Loss of Microtubule-Associated Protein 2 Immunoreactivity Linked to Dendritic Spine Loss in Schizophrenia
Microtubule-associated protein 2 (MAP2) is a neuronal protein that plays a role in maintaining dendritic structure through its interaction with microtubules. In schizophrenia, numerous studies have revealed that the typically robust immunoreactivity (IR) of MAP2 is significantly reduced across several cortical regions. The relationship between MAP2-IR reduction and lower dendritic spine density, which is frequently reported in schizophrenia, has not been explored in previous studies, and MAP2-IR loss has not been investigated in the primary auditory cortex (Brodmann area 41), a site of conserved pathology in schizophrenia. Using quantitative spinning disk confocal microscopy in two cohorts of subjects with schizophrenia and matched control subjects (schizophrenia subjects, n = 20; control subjects, n = 20), we measured MAP2-IR and dendritic spine (identified by the co-localization of phalloidin and spinophilin; Figure) density and spine number in deep layer 3 of BA41. Subjects with schizophrenia exhibited a significant reduction in MAP2-IR. The reductions in MAP2-IR were not associated with neuron loss, loss of MAP2 protein, clinical confounders, or technical factors. Dendritic spine density and number also were reduced in schizophrenia and correlated with MAP2-IR. In 12 (60%) subjects with Schizophrenia, MAP2-IR values were lower than the lowest values in control subjects; only in this group were spine density and number significantly reduced. These findings demonstrate that MAP2-IR loss is closely linked to dendritic spine pathology in schizophrenia. Because MAP2 shares substantial sequence, regulatory, and functional homology with MAP tau, the wealth of knowledge regarding tau biology and the rapidly expanding field of tau therapeutics provide resources for identifying how MAP2 is altered in schizophrenia and possible leads to novel therapeutics.
|Shelton MA, Newman JT, Gu H, Sampson AR, Fish KN, MacDonald ML, Moyer CE, DiBitetto JV, Dorph-Petersen KA, Penzes P, Lewis DA, Sweet RA: Loss of Microtubule-Associated Protein 2 Immunoreactivity Linked to Dendritic Spine Loss in Schizophrenia. Biol Psychiatry, in press. ePub: January 30, 2015.|