Inhibition of glial D-serine release rescues synaptic damage after brain injury.

Synaptic damage is one of the most prevalent pathophysiological responses to traumatic CNS injury and underlies much of the associated cognitive dysfunction; however, it is poorly understood. The D-amino acid, D-serine, serves as the primary co-agonist at synaptic NMDA receptors (NDMARs) and is a critical mediator of NMDAR-dependent transmission and synaptic plasticity. In physiological conditions, D-serine is produced and released by neurons from the enzymatic conversion of L-serine by serine racemase (SRR). However, under inflammatory conditions, glial cells become a major source of D-serine. Here, we report that D-serine synthesized by reactive glia plays a critical role in synaptic damage after traumatic brain injury (TBI) and identify the therapeutic potential of inhibiting glial D-serine release though the transporter Slc1a4 (ASCT1). Furthermore, using cell-specific genetic strategies and pharmacology, we demonstrate that TBI-induced synaptic damage and memory impairment requires D-serine synthesis and release from both reactive astrocytes and microglia. Analysis of the murine cortex and acutely resected human TBI brain also show increased SRR and Slc1a4 levels. Together, these findings support a novel role for glial D-serine in acute pathological dysfunction following brain trauma, whereby these reactive cells provide the excess co-agonist levels necessary to initiate NMDAR-mediated synaptic damage.

EphB3 interacts with initiator caspases and FHL-2 to activate dependence receptor cell death in oligodendrocytes after brain injury.

Clinical trials examining neuroprotective strategies after brain injury, including those targeting cell death mechanisms, have been underwhelming. This may be in part due to an incomplete understanding of the signalling mechanisms that induce cell death after traumatic brain injury. The recent identification of a new family of death receptors that initiate pro-cell death signals in the absence of their ligand, called dependence receptors, provides new insight into the factors that contribute to brain injury. Here, we show that blocking the dependence receptor signalling of EphB3 improves oligodendrocyte cell survival in a murine controlled cortical impact injury model, which leads to improved myelin sparing, axonal conductance and behavioural recovery. EphB3 also functions as a cysteine-aspartic protease substrate, where the recruitment of injury-dependent adaptor protein Dral/FHL-2 together with capsase-8 or -9 leads to EphB3 cleavage to initiate cell death signals in murine and human traumatic brain-injured patients, supporting a conserved mechanism of cell death. These pro-apoptotic responses can be blocked via exogenous ephrinB3 ligand administration leading to improved oligodendrocyte survival. In short, our findings identify a novel mechanism of oligodendrocyte cell death in the traumatically injured brain that may reflect an important neuroprotective strategy in patients.

Enhanced astrocytic d-serine underlies synaptic damage after traumatic brain injury.

After traumatic brain injury (TBI), glial cells have both beneficial and deleterious roles in injury progression and recovery. However, few studies have examined the influence of reactive astrocytes in the tripartite synapse following TBI. Here, we have demonstrated that hippocampal synaptic damage caused by controlled cortical impact (CCI) injury in mice results in a switch from neuronal to astrocytic d-serine release. Under nonpathological conditions, d-serine functions as a neurotransmitter and coagonist for NMDA receptors and is involved in mediating synaptic plasticity. The phasic release of neuronal d-serine is important in maintaining synaptic function, and deficiencies lead to reductions in synaptic function and plasticity. Following CCI injury, hippocampal neurons downregulated d-serine levels, while astrocytes enhanced production and release of d-serine. We further determined that this switch in the cellular source of d-serine, together with the release of basal levels of glutamate, contributes to synaptic damage and dysfunction. Astrocyte-specific elimination of the astrocytic d-serine-synthesizing enzyme serine racemase after CCI injury improved synaptic plasticity, brain oscillations, and learning behavior. We conclude that the enhanced tonic release of d-serine from astrocytes after TBI underlies much of the synaptic damage associated with brain injury.

Neocortical Chandelier Cells Developmentally Shape Axonal Arbors through Reorganization but Establish Subcellular Synapse Specificity without Refinement.

Diverse types of cortical interneurons (INs) mediate various kinds of inhibitory control mechanisms to balance and shape network activity. Distinct IN subtypes develop uniquely organized axonal arbors that innervate different subcellular compartments of excitatory principal neurons (PNs), which critically contribute to determining their output properties. However, it remains poorly understood how they establish this peculiar axonal organization and synaptic connectivity during development. Here, taking advantage of genetic labeling of IN progenitors, we examined developmental processes of axonal arbors and synaptic connections formed by murine chandelier cells (ChCs), which innervate axon initial segments (AISs) of PNs and thus powerfully regulate their spike generation. Our quantitative analysis by light microscopy revealed that ChCs overgrow and subsequently refine axonal branches as well as varicosities. Interestingly, we found that although a significant number of axonal varicosities are formed off AISs in addition to on AISs, presynaptic markers are predominantly colocalized with those on AISs throughout development. Immunoelectron microscopic (IEM) analysis also demonstrated that only varicosities apposed to AISs contain presynaptic profiles. These results suggest that subcellular synapse specificity of ChCs is genetically predetermined while axonal geometry is shaped through remodeling. Molecular cues localized at AISs may regulate target recognition and synapse formation by ChCs.