Promotion of neuroplasticity by modifying perineuronal nets using polysialic acid

Abstract

Polysialic acid (PSA) is a linear homopolymer formed of chains of 2,8-linked sialic acid. Found predominantly attached to the neural cell adhesion molecule, PSA acts to reduce cell-cell adhesion during development. It is also found in some areas of the adult central nervous system (CNS) associated with persistent neuroplasticity. Preliminary data from our laboratory indicated an inverse relationship between PSA expression and the formation of perineuronal nets (PNNs), specialised extracellular matrix structures with a role in limiting plasticity in the adult CNS. The primary aims of this thesis were to investigate this relationship in more detail, using in vitro models of PNN formation and in vivo. Also, to evaluate whether lentiviral vector-mediated PSA expression can enhance locomotor recovery and neuroplasticity in a rodent model of spinal cord injury. PNNs were heterogeneously distributed throughout the grey matter of the rat cervical spinal cord, and increased in numbers down the dorsoventral axis. Induced expression of PSA in the spinal cord of either naïve or injured rats did not alter the number or density of PNNs. Similarly, enzymatic removal of PSA from the surface of cultured embryonic neurons did not affect the formation of the PNNs. In a rodent model of cervical spinal cord injury, induced PSA expression resulted in an improvement in hindlimb, but not forelimb, locomotor function compared to animals injected with control virus. Interestingly, this was not associated with an increased density of serotonin or synaptophysin-labelled boutons in the areas of induced PSA expression. Taken together, the data presented in this thesis suggests that while induced PSA expression may contribute to improved locomotor function in a model of cervical spinal cord injury, this is not due to a reduction in the density or number of PNNs in the spinal cord.