title: Neuronal D-serine regulates dendritic architecture in the somatosensory cortex.
abstract: D-Serine, which is synthesized by the enzyme serine racemase (SR), is a co-agonist at the N-methyl-D-aspartate receptor (NMDAR). In an animal model of NMDAR hypofunction, the constitutive SR knockout (SR-/-) mouse, pyramidal neurons in primary somatosensory cortex (S1) have reductions in the complexity, total length, and spine density of apical and basal dendrites. We wondered whether the dendritic pathology required deprivation of D-serine throughout development or reflected the loss of D-serine only in adulthood. To address this question, we used mice homozygous for floxed SR in which we bred CaMKIICre2834, which is expressed in forebrain glutamatergic neurons starting at 3-4 weeks post-partum (nSR-/-). Our prior studies demonstrated that the majority of cortical SR is expressed in glutamatergic neurons. We found that similar to SR-/- mice, pyramidal neurons in S1 of nSR-/- also had significantly reduced dendritic arborization and spine density, albeit to a lesser degree. S1 neurons of nSR-/- mice had reduced total basal dendritic length that was accompanied by less complex arborization. These characteristics were unaltered in the apical dendritic compartment. In contrast, spine density on S1 neurons was significantly reduced on apical, but not basal dendrites of nSR-/- mice. These results demonstrate that in adulthood neuronally derived D-serine, which is required for optimal activation of post-synaptic NMDAR activity, regulates pyramidal neuron dendritic arborization and spine density. Moreover, they highlight the glycine modulatory site (GMS) of the NMDAR as a potential target for therapeutic intervention in diseases characterized by synaptic deficits, like schizophrenia.
authors.affiliation: Department of Psychiatry, Harvard Medical School, and Laboratory for Psychiatric and Molecular Neuroscience, McLean Hospital, Belmont, MA 02478, USA. dbalu@mclean.harvard.edu
authors.forename: Darrick T
authors.initials: DT
authors.lastname: Balu
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Coyle
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D004396:Coloring Agents; D003712:Dendrites / Q000502:physiology* / Q000648:ultrastructure; D049229:Dendritic Spines / Q000502:physiology / Q000648:ultrastructure; D005838:Genotype; D018698:Glutamic Acid / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure; D057907:Post-Synaptic Density / Q000502:physiology; D017966:Pyramidal Cells / Q000502:physiology; D017459:Receptors, Amino Acid / Q000235:genetics / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D012694:Serine / Q000502:physiology*; D013003:Somatosensory Cortex / Q000166:cytology / Q000502:physiology*
chemical_list: D004396:Coloring Agents; D017459:Receptors, Amino Acid; D016194:Receptors, N-Methyl-D-Aspartate; C038039:serine receptor; D018698:Glutamic Acid; D012694:Serine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2