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D-serine, the D-stereoisomer of serine, synthesized in the brain by serine racemase from its L-stereoisomer is considered a co-agonist I co-activator of glutamatergic N-methyl-0-aspartate receptors (NMDARs). However, this action of D-serine seems exclusive to di-heteromeric NMOARs containing subunits GluN1 and GluN2.
We have determined that D-serine works as a potent antagonist I inhibitor of GluN3-containing triheteromeric NMDARs that were discovered in our laboratory recently and found to exist in various regions of the brain. The discovery of this seemingly opposite effect on NMDARS has many therapeutic and non-therapeutic advantages including, but not restricted to, the following:
1. D-serine, unlike other NMOAR antagonists,may be well-tolerated in the brain, because it is naturally synthesized in the brain
2. D-serine's effect seems to be subunit specific (affecting only NMDARs that contain GluN3A or GluN3B whether they be di- or triheteromeric) making it amenable for targeted therapeutics (not all NMDARs would be affected by it in this way)
3. D-serine's antagonism of GluN3-containing triheteromeric NMDARs may be important because these receptors appear significantly more permeable 1 selective for calcium, a potent excitotoxicant that underlies cell death under a number of scenarios including epilepsy. Hence blocking these receptors specifically may aid in averting underlying pathology
4. D-serine can be used as a tool in basic research for identifying the expression of and determining the location of GluN3-containing triheteromeric NMDARs in the brain
D-serine is an antagonist of GluN2 containing triheteromeric NMDA receptors found in the temporal lobe of the brain. It has been shown that D-serine may be used to treat neurological disorders, such as epilepsy, that cause seizures.
Unexpectedly, it was recently discovered that D-serine inhibits neuroinflammation of brain cells after a brain injury by reducing the neurotoxic immune response of glial cells after the injury. Accordingly, D-serine may be used in the treatment of brain injuries to help prevent neural cell loss caused by harmful immune responses. Following brain injury an immune response is triggered and immune cells are directed to and sequestered to the site of injury. These immune cells release cytokines that exasperate the survivability of healthy neurons. Application of D-serine stopes the infiltration of these immune response cells to the site of injury, thereby preventing loss of healthy neurons by reducing the neuroinflammation response.
CESOP is a microfluidic device that enables focal application and clearance of drugs/compounds to nuclei or regions within acute brain slices submerged in artificial cerebrospinal fluid or other bathing media under non-laminar/turbulent flow conditions. The CESOP technique has distinct advantages over either both perfusion or local perfusion for studying how drug application to one region of the brain affects a neighboring/juxtaposed region. The CESOP device/method enables rapid focal application of drugs/compounds while restricting their spillover to neighboring regions. Turbulent/non-laminar flow conditions that manifest in slice recording chambers exacerbate spillover thereby hindering electrophysiological recordings and the study of region-specific drug effects. CESOP solves this problem through concomitant ejection and suction of perfusate, even under moderately turbulent conditions.
ASTA is a methodology for precision harvesting and processing of tissue from acute brain slices for the purposes of cell and molecular biology/analysis. There are currently no known approaches to sampling tissue from hard-to-reach regions of the brain that has been cut acutely into 100 to 500 microns-thick sections for cell biological analysis. Laser dissection is inapplicable/inadequate, laser dissection is more suited for a monolayer of cells. ASTA solves this problem by incorporating 1) visually guided core sampling component and 2) a tissue processing component. Together, this methodology enables precision analysis and tracking of cellular and molecular changes across juxtaposed brain regions (nuclei) and lamina allowing for detailed characterization of disease-related pathology.
