Anesthetic and postanesthetic effects of isoflurane on neuronal activity in the rat hippocampus

In this study, we explored anesthetic and postanesthetic effects of isoflurane on GABA-ergic and glutamatergic systems in the rat hippocampus. Our results demonstrate that different neuronal targets affected by isoflurane recover from anesthesia at dissimilar rates. Neirofiziologiya/Neurophysiology, Vol. 39, Nos. 4/5, pp. 371–373, July–October, 2007.     

TLR7/8 triggering exerts opposing effects in acute versus latent HIV infection

TLRs trigger innate immunity by recognizing conserved motifs of microorganisms. Recently, ssRNAs from HIV and influenza virus were shown to trigger TLR7 and 8. Thus, we hypothesized that HIV ssRNA, by triggering TLR7/8, affects HIV pathogenesis. Indeed, HIV ssRNA rendered human lymphoid tissue of tonsillar origin or PBMC barely permissive to HIV replication. The synthetic compound R-848, which also triggers TLR7/8, showed similar anti-HIV activity. Loss of R-848's activity in lymphoid tissue depleted of B cells suggested a role for B cells in innate immunity. TLR7/8 triggering appears to exert antiviral effects through soluble factors: conditioned medium reduced HIV replication in indicator cells. Although a number of cytokines and chemokines were increased upon adding R-848 to lymphoid tissue, blocking those cytokines/chemokines (i.e., IFN-alpha receptor, IFN-gamma, MIP-1alpha, -1beta, RANTES, and stromal cell-derived factor-1) did not result in the reversal of R-848's anti-HIV activity. Thus, the nature of this soluble factor(s) remains unknown. Unlike lymphoid tissue acutely infected with HIV, triggering latently infected promonocytic cells induced the release of HIV virions. The anti-HIV effects of triggering TLR7/8 may inhibit rapid killing, while pro-HIV effects may guarantee a certain replication level. Compounds triggering TLR7/8 may be attractive drug candidates to purge latent HIV while preventing new infections.     

Effects of the cholinotoxin,AF 64A,on neuronal trace-metal distribution in the rat hippocampus and neocortex

Summary Ethylcholine mustard aziridinium ion (AF64A) is a neurotoxin which is specific for cholinergic nerve terminals. Besides its effects on elements of the acetylcholine system, we observed that, after 2 and 8 days, a single 20-nmol intracerebroventricular dose altered the Timm's staining of certain regions of the central nervous system and reduced the tissue levels of trace metals. In the hippocampal formation, there was a considerable decrease in the staining of the neuropil of the stratum radiatum and stratum oriens, which contain cholinergic nerve terminals. A reduction in staining was also demonstrated in the perikarya of cortical pyramidal cells. The diminished trace-metal level in both regions was confirmed by quantitative measurements of zinc and copper levels. A similar reduction was not observed at a lower dose (8 nmol) of the cholinotoxin. The results led to the conclusion that AF64A may cause the decrease of the trace-metal content of the postsynaptic neurons through an indirect mechanism.     

Cell-type specific depression of neuronal excitability in rat hippocampus by activation of ATP-sensitive potassium channels

The contribution of ATP-sensitive potassium (K(ATP)) channels to neuronal excitability was studied in different types of pyramidal cells and interneurones in hippocampal slices prepared from 9- to 15-day-old rats. The presence of functional K(ATP) channels in the neurones was detected through the sensitivity of whole-cell currents to diazoxide, a K(ATP) channel opener, and to tolbutamide, a K(ATP) channel inhibitor. The percentages of neurones with K(ATP) channels increase in the sequence: CA1 pyramidal cells (37%)相似文献   

学习训练对谷氨酸单钠所致大鼠海马损伤的神经保护作用

目的：探讨学习训练对谷氨酸神经毒性的保护作用。方法：在SD大鼠生后第3～9d腹腔注射谷氨酸单钠复制谷氨酸毒性模型,在1月龄和2月龄时训练大鼠学会以明暗辨别来获得食物,3月龄时取脑,在光镜下计数海马内存活神经元数,电镜下观察海马CA1区的超微结构,并计数突触数,测量突触活性带长度。结果：学习训练组海马CA3区和CA4区内的存活神经元数、海马CA1区内的突触数和突触活性带长度均大于非学习组,结论：结果提示学习训练可在一定程度上减轻MSG对海马的损伤。     

alpha- and betaCaMKII. Inverse regulation by neuronal activity and opposing effects on synaptic strength

We show that alpha and betaCaMKII are inversely regulated by activity in hippocampal neurons in culture: the alpha/beta ratio shifts toward alpha during increased activity and beta during decreased activity. The swing in ratio is approximately 5-fold and may help tune the CaMKII holoenzyme to changing intensities of Ca(2+) signaling. The regulation of CaMKII levels uses distinguishable pathways, one responsive to NMDA receptor blockade that controls alphaCaMKII alone, the other responsive to AMPA receptor blockade and involving betaCaMKII and possibly further downstream effects of betaCaMKII on alphaCaMKII. Overexpression of alphaCaMKII or betaCaMKII resulted in opposing effects on unitary synaptic strength as well as mEPSC frequency that could account in part for activity-dependent effects observed with chronic blockade of AMPA receptors. Regulation of CaMKII subunit composition may be important for both activity-dependent synaptic homeostasis and plasticity.     

Mechanisms of epileptogenic effects of some convulsants on the neuronal activity in the neocortex

The data obtained in the studies of neurophysiological aspects of epileptogenesis in the brain cortex, which have been carried out in our laboratory for many years, are used for the analysis of epileptogenic effects of a few convulsants (penicillin, strychnine, and d-tubocurarine) on the activity of neocortical neurons. It has been demonstrated that the development of the epileptiform activity in the cortex is accompanied by suppression of IPSP, and the above convulsants directly influence the mechanisms of postsynaptic inhibition. Epileptogenic effects of strychine and penicillin are based on blocking of chloride ion channels and depend on the direction of chloride currents. The role of excitatory and inhibitory synaptic interactions among neurons in generation of the epileptiform activity is discussed.     

The alpha4 regulatory subunit exerts opposing allosteric effects on protein phosphatases PP6 and PP2A

The protein Ser/Thr phosphatase family contains three enzymes called PP2A, PP4, and PP6 with separate biological functions inferred from genetics of the yeast homologues Pph21/22, Pph3, and Sit4. These catalytic subunits associate with a common subunit called alpha4 (related to yeast Tap42). Here, we characterized recombinant PP6 and PP2A catalytic monomers and alpha4.phosphatase heterodimers. Monomeric PP6 and PP2A showed identical kinetics using either p-nitrophenyl phosphate (pNPP) or 32P-myelin basic protein (MBP) as substrates, with matching Km and Vmax values. Using pNPP as substrate, PP6 and PP2A gave the same IC50 with active site inhibitors okadaic acid, microcystin-LR, calyculin A, and cantharidin. However, with MBP as substrate, PP6 was inhibited at 5-fold lower concentrations of toxins relative to PP2A, suggesting PP6 might be a preferred in vivo target of toxins. Heterodimeric alpha4.PP6 and alpha4.PP2A were starkly different. With MBP as substrate the alpha4.PP2A heterodimer had a 100-fold higher Vmax than alpha4.PP6, and neither heterodimer was active with pNPP. Thus, these phosphatases are distinguished by their different responses to allosteric binding of the common regulatory subunit alpha4. Transient expression of alpha4 differentially increased or decreased phosphorylation of endogenous phosphoproteins, consistent with opposing effects on PP2A and PP6.     

Contrasting effects of the persistent Na+ current on neuronal excitability and spike timing

The persistent Na+ current, INaP, is known to amplify subthreshold oscillations and synaptic potentials, but its impact on action potential generation remains enigmatic. Using computational modeling, whole-cell recording, and dynamic clamp of CA1 hippocampal pyramidal cells in brain slices, we examined how INaP changes the transduction of excitatory current into action potentials. Model simulations predicted that INaP increases afterhyperpolarizations, and, although it increases excitability by reducing rheobase, INaP also reduces the gain in discharge frequency in response to depolarizing current (f/I gain). These predictions were experimentally confirmed by using dynamic clamp, thus circumventing the longstanding problem that INaP cannot be selectively blocked. Furthermore, we found that INaP increased firing regularity in response to sustained depolarization, although it decreased spike time precision in response to single evoked EPSPs. Finally, model simulations demonstrated that I(NaP) increased the relative refractory period and decreased interspike-interval variability under conditions resembling an active network in vivo.     

AdipoRon exerts opposing effects on insulin sensitivity via fibroblast growth factor 21–mediated time-dependent mechanisms

Increasing evidence has shown that AdipoRon, a synthetic adiponectin receptor agonist, is involved in the regulation of whole-body insulin sensitivity and energy homeostasis. However, the mechanisms underlying these alterations remain unclear. Here, using hyperinsulinemic–euglycemic clamp and isotopic tracing techniques, we show that short-term (10 days) AdipoRon administration indirectly inhibits lipolysis in white adipose tissue via increasing circulating levels of fibroblast growth factor 21 in mice fed a high-fat diet. This led to reduced plasma-free fatty acid concentrations and improved lipid-induced whole-body insulin resistance. In contrast, we found that long-term (20 days) AdipoRon administration directly exacerbated white adipose tissue lipolysis, increased hepatic gluconeogenesis, and impaired the tricarboxylic acid cycle in the skeletal muscle, resulting in aggravated whole-body insulin resistance. Together, these data provide new insights into the comprehensive understanding of multifaceted functional complexity of AdipoRon.     

Temporal redistribution of inhibition over neuronal subcellular domains underlies state-dependent rhythmic change of excitability in the hippocampus

The behaviour-contingent rhythmic synchronization of neuronal activity is reported by local field potential oscillations in the theta, gamma and sharp wave-related ripple (SWR) frequency ranges. In the hippocampus, pyramidal cell assemblies representing temporal sequences are coordinated by GABAergic interneurons selectively innervating specific postsynaptic domains, and discharging phase locked to network oscillations. We compare the cellular network dynamics in the CA1 and CA3 areas recorded with or without anaesthesia. All parts of pyramidal cells, except the axon initial segment, receive GABA from multiple interneuron types, each with distinct firing dynamics. The axon initial segment is exclusively innervated by axo-axonic cells, preferentially firing after the peak of the pyramidal layer theta cycle, when pyramidal cells are least active. Axo-axonic cells are inhibited during SWRs, when many pyramidal cells fire synchronously. This dual inverse correlation demonstrates the key inhibitory role of axo-axonic cells. Parvalbumin-expressing basket cells fire phase locked to field gamma activity in both CA1 and CA3, and also strongly increase firing during SWRs, together with dendrite-innervating bistratified cells, phasing pyramidal cell discharge. Subcellular domain-specific GABAergic innervation probably developed for the coordination of multiple glutamatergic inputs on different parts of pyramidal cells through the temporally distinct activity of GABAergic interneurons, which differentially change their firing during different network states.     

Congruence of vascular network remodeling and neuronal dispersion in the hippocampus of reelin-deficient mice

In the hippocampus, neurons and fiber projections are strictly organized in layers and supplied with oxygen via a vascular network that also develops layer-specific characteristics in wild-type mice, as shown in the present study for the first time in a quantitative manner. By contrast, in the reeler mutant, well known for its neuronal migration defects due to the lack of the extracellular matrix protein reelin, emerging layer-specific characteristics of the vascular pattern were found to be remodeled during development of the dentate gyrus. Remarkably, in the first postnatal week, when a granule cell layer was still discernable in the reeler dentate gyrus, also the reeler vascular pattern resembled wild type. Thus, at postnatal day 6, unbranched microvessels traversed the granule cell layer and bifurcated when reaching the subgranular zone. Only after the first postnatal week vascular network remodeling in the reeler dentate gyrus became apparent, when the proportion of dispersed granule cells increased. Hence, vessel bifurcation frequency decreased in the maturing reeler dentate gyrus, but increased in wild type, resulting in significant differences (approx. 100%; p < 0.01) between adult wild type and reeler. Moreover, layer-specific vessel bifurcation frequencies disappeared in the maturing reeler dentate gyrus. Finally, a wild type-like vascular pattern was also found in the dentate gyrus of mice deficient for the reelin receptor very low density lipoprotein receptor (VLDLR), precluding a requirement of VLDLR for normal vascular pattern formation in the dentate gyrus. In sum, our findings show that vascular network remodeling in the reeler dentate gyrus is closely linked to the progression of granule cell dispersion.     

Cyclin-dependent kinase 5 and neuronal migration in the neocortex

The cyclin-dependent kinase 5 (Cdk5) plays an important role in the proper establishment of neocortical layers. Over the past several years, key molecular targets of Cdk5 have been identified that show intriguing connections to the adhesional and cytoskeletal components of cell movement. This molecular knowledge about Cdk5 signaling has begun to translate into an understanding of how Cdk5 regulates the cellular physiology of neocortical layer formation. Together with recent progress on the signaling relationship between Cdk5 and Reelin, the other key protein involved in neocortical layer formation, and their relationship to migration modes, research on understanding neocortical layer formation has arrived at a most promising crossroad.     

AMPA receptor regulation during synaptic plasticity in hippocampus and neocortex

Discovery of long-term potentiation (LTP) in the dentate gyrus of the rabbit hippocampus by Bliss and L?mo opened up a whole new field to study activity-dependent long-term synaptic modifications in the brain. Since then hippocampal synapses have been a key model system to study the mechanisms of different forms of synaptic plasticity. At least for the postsynaptic forms of LTP and long-term depression (LTD), regulation of AMPA receptors (AMPARs) has emerged as a key mechanism. While many of the synaptic plasticity mechanisms uncovered in at the hippocampal synapses apply to synapses across diverse brain regions, there are differences in the mechanisms that often reveal the specific functional requirements of the brain area under study. Here we will review AMPAR regulation underlying synaptic plasticity in hippocampus and neocortex. The main focus of this review will be placed on postsynaptic forms of synaptic plasticity that impinge on the regulation of AMPARs using hippocampal CA1 and primary sensory cortices as examples. And through the comparison, we will highlight the key similarities and functional differences between the two synapses.     

Outside and in: development of neuronal excitability

Investigation of the development of excitability has revealed that cells are often specialized at early stages to generate Ca(2+) transients. Studies of excitability have converged on the central role of Ca(2+) and K(+) channels in the plasmalemma that regulate Ca(2+) influx and have identified critical functions for receptor-activated channels in the endoplasmic reticulum that allow efflux of Ca(2+) from intracellular stores. The parallels between excitability in these two locations motivate future work, because comparison of their properties identifies shared attributes.     

Apparent opposing effects of cyclic AMP and dibutyryl-cyclic GMP on the neuronal firing of the blowfly chemoreceptors

Cyclic AMP and its dibutyryl derivative inhibit neuronal firing of the labellar sugar sensitive receptor of the blowfly when applied in conjunction with the stimulant sucrose. Furthermore, simultaneous application of aminophylline (phosphodiesterase inhibitor) and sucrose or in combination with cyclic AMP caused a similar depression of the sugar receptors response. In contrast, dibutyryl cyclic GMP elicited an increase in sugar receptor firing when applied with sucrose to the sugar receptor. Either 5′-AMP or 5′-GMP in combination with sucrose had no discernable effect on the sugar receptors response. Different ratio combinations of cyclic AMP and dibutyryl cyclic GMP showed the striking inhibitory effect of cyclic AMP upon the dibutyryl cyclic GMP elicited increases in receptor firing frequency. Therefore, it is suggested that these two nucleotides may be mediating different but complimentary aspects of sugar receptor function in a push-pull manner.     

Synchronization dynamics in the neuronal work of the neocortex and hippocampus during learning before and after the administration of nootropics and narcotics

The basal difference in action of the studied drugs was that nootropics (phenybut in a dose of 40 mg/kg and pyracetam in a dose of 200-400 mg/kg) did not change the initial action of pain reinforcement on synchronism in responses of the cortical neurones of alert nonimmobilized rabbits by inhibitory type (coincidence of the presence and absence of impulse activity) towards its decrease, while narcotics of various types (ethanol in a dose of 4-6 mg/kg, morphine-like opiate DAGO and opioid peptide DADLE in doses of 250 mkg/kg) eliminated the action of pain reinforcement on synchronism in responses of the cortical neurones both by inhibitory and activation (time of coincidence only of the presence of impulse activity) types. These and other drugs mainly weakened the initial action of both the inhibitory and reinforced light flashes of synchronism in neurones activity both by inhibitory and activation types. There was no constant parallelism between changes of synchronization and the frequency of the cortical impulses.