial maze, (2) exploration of a new object, (3) inhibition of a locomotor response (passive avoidance), and (4) paw-lick response to a thermal stimulus (54.5 degrees C) applied to the feet before and after intermittent footshock. The rats were then implanted with intrabrain electrodes and the level of SWD activity was assessed. Rats of the 24M group, compared with those of the 6M one, showed a significantly shorter exploratory response to a new object and diminished responsiveness to heat. The groups did not differ, however, in passive avoidance and radial maze performance. The analysis of 3-h ECoG sections revealed SWD bursts in 73% and nearly 93% of rats from groups 6M and 24M, respectively. The groups did not differ in the number of bursts or in the total duration of SWD activity. A correlation analysis of pooled data from both groups revealed that the exploration time of a new object was significantly (negatively) correlated with the number of SWD episodes. The total duration of SWD activity, and the number of perseveration errors in the radial maze, was significantly (positively) correlated with the total duration of SWD activity. The results suggest that SWD rats are behaviourally impaired in some test situations.

Animals↗
PubMed2002

Axonal projection, input and output synapses, and synaptic physiology of Cajal-Retzius cells in the developing rat neocortex.

Cajal-Retzius (CR) cells are among the earliest generated neurons and are thought to play a role in corticogenesis and early neuronal migration. However, the role of CR cells in an early cortical microcircuit is still rather unclear. We therefore have investigated the morphology and physiology of CR cells by using whole-cell patch-clamp recordings combined with intracellular biocytin filling in acute brain slices of postnatal day 5-11 rats. CR cells are characterized by a long horizontally oriented dendrite; the axonal collaterals form a dense horizontally oriented plexus in layer 1 and to a certain extent in layer 2/3, projecting over >2 mm of cortical surface. The bouton density is relatively high, and synaptic contacts are established preferentially with dendritic spines or shafts of excitatory neurons, presumably terminal tuft dendrites of pyramidal neurons. In turn, CR cells receive dense GABAergic and non-GABAergic input on somata, dendritic shafts, and spine-like appendages. Extracellular stimulation in layer 1 could activate both GABAergic and glutamatergic synaptic inputs. The GABAergic response was blocked by the GABA(A) receptor antagonist bicuculline. The glutamatergic response was mediated solely by NMDA receptors and was highly sensitive to ifenprodil, indicating that it was mediated mainly via NR1/NR2B subunit-containing receptors. NMDA EPSPs were apparent in 1 mm extracellular Mg2+, suggesting that this pure NMDA synapse is not silent functionally. Together, the long-range horizontal projection of the axon, the high density of synaptic boutons, and the functional synaptic input of CR cells suggest that they are an integral part of an early cortical network.

Animals↗
PubMed1999

Developmental switch in the short-term modification of unitary EPSPs evoked in layer 2/3 and layer 5 pyramidal neurons of rat neocortex.

Amplitudes of EPSPs evoked by repetitive presynaptic action potentials can either decrease (synaptic depression) or increase (synaptic facilitation). To determine whether facilitation and depression in the connections between neocortical pyramidal cells varied with the identity of the pre- or the postsynaptic cell and whether they changed during postnatal development, whole-cell voltage recordings were made simultaneously from two or three pyramidal cells in layers 2/3 and 5 of the rat sensorimotor cortex. Unitary EPSPs were evoked when pre- and postsynaptic neurons were in the same and in different layers. In young [postnatal day 14 (P14)] cortex, EPSPs evoked in all connected neurons depressed. The degree of depression was layer specific and was determined by the identity of the presynaptic cell. EPSPs evoked by stimulation of presynaptic layer 5 neurons depressed significantly more than did those evoked by stimulation of layer 2/3 neurons. In mature cortex (P28), however, the EPSPs evoked in these connected neurons facilitated to a comparable degree regardless of the layer in which pre- and postsynaptic neurons were located. The results suggest that in young cortex the degree of synaptic depression in connected pyramidal cells is determined primarily by whether the presynaptic cell was in layer 2/3 or 5 and that maturation of the cortex involves a developmental switch from depression to facilitation between P14 and P28 that eliminates the layer-specific differences. A functional consequence of this switch is that in mature cortex the spread of excitation between neocortical pyramidal neurons is enhanced when action potentials occur in bursts.

Animals↗
PubMed1999

Endothelial nitric oxide synthetase (eNOS) in astrocytes: another source of nitric oxide in neocortex.

The distribution of the endothelial form of nitric oxide synthetase (eNOS) was examined in the visual cortex of three species of primate and in the rat using immunocytochemistry. Labeled cells were found in both the gray and white matter. These cells were stellate in appearance and labeled cell processes were seen contacting blood vessels or the pia, suggesting that, by morphological criteria, the cells were astrocytes. All eNOS positive cells were double labeled with an antibody against S100beta. Although all cells were double labeled in the white matter, in the gray matter, some S100beta positive cells did not contain detectable levels of eNOS. eNOS positive astrocytic processes appeared to form prominent and distinctive structures next to neurons, especially in cortical layer IIIC. We postulate that these eNOS-positive structures form astrocytic perisynaptic sheaths on neuronal somas in the cortex. If this is true, then nitric oxide can influence neuronal transmission directly at axosomatic synapses in the cortex. In addition, the presence of eNOS in astrocytes and in their processes that contact blood vessels suggests that the link between local cortical activity and changes in cerebral blood flow could be mediated by astrocytic release of nitric oxide.

Animals↗
PubMedDate not supplied

[An improved method for isolating a section of the rat neocortex].

Neocortical island chronically isolated from surrounding cortical and subcortical structures with preserved pial blood supply has long been a model for research into the mechanisms of cortex functioning. To fully cut the cortex we improved the type of knife by using a retractable tungsten wire. The tip of a syringe needle was bent and cut away all but the beginning of the bend. In anesthetized rats the somatosensory cortex was exposed, the guide needle was lowered down to the desired depth into the cortex avoiding blood vessels. The wire then was pulled out through the curved needle tip until the tip of the wire touched the pia mater. The device was then raised, lowered, rotated to achieve complete separation of the cortical island from the surrounding tissues. The wire was retracted into the needle before withdrawal of the device. Analysis of neocortical slices 8 weeks later showed lesions of the white matter and transcortical cuts.

Animals↗
PubMed1999

Molecular analysis of developmental plasticity in neocortex.

Gene expression studies indicate that during activity-dependent developmental plasticity, N-methyl-D-aspartate receptor activation causes a Ca(2+)-dependent increase in expression of transcription factors and their downstream targets. The products of these plasticity genes then operate collectively to bring about the structural and functional changes that underlie ocular dominance plasticity in visual cortex. Identifying and characterizing plasticity genes provides a tool for molecular dissection of the mechanisms involved. Members of second-messenger pathways identified in adult plasticity paradigms and elements of the transmission machinery are the first candidate plasticity genes tested for their role in activity-dependent developmental plasticity. Knockout mice with deletions of such genes have allowed analyzing their function in the context of different systems and in different paradigms. Studies of mutant mice reveal that activity-dependent plasticity is not necessarily a unified phenomenon. The relative importance of a gene can vary with the context of its expression during different forms of plasticity. Forward genetic screens provide additional new candidates for testing, some with well-defined cellular functions that provide insight into possible plasticity mechanisms.

Animals↗