The GABAB1b isoform mediates long-lasting inhibition of dendritic Ca2+ spikes in layer 5 somatosensory pyramidal neurons

The apical tuft of layer 5 pyramidal neurons is innervated by a large number of inhibitory inputs with unknown functions. Here, we studied the functional consequences and underlying molecular mechanisms of apical inhibition on dendritic spike activity. Extracellular stimulation of layer 1, during blockade of glutamatergic transmission, inhibited the dendritic Ca2+ spike for up to 400 ms. Activation of metabotropic GABAB receptors was responsible for a gradual and long-lasting inhibitory effect, whereas GABAA receptors mediated a short-lasting (approximately 150 ms) inhibition. Our results suggest that the mechanism underlying the GABAB inhibition of Ca2+ spikes involves direct blockade of dendritic Ca2+ channels. By using knockout mice for the two predominant GABAB1 isoforms, GABAB1a and GABAB1b, we showed that postsynaptic inhibition of Ca2+ spikes is mediated by GABAB1b, whereas presynaptic inhibition of GABA release is mediated by GABAB1a. We conclude that the molecular subtypes of GABAB receptors play strategically different physiological roles in neocortical neurons.     

Emergence of layer IV barrel cytoarchitecture is delayed in somatosensory cortex of GAP-43 deficient mice following delayed development of dendritic asymmetry

The emergence of barrel cytoarchitecture in mouse somatosensory cortex is extremely well defined. However, mechanisms underlying the development of this cellular organization are not completely understood. While it is generally accepted that hollows emerge via passive displacement of cortical cells by dense thalamocortical afferent clusters in barrel centers, it is not known what causes cellular segregation of barrel sides and septa. Here, we hypothesized that the emergence of sides and septa is related to the progressive asymmetry of dendrites from the cells of the barrel side toward the barrel hollow during development. We tested this hypothesis in the barrel cortex of growth-associated protein-43 heterozygous mice (GAP43 (+/?) mice) that display a 2-day delay in retraction of septally oriented dendrites compared to (+/+) littermates. We predicted that this delayed retraction would result in a subsequent 2-day delay in the emergence of barrel sides and septa. Using cresyl violet staining of barrel cortex, we found that initial emergence of hollows was not different between GAP43 (+/?) mice and (+/+) littermate controls. However, the emergence of sides and septa was delayed by 2 days, supporting our hypothesis that the emergence of barrel sides and septa is related to, and perhaps reliant upon, the developmental step of dendritic orientation toward barrel hollows. This process, which is mechanistically distinct from the emergence of barrel hollows, is likely due to both active and passive events resulting from asymmetric cell orientation.     

Localization of sensorimotor cortex in neurosurgery by recording of somatosensory evoked potentials

The current method of localizing somatosensory and motor cortex during neurosurgical removal of abnormal tissue is Penfield's method of cortical stimulation. While useful, this method has drawbacks, in particular the need to operate under local anesthesia. Another method of localization, described here, involves intra-operative recording of short-latency somatosensory evoked potentials to stimulation of the contralateral median nerve, from electrodes placed directly on central cortex. Proper localization involves identification of potentials which invert in polarity across the central sulcus, identification of other potentials which are largest in the medial portion of the hand area of somatosensory cortex and do not polarity invert, and determination of the region of maximal potential amplitude. This method of localization works equally well whether the patient is under local or general anesthesia, but it occasionally fails in patients with tumors abutting or invading the hand area of sensorimotor cortex.     

Afferent impulses in cat vagus nerve fibers studied by coincidence of recorded action potentials

Tonic electrical activity of different groups of afferent fibers of the intact vagus nerve arising in stretch receptors of the lungs was investigated in acute experiments on cats. The method of coincidence of recorded action potentials was used: Recordings were taken from two points of the nerve, the flow of impulses was delayed by the time taken for their conduction along the nerve between the channels in the one that received it first, and impulses from both channels were then led to a coincidence unit. Fibers with a range of conduction velocities from 8 to 65 m/sec were shown to participate in the transmission of tonic activity from stretch receptors of the lungs to the CNS. Two groups of most active afferent fibers with conduction velocities within the range 35–46 m/sec (mean 41±2.5 m/sec) and 26–34 m/sec (mean 29.4±1.4 m/sec) were distinguished.     

Object selectivity of local field potentials and spikes in the macaque inferior temporal cortex

Local field potentials (LFPs) arise largely from dendritic activity over large brain regions and thus provide a measure of the input to and local processing within an area. We characterized LFPs and their relationship to spikes (multi and single unit) in monkey inferior temporal cortex (IT). LFP responses in IT to complex objects showed strong selectivity at 44% of the sites and tolerance to retinal position and size. The LFP preferences were poorly predicted by the spike preferences at the same site but were better explained by averaging spikes within approximately 3 mm. A comparison of separate sites suggests that selectivity is similar on a scale of approximately 800 microm for spikes and approximately 5 mm for LFPs. These observations imply that inputs to IT neurons convey selectivity for complex shapes and that such input may have an underlying organization spanning several millimeters.     

The frequency dependence of evoked and postsynaptic potentials in the somatosensory cortex of the cat.

Intracellular records were made from neurones of the somatosensory cortex of cats, during stimulation of the ventrobasal complex of the thalamus. The aim of the experiments was to detect correlations between frequency dependence of surface evoked potentials and that of unit discharges. The amplitude of the surface evoked potential showed a strong diminution when the frequency of the thalamic stimulation was raised from 1 cps to 15 cps. In spite of this, frequency dependence in amplitude of unit discharges was never seen. As regards their frequency of occurrence the unit responses (full spikes, dendritic, postsynaptic potentials) behaved differently: a part of them showed increasing, another part gave decreasing occurrence, and the remaining portion did not change it. The authors conclude that temporal dispersion fails to give account for the frequency dependence, therefore further possibilities have to be examined.     

The refractory periods and threshold potentials of sequential spikes measured by whole-cell recording

Neurons in the central nervous system are thought to program neural language via firing sequential spikes for guiding animal behaviors. The quantitative profiles of spike intrinsic properties are critically important to understand spike programming. We developed approaches with whole-cell recordings to measure the threshold potentials and refractory periods (RPs) of sequential spikes, and to analyze the relationships of these factors with spike timing precision and capacity at the regular-spiking and fast-spiking neurons in cortical slice. The RPs and threshold potentials of sequential spikes at these two groups of neurons are different and are linearly correlated with spike timing precision and capacity. These data suggest that RPs and threshold potentials essentially navigate the spike programming for the precise and loyal encoding of meaningful neural signals. Our study provides the avenues for decoding the spectrum of the neural signals quantitatively.     

Depression of evoked potentials in rat thalamic ventro-basal complex and somatosensory cortex after reticular stimulation

Experiments on unanesthetized rats immobilized with D-tubocurarine showed that electrical stimulation (100/sec) of the central gray matter and the mesencephalic and medullary reticular formation considerably depressed potentials in the somatic thalamic relay nucleus and somatosensory cortex evoked by stimulation of the forelimb or medial lemniscus. The mean threshold values of the current used for electrical stimulation of these structures did not differ significantly and were 70 (20–100), 100 (20–120), and 120 (50–200) µA, respectively. On comparison of the amplitude-temporal characteristics of inhibition of evoked potentials during electrical stimulation of the above-mentioned structures by a current of twice the threshold strength, no significant differences were found. Immediately after the end of electrical stimulation the amplitude of the cortical evolved potential and the post-synaptic components of the thalamic evoked potential was 50–60% (P<0.01) below the control values. The duration of this depression varied from 0.5 to 1 sec. An increase in the intensity of electrical stimulation of brain-stem structures to between three and five times the threshold led to depression of the presynaptic component of the thalamic evoked potential also. Depression of the evoked potential as described above was found with various ratios between the intensities of conditioning and testing stimuli.M. V. Lomonosov Moscow State University. Translated from Neirofiziologiya, Vol. 8, No. 5, pp. 467–475, September–October, 1976.     

Spike-timing-dependent potentiation of sensory surround in the somatosensory cortex is facilitated by deprivation-mediated disinhibition

Functional maps in the cerebral cortex reorganize in response to changes in experience, but the synaptic underpinnings remain uncertain. Here, we demonstrate that layer (L) 2/3 pyramidal cell synapses in mouse barrel cortex can be potentiated upon pairing of whisker-evoked postsynaptic potentials (PSPs) with action potentials (APs). This spike-timing-dependent long-term potentiation (STD-LTP) was only effective for PSPs evoked by deflections of a whisker in the neuron's receptive field center, and not its surround. Trimming of all except two whiskers rapidly opened the possibility to drive STD-LTP by the spared surround whisker. This facilitated STD-LTP was associated with a strong decrease in the surrounding whisker-evoked inhibitory conductance and partially occluded picrotoxin-mediated LTP facilitation. Taken together, our data demonstrate that sensory deprivation-mediated disinhibition facilitates STD-LTP from the sensory surround, which may promote correlation- and experience-dependent expansion of receptive fields.     

Processing in layer 4 of the neocortical circuit: new insights from visual and somatosensory cortex

Recent experimental and theoretical results in cat primary visual cortex and in the whisker-barrel fields of rodent primary somatosensory cortex suggest common organizing principles for layer 4, the primary recipient of sensory input from the thalamus. Response tuning of layer 4 cells is largely determined by a local interplay of feed-forward excitation (directly from the thalamus) and inhibition (from layer 4 inhibitory interneurons driven by the thalamus). Feed-forward inhibition dominates excitation, inherits its tuning from the thalamic input, and sharpens the tuning of excitatory cells. Recurrent excitation enhances responses to effective stimuli.     

The Radiation Issue in Cardiology: the time for action is now

Background

The study was designed to evaluate whether the preserved coronary flow reserve (CFR) 72 hours after reperfused acute myocardial infarction (AMI) is associated with less microvascular dysfunction and is predictive of left ventricular (LV) functional recovery and the final infarct size at follow-up.

Methods

In our study, CFR was assessed by transthoracic Doppler echocardiography (TDE) in 44 patients after the successful percutaneous coronary intervention during the acute AMI phase. CFR was correlated with contractile reserve assessed by low-dose dobutamine echocardiography and with the total perfusion defect measured by single-photon emission computed tomography 72 hours after reperfusion and at 5 months follow-up. The ROC analysis was performed to determine test sensitivity and specificity based on CFR. Categorical data were compared by an χ² analysis, continuous variables were analysed with the independent Student's t test. In order to analyse correlation between CFR and the parameters of LV function and perfusion, the Pearson correlation analysis was conducted. The linear regression analysis was used to assess the relationship between CFR and myocardial contractility as well as the final infarct size.

Results

We estimated the CFR cut-off value of 1.75 as providing the maximal accuracy to distinguish between patients with preserved and impaired CFR during the acute AMI phase (sensitivity 91.7%, specificity 75%). Wall motion score index was better in the subgroup with preserved CFR as compared to the subgroup with reduced CFR: 1.74 (0.29) vs. 1.89 (0.17) (p < 0.001) during the acute phase and 1.47 (0.30) vs. 1.81 (0.20) (p < 0.001) at follow-up, respectively. LV ejection fraction was 47.78% (8.99) in preserved CFR group vs. 40.79% (7.25) in impaired CFR group (p = 0.007) 72 hours after reperfusion and 49.78% (8.70) vs. 40.36% (7.90) (p = 0.001) after 5 months at follow-up, respectively. The final infarct size was smaller in patients with preserved as compared to patients with reduced CFR: 5.26% (6.14) vs. 23.28% (12.19) (p < 0.001) at follow-up.

Conclusion

The early measurement of CFR by TDE can be of high value for the assessment of successful reperfusion in AMI and can be used to predict LV functional recovery, myocardial viability and the final infarct size.     

Human dendritic cell expression of HLA-DO is subset specific and regulated by maturation

Expression of HLA-DO (DO) in cells that express HLA-DM (DM) results in an altered repertoire of MHC class II/peptide complexes, indicating that DO modulates DM function. Human and murine B cells and thymic epithelial cells express DO, while monocytes/macrophages do not. Monocyte-derived dendritic cells (DC) also have been found to be DO-negative, leading to the assumption that DC do not express DO. In this study, we report that, in fact, certain types of human primary DC express DO. These include Langerhans cells (LC) and some subtypes of circulating blood DC. Specifically, the majority of BDCA-3(+) DC, a small subset of uncertain function, are DO(+), while smaller proportions of CD11c(+), BDCA-1(+) (myeloid) DC, at most a minority of CD123(+)/BDCA-2(+) (plasmacytoid) DC, and no detectable CD16(+) (myeloid) DC, express DO. Immunohistochemistry of human tonsil sections demonstrates that tonsillar interdigitating DC are also DO(+). In a subset of immature LC with higher DO expression, an increased fraction of surface DR molecules carry CLIP peptides, indicating that DO functions as a DM inhibitor in these cells. LC expression of DO is down-regulated by maturation stimuli. DM levels also decrease under these conditions, but the DM:DO ratio generally increases. In the myeloid cell types tested, DO expression correlates with levels of DObeta, but not DOalpha, implying that modulation of DObeta regulates DO dimer abundance in these cells. The range of APC types shown to express DO suggests a broader role for DO in immune function than previously appreciated.     

The assessment of severe head injury by short-latency somatosensory and brain-stem auditory evoked potentials

The relative prognostic value of short-latency somatosensory evoked potentials (SEPs) and brain-stem auditory evoked potentials (BAEPs) was assessed in 35 patients with post-traumatic coma. Analysis of the evoked potentials was restricted to those recorded within the first 4 days following head injury. Abnormal SEPs were defined as an increase in central somatosensory conduction time or an absence of the initial cortical potential following stimulation of either median nerve. Abnormal BAEPs were classified as an increase in the wave I–V interval or the loss of any or all of its 3 most stable components (waves I, III and V) following stimulation of either ear. SEPs reliably both good and bad outcomes. All 17 patients in whom SEPs were graded as normal had a favourable outcome and 15 of 18 patients in whom SEPs were abnormal had an unfavourable outcome. Although abnormal BAEPs were associated with an unfavourable outcome in almost all patients (6 of 7), only 19 of 28 patients with normal BAEPs had a favourable outcome. The finding of normal BAEPs was therefore of little prognostic significance. These results confirm the superiority and greater sensitivity of the SEP in detecting abnormalities of brain function shortly after severe head trauma.     

Gabrb3 is required for the functional integration of pyramidal neuron subtypes in the somatosensory cortex

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Modulation of the photically evoked potentials in the motor cortex of cats by influences of the somatosensory system and the reticular formation]

The influence of somatosensor stimulation and electric stimulation in the mesencephalic reticular formation upon evoked potentials (EP) of the motor cortex (MC) produced by electric stimulation of the Chiasma opticum and the Corpus geniculatum laterale, respectively, was investigated in unnarcotized, immobilized cats. By preliminary electrical stimulation of the contralateral front limb, intensity-dependent changes of the early positive component of the EP in the MC could be produced. Similar changes were found after passive movement of the limb and following electrical stimulation in the reticular formation of the mesencephalon. The EP in the MC completely disappeared after i.v. administration of 15 mg/kg Nembutal. It is concluded that the impulses reaching the MC after stimulation in the visual system can be modulated in various ways, and thus exhibit a relatively high information content. Possible mechanisms of the modulating influences and their significance are discussed.     

DC-SIGN mediated sphingomyelinase-activation and ceramide generation is essential for enhancement of viral uptake in dendritic cells

As pattern recognition receptor on dendritic cells (DCs), DC-SIGN binds carbohydrate structures on its pathogen ligands and essentially determines host pathogen interactions because it both skews T cell responses and enhances pathogen uptake for cis infection and/or T cell trans-infection. How these processes are initiated at the plasma membrane level is poorly understood. We now show that DC-SIGN ligation on DCs by antibodies, mannan or measles virus (MV) causes rapid activation of neutral and acid sphingomyelinases followed by accumulation of ceramides in the outer membrane leaflet. SMase activation is important in promoting DC-SIGN signaling, but also for enhancement of MV uptake into DCs. DC-SIGN-dependent SMase activation induces efficient, transient recruitment of CD150, which functions both as MV uptake receptor and microbial sensor, from an intracellular Lamp-1+ storage compartment shared with acid sphingomyelinase (ASM) within a few minutes. Subsequently, CD150 is displayed at the cell surface and co-clusters with DC-SIGN. Thus, DC-SIGN ligation initiates SMase-dependent formation of ceramide-enriched membrane microdomains which promote vertical segregation of CD150 from intracellular storage compartments along with ASM. Given the ability to promote receptor and signalosome co-segration into (or exclusion from) ceramide enriched microdomains which provide a favorable environment for membrane fusion, DC-SIGN-dependent SMase activation may be of general importance for modes and efficiency of pathogen uptake into DCs, and their routing to specific compartments, but also for modulating T cell responses.