CD44 antagonism after traumatic brain injury influences the adult neurogenic niche and behavioral outcomes

Traumatic brain injury (TBI) alters the neurogenic niche in the adult hippocampal dentate gyrus (DG), including alterations to astrocytes and the aberrant growth and migration of newborn granule cells (GCs). The astrocytes at the base of the DG granule cell layer (GCL) are one progenitor cell type that generates the newborn GCs and provides a scaffold for the newborn GCs to migrate into the hippocampal circuitry. These radial glial-like cells are also activated after TBI, resulting in the formation of an ectopic glial scaffold. One mechanism of astrocyte activation is through the activity of macrophage migration inhibitory factory (MIF) binding to its receptor CD74. Previous studies have shown that the astroglial response to TBI was reduced by ISO1, a MIF antagonist. A requisite for MIF/CD74 signaling is the presence of CD44 at the cell-surface CD74 receptor complex. However, the role of CD44 in the astrocytic response to TBI has not been investigated. Mice received a lateral fluid percussion injury (FPI) or sham injury, followed by treatment with verbascocide (VB), a CD44 antagonist, or vehicle. The results showed that VB treatment improved digigait motor performance and FPI-induced cognitive deficits in the pattern recognition test (PRT). VB treatment also prevented the hypertrophy of the radial glial-like astrocytes and mitigated the formation of the ectopic glial scaffold. Concomitant with rescuing the astrocyte hypertrophy, VB also inhibited the aberrant growth and migration of immature neurons in the hippocampal DG. Thus, CD44 can modulate the astrocytic response to FPI and can improve related brain structure and functional outcomes.