Synaptic Transmission In Response Research Articles

Developmental homeostasis of mouse retinocollicular synapses.

Spontaneous retinal waves during development are thought to provide an instructive signal for precise retinotopic mapping by correlating the activity of neighboring retinal ganglion cells. In mutant mice (beta2-/-) that lack correlated waves, retinocollicular map refinement is impaired. In vivo recordings reveal that neurons in the superior colliculus of beta2-/- mice have large receptive fields and low peak visual responses, resulting in a conservation of total integrated response. We find that this "response homeostasis" is maintained on a cell-by-cell basis, and argue that it does not depend on regulation from the visual cortex during adulthood. Instead, in vitro recordings show that homeostasis arises from the conservation of total synaptic input from the retina, and that it is maintained via different mechanisms over development. In the absence of correlated retinal waves, beta2-/- neurons sample a larger number of weaker retinal inputs relative to controls after the first postnatal week. Once retinal waves are restored, developmental learning rules and homeostasis drive refinement so that fewer, stronger synapses are retained, as in wild-type mice, but from a larger retinal area. Homeostasis in neurons has been shown previously to regulate the gain of synaptic transmission in response to perturbations of activity. Our results suggest that during the development of sensory maps, a unique consequence of homeostatic mechanisms is the precise shaping of neuronal receptive fields in conjunction with activity-dependent competition.

Chronic high‐frequency stimulation of the subthalamic nucleus and L‐DOPA treatment in experimental parkinsonism: effects on motor behaviour and striatal glutamate transmission

Hyperactivity of striatal glutamatergic synaptic transmission in response to dopamine depletion plays a major role in the pathogenesis of parkinsonian motor symptoms. In the present study we investigated the impact, on this hyperactivity, of chronic dyskinesiogenic L-DOPA treatment, combined or not with high-frequency stimulation (HFS) of the subthalamic nucleus (STN). In vitro patch-clamp recordings were performed from striatal spiny neurons of hemiparkinsonian rats (intranigral 6-OHDA injection). Here we show that dyskinesiogenic L-DOPA treatment exacerbated striatal glutamatergic hyperactivity induced by 6-OHDA lesion. Chronic 5-day STN HFS had the opposite effect, reducing striatal glutamatergic transmission in both parkinsonian and dyskinetic animals. Consistently, chronic HFS stimulation could progressively ameliorate motor parkinsonian signs (akinesia) but, conversely, did not improve L-DOPA-induced dyskinesia (LID). Thus, the effects of L-DOPA and HFS on corticostriatal transmission seem to be dissociated. These data show for the first time that dyskinesiogenic L-DOPA treatment and chronic STN HFS with antiakinetic effects induce opposite plastic rearrangements in the striatum. The interaction between these two treatments provides further evidence that striatal glutamatergic hyperactivity is a pathophysiological correlate of akinesia rather than LID.

Bilirubin potentiates inhibitory synaptic transmission in lateral superior olive neurons of the rat

Bilirubin is a well-known neurotoxin that can result in multiple neurologic deficits. Previous studies have suggested that bilirubin affects aspects of synaptic transmission; however the acute effects of bilirubin on synaptic transmission have not been examined in real-time. In this study, using whole-cell voltage-clamp recordings, we observed the effect of bilirubin on inhibitory postsynaptic currents (IPSC) in postnatal 13–15-day-old neurons dissociated from lateral superior olive nuclei (LSO), one of the brainstem auditory nucleus that are highly vulnerable to bilirubin. The results showed that 10 −5 M bilirubin increased the frequency of spontaneous IPSC without causing change in their amplitudes or in the response to bath applied glycine, suggesting a presynaptic locus for the action. In the presence of tetrodotoxin, the frequency of miniature IPSC was also potentiated by 10 −5 M bilirubin. The facilitation by bilirubin was concentration dependent and increased with an increase in exposure time. Bicuculline only partially reduced the action of bilirubin. The action of bilirubin was observed in extracellular Ca 2+-free ([Ca 2+] o free) solution but was fully occluded by pretreatment with BAPTA-AM in [Ca 2+] o free solution. Thus, in LSO neurons, bilirubin facilitates inhibitory synaptic transmission, in a manner independent of voltage-activated Na + and Ca 2+ channels but dependent on presynaptic [Ca 2+] i. The increase of inhibitory synaptic transmission in response to acute bilirubin is a novel effect of bilirubin on the central nervous system and may have implications for neurotoxicity and the impairment of auditory transduction seen in hyperbilirubinemia.

Control of Daily Transcript Oscillations in Drosophila by Light and the Circadian Clock

The transcriptional circuits of circadian clocks control physiological and behavioral rhythms. Light may affect such overt rhythms in two ways: (1) by entraining the clock circuits and (2) via clock-independent molecular pathways. In this study we examine the relationship between autonomous transcript oscillations and light-driven transcript responses. Transcript profiles of wild-type and arrhythmic mutant Drosophila were recorded both in the presence of an environmental photocycle and in constant darkness. Systematic autonomous oscillations in the 12- to 48-h period range were detectable only in wild-type flies and occurred preferentially at the circadian period length. However, an extensive program of light-driven expression was confirmed in arrhythmic mutant flies. Many light-responsive transcripts are preferentially expressed in the compound eyes and the phospholipase C component of phototransduction, NORPA (no receptor potential), is required for their light-dependent regulation. Although there is evidence for the existence of multiple molecular clock circuits in cyanobacteria, protists, plants, and fungi, Drosophila appears to possess only one such system. The sustained photic expression responses identified here are partially coupled to the circadian clock and may reflect a mechanism for flies to modulate functions such as visual sensitivity and synaptic transmission in response to seasonal changes in photoperiod.

Neuroscience: A Vibrant Connection

Communication is crucial between organisms and within organisms—down to the scale of cellular and subcellular structures. It is particularly important for the nervous system, which is devoted to information processing. In addition to other more general ways of information exchange with their neighbors and their environment, nerve cells have special structures called synapses for communication with each other as well as with target cells such as muscles. Ever since their first description, synapses have caught the attention and imagination of neuroscientists. Some of the finest minds in the neuroscientific community have devoted much of their energy to furthering our understanding of the basic mechanisms and the fine-tuning of synaptic transmission, information flow, and plasticity, as well as synapse formation and development. In recent years, enormous progress has been made in the unraveling of every level of these phenomena. The picture emerging is that the synapse, far from being a static entity, is one of the most dynamic structures in the nervous system. This is true not only during its development and formation but throughout the lifetime of an organism. This special issue of Science presents a synopsis of some of the recent developments in this core area of neuroscience. We have also aimed to show where our understanding is still incomplete and where the emphasis of future research might lie. Cohen-Cory (p. [770][1]) reviews the classic and more recent findings in the field of synaptogenesis and their relationship to activity-dependent processes from both a cellular and a systems neuroscience point of view. Sheng and Kim (p. [776][2]) present the most recent results on molecular interactions and activated biochemical pathways on the postsynaptic side. They describe mechanisms that lead to synaptic plasticity and modulated synaptic transmission in response to different patterns of synapse activation. By comparing the exocytotic events in chromaffin cells and in neurons, Rettig and Neher (p. [781][3]) review the presynaptic machinery involved in exocytosis. Their overview shows that much can be gained from the right choice of a useful model system. In their Viewpoint, Dustin and Colman (p. [785][4]) compare the neuronal and the immunological synapse, showing that there is more than semantics to the use of this term and that both neuroscientists and immunologists can gain much from the progress being made in the understanding of phenomena in these complementary fields. And finally, in another Viewpoint, Selkoe (p. [789][5]) presents a case for synapses being the initial targets in Alzheimer's disease, because it appears that subtle alterations in synaptic function are the earliest features of this disease. Understanding the basic mechanisms of Alzheimer's may also be helpful in our efforts to tackle many other neurodegenerative disorders. [1]: /lookup/doi/10.1126/science.1075510 [2]: /lookup/doi/10.1126/science.1075333 [3]: /lookup/doi/10.1126/science.1075375 [4]: /lookup/doi/10.1126/science.1076386 [5]: /lookup/doi/10.1126/science.1074069

Ras-Up, Rap-Down

Changes in excitatory synaptic transmission in response to repetitive stimulation involve changes in the presence of AMPA-type glutamate receptors (AMPARs) in the synapses. AMPARs composed of subunits with long cytoplasmic tails are inserted into synapses during activity-induced synaptic enhancement; whereas AMPARs with short cytoplasmic tails are removed from synapses in response to activity-induced synaptic depression. Zhu et al. examined how the guanosine triphosphatases (GTPases) Ras and Rap influence hippocampal synaptic activity and the AMPARs in the synapses. In hippocampal slices that ectopically expressed consitutively active forms of Ras, there was enhancement of AMPAR-mediated synaptic activity. In hippocampal slices that ectopically expressed consitutively active forms of Rap, there was depression of AMPAR-mediated synaptic activity. Expression of dominant-negative Ras inhibited AMPAR activity, and expression of wild-type Ras enhanced AMPAR activity. Drugs that blocked the mitogen-activated and extracellular signal-regulated protein kinase (MEK) inhibited the Ras-mediated enhancement of AMPAR activity. Active Ras promoted the delivery of long forms of the AMPAR, and dominant-negative Ras inhibited synaptic potentiation in response to repetitive stimulation, which suggests a role for Ras in synaptic plasticity associated with long-term potentiation. In contrast, dominant-negative Rap enhanced tonic AMPAR activity, whereas wild-type Rap inhibited tonic AMPAR activity. Rap stimulated the phosphorylation of the p38 mitogen-activated protein kinase (MAPK). Also, the ability of active Rap to depress synaptic activity was blocked if the slices were treated with a p38 MAPK inhibitor. Dominant-negative Rap blocked the induction of long-term depression. Rap appeared to promote the removal of the same AMPAR subtypes that were removed from synapses during long-term depression, the short-tailed AMPAR subunits. Thus, Ras and Rap antagonize each other for regulation of AMPAR synaptic activity. J. J. Zhu, Y. Qin, M. Zhao, L. Van Aelst, R. Malinow, Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell 110 , 443-455 (2002). [Online Journal]

Modulation of protein kinase A activation by fibronectin matrix proteins at developing neuromuscular synapses in Xenopus laevis cell cultures.

Extracellular matrix proteins, such as fibronectin, laminin, and collagen, have been implicated in a wide variety of cellular properties, which include cell adhesion, migration, differentiation, and proliferation. In this study, we investigated the modulation of protein kinase A (PKA) activity by matrix proteins at developing motoneurons. The cultures of spinal neurons and myotomal cells were prepared from 1-day-old Xenopus laevis embryos. Spontaneous synaptic currents (SSC) were recorded from innervated myocytes of natural synapses by whole-cell voltage-clamped recordings (V(h) = -60 to approximately -65 mV). Bath application of agents, which directly or indirectly activate PKA, such as forskolin (20 microM), dibutyryl cAMP (DBcAMP) (1 mM), isoproterenol (10 microM), or albuterol (10 microM), significantly increased SSC frequency in cultures grown on fibronectin (FN)-coated substratum, but not on laminin- or collagen-coated glasses. The evoked synaptic currents increased in response to forskolin in neurons grown on FN substratum. Triflavin, an Arg-Gly-Asp-dependent disintegrin, inhibited potentiating action of isoproterenol in neurons grown on FN substratum, suggesting that integrin is involved in the potentiation of the PKA pathway in the regulation of acetylcholine (ACh) release. There is collaboration of neurotrophic factors and the FN matrix in regulating synaptic transmission in response to DBcAMP. Chronic treatment with neurotrophic factors, such as ciliary neurotrophic factor (150 ng/ml), glial cell line-derived neurotrophic factor (30 ng/ml), or neurotrophin-3 (50 ng/ml), enhanced the SSC-increasing action of DBcAMP in neurons grown on FN-coated glasses. These results suggest that the FN matrix potentiates synaptic transmission in response to PKA activation. Neurotrophic factors may collaborate with FN to regulate spontaneous ACh secretion at developing motoneurons, which may play an important role in the maturation of embryonic neuromuscular synapses.

Rapid, Activation-Induced Redistribution of Ionotropic Glutamate Receptors in Cultured Hippocampal Neurons

We have examined the membrane localization of an AMPA receptor subunit (GluR1) and an NMDA receptor subunit (NR1) endogenously expressed in primary cultures of rat hippocampal neurons. In unstimulated cultures, both GluR1 and NR1 subunits were concentrated in SV2-positive synaptic clusters associated with dendritic shafts and spines. Within 5 min after the addition of 100 microM glutamate to the culture medium, a rapid and selective redistribution of GluR1 subunits away from a subset of synaptic sites was observed. This redistribution of GluR1 subunits was also induced by AMPA, did not require NMDA receptor activation, did not result from ligand-induced neurotoxicity, and was reversible after the removal of agonist. The activation-induced redistribution of GluR1 subunits was associated with a pronounced (approximately 50%) decrease in the frequency of miniature EPSCs, consistent with a role of GluR1 subunit redistribution in mediating rapid regulation of synaptic efficacy. We conclude that ionotropic glutamate receptors are regulated in native neurons by rapid, subtype-specific membrane trafficking, which may modulate synaptic transmission in response to physiological or pathophysiological activation.

Effect of electrical cutaneous stimulation on the level of succinate dehydrogenase activation and changes in glutamatergic synaptic transmission in response to sensory stimulation

It is shown that the rise of succinate dehydrogenase activity in the hippocampus depends on the number of sensory stimuli presented before decapitation, which correlates with changes in the efficiency of glutamatergic synaptic transmission in hippocampal sections from the same animal. Electrocutaneous stimulation potentiates the activation of succinate dehydrogenase induced by sensory stimulation probably due to enhanced glutamate release.

The nitric oxide‐cyclic GMP pathway and synaptic plasticity in the rat superior cervical ganglion

1. We have investigated the possibility that nitric oxide (NO) and soluble guanylyl cyclase, an enzyme that synthesizes guanosine 3':5'-cyclic monophosphate (cyclic GMP) in response to NO, contributes to plasticity of synaptic transmission in the rat isolated superior cervical ganglion (SCG). 2. Exposure of ganglia to the NO donor, nitroprusside, caused a concentration-dependent accumulation of cyclic GMP which was augmented in the presence of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine. The compound, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a selective inhibitor of soluble guanylyl cyclase, completely blocked this cyclic GMP response. 3. As assessed by extracellular recording, nitroprusside (100 microM) and another NO donor, S-nitrosoglutathione (30 microM) increased the efficacy of ganglionic synaptic transmission in response to electrical stimulation of the preganglionic nerve, an effect that was reversible and which could be replicated by the cyclic GMP analogue, 8-bromo-cyclic GMP. Ganglionic depolarizations resulting from stimulation of nicotinic receptors with carbachol were not increased by nitroprusside. The potentiating actions of the NO donors on synaptic transmission, but not that of 8-bromo-cyclic GMP, were inhibited by ODQ. 4. Brief tetanic stimulation of the preganglionic nerve resulted in a long-term potentiation (LTP) of synaptic transmission that was unaffected by ODQ, either in the absence or presence of the NO synthase inhibitor, NG-nitro-L-arginine (L-NOARG, 100 microM). A lack of influence of L-NOARG was confirmed in intracellular recordings of LTP of the excitatory postsynaptic potential. Furthermore, under conditions where tetanically-induced LTP was saturated, nitroprusside was still able to potentiate synaptic transmission, as judged from extracellular recording. 5. We conclude that NO is capable of potentiating ganglionic neurotransmission and this effect is mediated through the stimulation of soluble guanylyl cyclase and the accumulation of cyclic GMP. However, this potentiation is distinct from LTP of nicotinic synaptic transmission, in which neither NO nor soluble guanylyl cyclase appear to participate.