Witnessing pain and distress in others can cause psychological trauma and increase odds of developing PTSD in the future, on exposure to another stressful event. However, the underlying synaptic ...process remains unknown. Here we report that mice exposed to a conspecific receiving electrical footshocks exhibited enhanced passive avoidance (PA) learning when trained 24 h after the exposure. The exposure activated neurons in the dorsomedial prefrontal cortex (dmPFC) and basolateral amygdala (BLA) and altered synaptic transmission from dmPFC to BLA. It increased amplitude, slowed decay of NMDA receptor-mediated currents, and generated silent synapses. Administration of sub-anesthetic ketamine immediately after the exposure prevented the enhancement of PA learning and silent synapse formation. These findings suggest that ketamine can prevent pathophysiological consequences of psychological trauma.
General anesthetics induce apoptotic neurodegeneration in the developing mammalian brain. General anesthesia (GA) also causes significant disturbances in mitochondrial morphogenesis during intense ...synaptogenesis. Mitochondria are dynamic organelles that undergo remodeling via fusion and fission. The fine balance between these two opposing processes determines mitochondrial morphometric properties, allowing for their regeneration and enabling normal functioning. As mitochondria are exquisitely sensitive to anesthesia-induced damage, we examined how GA affects mitochondrial fusion/fission.
Seven-day-old rat pups received anesthesia containing a sedative dose of midazolam followed by a combined nitrous oxide and isoflurane anesthesia for 6 h.
GA causes 30% upregulation of reactive oxygen species (n = 3-5 pups/group), accompanied by a 2-fold downregulation of an important scavenging enzyme, superoxide dismutase (n = 6 pups/group). Reactive oxygen species upregulation is associated with impaired mitochondrial fission/fusion balance, leading to excessive mitochondrial fission. The imbalance between fission and fusion is due to acute sequestration of the main fission protein, dynamin-related protein 1, from the cytoplasm to mitochondria, and its oligomerization on the outer mitochondrial membrane. These are necessary steps in the formation of the ring-like structures that are required for mitochondrial fission. The fission is further promoted by GA-induced 40% downregulation of cytosolic mitofusin-2, a protein necessary for maintaining the opposing process, mitochondrial fusion (n = 6 pups/group).
Early exposure to GA causes acute reactive oxygen species upregulation and disturbs the fine balance between mitochondrial fission and fusion, leading to excessive fission and disturbed mitochondrial morphogenesis. These effects may play a causal role in GA-induced developmental neuroapoptosis.
Brief monocular deprivation (MD) shifts ocular dominance and reduces the density of thalamic synapses in layer 4 of the mouse primary visual cortex (V1). We found that microglial lysosome content is ...also increased as a result of MD. Previous studies have shown that the microglial fractalkine receptor CX3CR1 is involved in synaptic development and hippocampal plasticity. We therefore tested the hypothesis that neuron-to-microglial communication via CX3CR1 is an essential component of visual cortical development and plasticity in male mice. Our data show that CX3CR1 is not required for normal development of V1 responses to visual stimulation, multiple forms of experience-dependent plasticity, or the synapse loss that accompanies MD in layer 4. By ruling out an essential role for fractalkine signaling, our study narrows the search for understanding how microglia respond to active synapse modification in the visual cortex.
Microglia in the visual cortex respond to monocular deprivation with increased lysosome content, but signaling through the fractalkine receptor CX3CR1 is not an essential component in the mechanisms of visual cortical development or experience-dependent synaptic plasticity.
Dendrites, axons, and synapses are dynamic during circuit development; however, changes in microcircuit connections as branches stabilize have not been directly demonstrated. By combining in vivo ...time-lapse imaging of
Xenopus tectal neurons with electron microscope reconstructions of imaged neurons, we report the distribution and ultrastructure of synapses on individual vertebrate neurons and relate these synaptic properties to dynamics in dendritic and axonal arbor structure over hours or days of imaging. Dynamic dendrites have a high density of immature synapses, whereas stable dendrites have sparser, mature synapses. Axons initiate contacts from multisynapse boutons on stable branches. Connections are refined by decreasing convergence from multiple inputs to postsynaptic dendrites and by decreasing divergence from multisynapse boutons to postsynaptic sites. Visual deprivation or NMDAR antagonists decreased synapse maturation and elimination, suggesting that coactive input activity promotes microcircuit development by concurrently regulating synapse elimination and maturation of remaining contacts.
► Rapid synaptic reorganization during circuit assembly ► Concurrent synapse elimination and maturation during microcircuit formation ► Combining in vivo time-lapse imaging and retrospective ultrastructure studies ► Both synapse elimination and maturation are activity dependent
Fast-spiking cells (FS cells) are a prominent subtype of neocortical GABAergic interneurons with important functional roles. Multiple FS cell properties are coordinated for rapid response. Here, we ...describe an FS cell feature that serves to gate the powerful inhibition produced by FS cell activity. We show that FS cells in layer 2/3 barrel cortex possess a dampening mechanism mediated by Kv1.1-containing potassium channels localized to the axon initial segment. These channels powerfully regulate action potential threshold and allow FS cells to respond preferentially to large inputs that are fast enough to “outrun” Kv1 activation. In addition, Kv1.1 channel blockade converts the delay-type discharge pattern of FS cells to one of continuous fast spiking without influencing the high-frequency firing that defines FS cells. Thus, Kv1 channels provide a key counterbalance to the established rapid-response characteristics of FS cells, regulating excitability through a unique combination of electrophysiological properties and discrete subcellular localization.
Abstract Altered GABA-mediated inhibition is proposed to play a role in the pathogenesis of epilepsy. Previous studies have demonstrated a loss of somatostatin-containing GABAergic interneurons ...innervating granule cells in epileptic animals. However, the reorganization of synapses between interneurons and granule cells has not been investigated. We studied synapse organization in an animal model of temporal lobe epilepsy (TLE) using continuous hippocampal stimulation. The distribution of axon terminals and inhibitory synapses on granule cell dendrites was studied using a combination of immunohistochemistry and pre-embedding electron microscopy techniques. A whole-cell patch-clamp technique was applied to study the functional changes in GABAergic input from different interneurons. In epileptic animals, the density of cholecystokinin (CCK)-immunoreactive (IR) fibers and α2 subunit containing GABAA receptors in the inner molecular layer of the dentate gyrus was reduced. Quantitative immuno-electron microscopy study revealed that the ratio of CCK-containing symmetric synapses to the total symmetric synapses was reduced. The frequency of GABAergic synaptic currents (sIPSC) was decreased and their amplitude was increased. The inhibitory effect of the activation of cannabinoid 1 (CB1) receptors was also reduced in epileptic animals. Isolation of CCK- and parvalbumin (PV)-containing GABAergic inputs by N- and P/Q-type calcium channel blockers respectively suggested that GABA release from CCK-containing interneurons was selectively reduced in epileptic rats. This study found that there was a loss of CCK-containing GABAergic synapses to granule cells both morphologically and functionally. These studies add to our understanding of the mechanisms that contribute to altering GABAergic inhibition of granule cells in TLE.
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 presynaptic 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 before postnatal day 20 (P20), but they have no apparent effect after the onset of the critical period for receptive field plasticity (>P23). Immunoelectron microscopy revealed that the loss of presynaptic NMDAR function is likely attributable 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 presynaptic but not postsynaptic NMDARs, whereas the induction of tLTD in older mice requires activation of postsynaptic NMDARs. By demonstrating that both presynaptic 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.
Axon degeneration during development is required to sculpt a functional nervous system and is also a hallmark of pathological insult, such as injury 1, 2. Despite similar morphological ...characteristics, very little overlap in molecular mechanisms has been reported between pathological and developmental degeneration 3–5. In the peripheral nervous system (PNS), developmental axon pruning relies on receptor-mediated extrinsic degeneration mechanisms to determine which axons are maintained or degenerated 5–7. Receptors have not been implicated in Wallerian axon degeneration; instead, axon autonomous, intrinsic mechanisms are thought to be the primary driver for this type of axon disintegration 8–10. Here we survey the role of neuronally expressed, paralogous tumor necrosis factor receptor super family (TNFRSF) members in Wallerian degeneration. We find that an orphan receptor, death receptor 6 (DR6), is required to drive axon degeneration after axotomy in sympathetic and sensory neurons cultured in microfluidic devices. We sought to validate these in vitro findings in vivo using a transected sciatic nerve model. Consistent with the in vitro findings, DR6−/− animals displayed preserved axons up to 4 weeks after injury. In contrast to phenotypes observed in Wlds and Sarm1−/− mice, preserved axons in DR6−/− animals display profound myelin remodeling. This indicates that deterioration of axons and myelin after axotomy are mechanistically distinct processes. Finally, we find that JNK signaling after injury requires DR6, suggesting a link between this novel extrinsic pathway and the axon autonomous, intrinsic pathways that have become established for Wallerian degeneration.
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•DR6 has a modest role in developmental axon degeneration•DR6 is required for Wallerian degeneration in vitro and in vivo•Axon degeneration and demyelination can be mechanistically uncoupled post-injury•DR6 is required for the activation of classic Wallerian degeneration pathways
TNFR family members contribute to axon degeneration during development, but receptors have not been identified for Wallerian degeneration. Gamage et al. show that death receptor 6 is required for injury-induced nerve degeneration. This is the first report of a receptor capable of promoting axon degeneration after injury.
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