Genetic Deletion of Paired Immunoglobulin-Like Receptor B Does Not Promote Axonal Plasticity or Functional Recovery after Traumatic Brain Injury

Abstract

The rewiring of neural networks is a fundamental step in recovering behavioral functions after brain injury. However, there is limited potential for axonal plasticity in the adult CNS. The myelin-associated proteins Nogo, myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMgp) are known to inhibit axonal plasticity, and thus targeting the inhibitory pathways they participate in is a potential means of promoting plasticity and functional recovery. Each of Nogo, MAG, and OMgp interacts with both the Nogo receptor (NgR) and paired immunoglobulin-like receptor B (PirB). Here, we determined whether blocking PirB activity enhances axonal reorganization and functional recovery after cortical injury. We found that axons of the contralesional corticospinal tract sprouted into the denervated side of the cervical spinal cord after unilateral injury of the motor cortex. The extent to which this axonal reorganization occurred was far greater in mice lesioned during early postnatal days than in mice lesioned at an age when myelin had begun to form. This suggests that myelin-associated proteins might limit axonal remodeling in vivo. However, the number of sprouting fibers within either the corticospinal or corticorubral tract was not enhanced in PirB Ϫ/Ϫ mice. Blocking PirB signaling also failed to enhance functional recovery with three motor tests. Our results suggest that blocking the function of PirB is not sufficient to promote axonal reorganization or functional recovery after cortical injury.

A Multi-domain Fragment of Nogo-A Protein Is a Potent Inhibitor of Cortical Axon Regeneration via Nogo Receptor 1

“…The low levels of PirB protein expression in cortical cultures and in adult brain are consistent with a recent report indicating that CST or rubrospinal sprouting into the denervated spinal cord is not enhanced in PirB Ϫ/Ϫ mice after unilateral traumatic brain injury (27). Moreover, CST regeneration is not enhanced in PirB Ϫ/Ϫ mice after dorsal hemisection spinal cord injury (28).…”

Paired immunoglobulin-like receptor B knockout does not enhance axonalregeneration or locomotor recovery after spinal cord injury

“…Further, in sections of the cerebral cortex, the PIR-B-alkaline phosphatase fusion protein is detected in association with the cell bodies and dendrites of cortical pyramidal neurons. We also reported that corticospinal neurons expressed PIR-B (13). In addition, we found that interneurons associated with the BDA-labeled CST in the spinal cord were immunoreactive for PIR-B.…”

“…4, D and E). These results indicate that PIR-B may be expressed in the interneurons in the spinal cord as well as the pyramidal neurons in the cerebral cortex (7,13).…”

Mechanisms of Axonal Damage and Repair after Central Nervous System Injury

“…However, another candidate receptor, paired immunoglobulin-like receptor B (PirB), has recently been identified [18]. Activation of PirB leads to inhibition of neural and axonal regeneration, but again, genetic deletion of PirB did not promote axonal plasticity and functional recovery in a mouse model of traumatic brain injury [19]. Taken together, those myelin-derived inhibitory molecules (Nogo/MAG/OMgp) and their receptors (NgR and PirB) negatively impact neurite extension, and therefore, those signaling pathways could be potential targets for axonal repairing and remodeling for CNS diseases.…”