Polysialylated neuronal
cell adhesion molecule (
PSA-NCAM), a polysialylated
protein constitutively expressed in the hippocampus, is involved in neuronal growth, synaptic plasticity and
neurotrophin signaling. In particular,
PSA-NCAM mediates Ret-independent
glial-derived neurotrophic factor (
GDNF) signaling, leading to downstream FAK activation.
GDNF has potent seizure-suppressant action, whereas
PSA-NCAM is upregulated by seizure activity. However, the involvement of Ret-independent
GDNF signaling in
temporal lobe epilepsy (TLE) is not established. We tested the effects of
PSA-NCAM inactivation on neurodegeneration and epileptogenesis in a mouse model of TLE. In this model, unilateral intrahippocampal
kainic acid (KA) injection induced degeneration of CA1, CA3c and hilar neurons, followed by spontaneous recurrent
focal seizures. In the contralateral, morphologically preserved hippocampus, a long-lasting increase of
PSA-NCAM immunoreactivity was observed. Inactivation of
PSA-NCAM by
endoneuraminidase (EndoN) administration into the contralateral ventricle of KA-treated mice caused severe degeneration of CA3a,b neurons and dentate gyrus granule cells in the epileptic focus, and led to early onset of
focal seizures. This striking trans-hemispheric alteration suggested that
PSA-NCAM mediates
GDNF signaling, leading to transport of neuroprotective signals into the lesioned hippocampus. This hypothesis was confirmed by injecting
GDNF antibodies into the contralateral hippocampus of KA-treated mice, thereby reproducing the enhanced neurodegeneration seen after
PSA-NCAM inactivation. Furthermore, contralateral EndoN and anti-
GDNF treatment decreased
GDNF family receptor alpha1 immunoreactivity and FAK phosphorylation in the epileptic focus. Thus, Ret-independent
GDNF signaling across the commissural projection might protect CA3a,b neurons and delay seizure onset. These findings implicate
GDNF in the control of epileptogenesis and offer a possible mechanism explaining lesion asymmetry in mesial TLE.