Developmental Switch in the Contribution of Presynaptic and Postsynaptic NMDA Receptors to Long-Term Depression

NMDA receptor (NMDAR) activation is required for many forms of learning and memory as well as sensory system receptive field plasticity, yet the relative contribution of pre- and postsynaptic NMDARs over cortical development remains unknown. Here we demonstrate a rapid developmental loss of functional presynaptic NMDARs in the neocortex. Presynaptic NMDARs enhance neurotransmitter release at synapses onto visual cortex pyramidal cells in young mice (P21). Immuno-electron microscopy revealed that the loss of presynaptic NMDAR function is likely due in part to a 50% reduction in the prevalence of presynaptic NMDARs. Coincident with the observed loss of presynaptic NMDAR function, there is an abrupt change in the mechanisms of timing-dependent long-term depression (tLTD). Induction of tLTD before the onset of the critical period requires activation of pre- but not postsynaptic NMDARs, while the induction of tLTD in older mice requires activation of postsynaptic NMDARs. By demonstrating that both pre- and postsynaptic NMDARs contribute to the induction of synaptic plasticity, and that their relative roles shift over development, our findings define a novel, and perhaps general, property of synaptic plasticity in emerging cortical circuits

Current and Calcium Responses to Local Activation of Axonal NMDA Receptors in Developing Cerebellar Molecular Layer Interneurons

In developing cerebellar molecular layer interneurons (MLIs), NMDA increases spontaneous GABA release. This effect had been attributed to either direct activation of presynaptic NMDA receptors (preNMDARs) or an indirect pathway involving activation of somato-dendritic NMDARs followed by passive spread of somatic depolarization along the axon and activation of axonal voltage dependent Ca2+ channels (VDCCs). Using Ca2+ imaging and electrophysiology, we searched for preNMDARs by uncaging NMDAR agonists either broadly throughout the whole field or locally at specific axonal locations. Releasing either NMDA or glutamate in the presence of NBQX using short laser pulses elicited current transients that were highly sensitive to the location of the spot and restricted to a small number of varicosities. The signal was abolished in the presence of high Mg2+ or by the addition of APV. Similar paradigms yielded restricted Ca2+ transients in interneurons loaded with a Ca2+ indicator. We found that the synaptic effects of NMDA were not inhibited by blocking VDCCs but were impaired in the presence of the ryanodine receptor antagonist dantrolene. Furthermore, in voltage clamped cells, bath applied NMDA triggers Ca2+ elevations and induces neurotransmitter release in the axonal compartment. Our results suggest the existence of preNMDARs in developing MLIs and propose their involvement in the NMDA-evoked increase in GABA release by triggering a Ca2+-induced Ca2+ release process mediated by presynaptic Ca2+ stores. Such a mechanism is likely to exert a crucial role in various forms of Ca2+-mediated synaptic plasticity

Presynaptic NMDA Receptors Mediate IPSC Potentiation at GABAergic Synapses in Developing Rat Neocortex

NMDA receptors are traditionally viewed as being located postsynaptically, at both synaptic and extrasynaptic locations. However, both anatomical and physiological studies have indicated the presence of NMDA receptors located presynaptically. Physiological studies of presynaptic NMDA receptors on neocortical GABAergic terminals and their possible role in synaptic plasticity are lacking.We report here that presynaptic NMDA receptors are present on GABAergic terminals in developing (postnatal day (PND) 12-15) but not older (PND21-25) rat frontal cortex. Using MK-801 in the recording pipette to block postsynaptic NMDA receptors, evoked and miniature IPSCs were recorded in layer II/III pyramidal cells in the presence of AMPA/KA receptor antagonists. Bath application of NMDA or NMDA receptor antagonists produced increases and decreases in mIPSC frequency, respectively. Physiologically patterned stimulation (10 bursts of 10 stimuli at 25 Hz delivered at 1.25 Hz) induced potentiation at inhibitory synapses in PND12-15 animals. This consisted of an initial rapid, large increase in IPSC amplitude followed by a significant but smaller persistent increase. Similar changes were not observed in PND21-25 animals. When 20 mM BAPTA was included in the recording pipette, potentiation was still observed in the PND12-15 group indicating that postsynaptic increases in calcium were not required. Potentiation was not observed when patterned stimulation was given in the presence of D-APV or the NR2B subunit antagonist Ro25-6981.The present results indicate that presynaptic NMDA receptors modulate GABA release onto neocortical pyramidal cells. Presynaptic NR2B subunit containing NMDA receptors are also involved in potentiation at developing GABAergic synapses in rat frontal cortex. Modulation of inhibitory GABAergic synapses by presynaptic NMDA receptors may be important for proper functioning of local cortical networks during development

Pre and Post Synaptic NMDA Effects Targeting Purkinje Cells in the Mouse Cerebellar Cortex

N-methyl-D-aspartate (NMDA) receptors are associated with many forms of synaptic plasticity. Their expression level and subunit composition undergo developmental changes in several brain regions. In the mouse cerebellum, beside a developmental switch between NR2B and NR2A/C subunits in granule cells, functional postsynaptic NMDA receptors are seen in Purkinje cells of neonate and adult but not juvenile rat and mice. A presynaptic effect of NMDA on GABA release by cerebellar interneurons was identified recently. Nevertheless whereas NMDA receptor subunits are detected on parallel fiber terminals, a presynaptic effect of NMDA on spontaneous release of glutamate has not been demonstrated. Using mouse cerebellar cultures and patch-clamp recordings we show that NMDA facilitates glutamate release onto Purkinje cells in young cultures via a presynaptic mechanism, whereas NMDA activates extrasynaptic receptors in Purkinje cells recorded in old cultures. The presynaptic effect of NMDA on glutamate release is also observed in Purkinje cells recorded in acute slices prepared from juvenile but not from adult mice and requires a specific protocol of NMDA application

Bidirectional Coupling between Astrocytes and Neurons Mediates Learning and Dynamic Coordination in the Brain: A Multiple Modeling Approach

In recent years research suggests that astrocyte networks, in addition to nutrient and waste processing functions, regulate both structural and synaptic plasticity. To understand the biological mechanisms that underpin such plasticity requires the development of cell level models that capture the mutual interaction between astrocytes and neurons. This paper presents a detailed model of bidirectional signaling between astrocytes and neurons (the astrocyte-neuron model or AN model) which yields new insights into the computational role of astrocyte-neuronal coupling. From a set of modeling studies we demonstrate two significant findings. Firstly, that spatial signaling via astrocytes can relay a “learning signal” to remote synaptic sites. Results show that slow inward currents cause synchronized postsynaptic activity in remote neurons and subsequently allow Spike-Timing-Dependent Plasticity based learning to occur at the associated synapses. Secondly, that bidirectional communication between neurons and astrocytes underpins dynamic coordination between neuron clusters. Although our composite AN model is presently applied to simplified neural structures and limited to coordination between localized neurons, the principle (which embodies structural, functional and dynamic complexity), and the modeling strategy may be extended to coordination among remote neuron clusters

Not on Shaky Grounds : \u3ci\u3eLawrence v. Texas\u3c/i\u3e, 123 S. Ct. 2472 (2003), and the Constitutionality of State DOMAs Such as Nebraska\u27s Marriage Provision, NEB. CONST. art. I, § 29

In June 2003 the U.S. Supreme Court struck down a controversial homosexual sodomy statute in Lawrence v. Texas. The issue was whether the Due Process Clause of the Fourteenth Amendment permitted a state to criminalize private and consensual sexual activity between adults. The Court held that it did not. Since the decision, much of the public discourse has turned to the subject of marriage and whether or not existing state laws that exclude same-sex marriages from public recognition will be able to stand in light of Lawrence. People on both sides of the issue assert that Lawrence paves the way for future challenges to existing state marriage laws that define marriage as being between a man and a woman. A broad reading of Lawrence may suggest that Defense of Marriage Acts (“DOMAs”) are on shaky ground, while a narrow reading suggests that DOMAs are secure for now. The purpose of this Note is to examine the Court’s decision in Lawrence and to discuss what impact, if any, its holding and reasoning might have on future constitutional challenges to Nebraska’s marriage provision. Part II of this Note reviews the background of Lawrence as well as the holding in Bowers v. Hardwick, which the Lawrence Court overruled and concludes with an overview of Nebraska’s marriage provision in Section 29 of the Nebraska Constitution. Part III examines some of the language in the majority and concurring opinions of Lawrence and how it might be employed in efforts to overturn Nebraska’s DOMA. The majority’s use of foreign law is discussed and the due process analysis in Lawrence is evaluated. In Part IV, I argue that Lawrence’s impact upon Nebraska’s marriage provision and similar enactments in other states should be minimal, because the issues of sodomy and marriage are two different issues, state laws that restrict the definition of marriage to one man and woman are rationally related to a legitimate state interest, and the Court in Lawrence explicitly limited its holding to sodomy laws

Towards resilient health systems: opportunities to align surgical and disaster planning

Natural disasters significantly contribute to human death and suffering. Moreover, they exacerbate pre-existing health inequalities by imposing an additional burden on the most vulnerable populations. Robust local health systems can greatly mitigate this burden by absorbing the extraordinary patient volume and case complexity immediately after a disaster. This resilience is largely determined by the predisaster local surgical capacity, with trauma, neurosurgical, obstetrical and anaesthesia care of particular importance. Nevertheless, the disaster management and global surgery communities have not coordinated the development of surgical systems in low/middle-income countries (LMIC) with disaster resilience in mind. Herein, we argue that an appropriate peridisaster response requires coordinated surgical and disaster policy, as only local surgical systems can provide adequate disaster care in LMICs. We highlight three opportunities to help guide this policy collaboration. First, the Lancet Commission on Global Surgery and the Sendai Framework for Disaster Risk Reduction set forth independent roadmaps for global surgical care and disaster risk reduction; however, ultimately both advocate for health system strengthening in LMICs. Second, the integration of surgical and disaster planning is necessary. Disaster risk reduction plans could recognise the role of surgical systems in disaster preparedness more explicitly and pre-emptively identify deficiencies in surgical systems. Based on these insights, National Surgical, Obstetric, and Anesthesia Plans, in turn, can better address deficiencies in systems and ensure increased disaster resilience. Lastly, the recent momentum for national surgical planning in LMICs represents a political window for the integration of surgical policy and disaster risk reduction strategies