PSA‐NCAM‐dependent GDNF signaling limits neurodegeneration and epileptogenesis in temporal lobe epilepsy

Abstract

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.

Role of a Neural Cell Adhesion Molecule Found in Cerebrospinal Fluid as a Potential Biomarker for Epilepsy

“…This result conflicts with previous findings in which brain tissues showed elevated NCAM-1 expression [43][44][45]. NCAM-1 is known to promote synaptic remodeling and maintenance of synaptic structure, thereby affecting adhesion of cells and regulating neuronal activities.…”

GFRα1 Regulates Purkinje Cell Migration by Counteracting NCAM Function

“…On the other hand, we found NCAM to be co-expressed with GFRα1 in embryonic PCs, and in situ PLA experiments indicated that they are associated in vivo. Earlier work has shown that the GFRα1/NCAM complex provides a high-affinity binding site for GDNF (Paratcha et al., 2003) and mediates effects of this ligand on cell migration, neurite outgrowth, and axon guidance (Charoy et al., 2012, Duveau and Fritschy, 2010, Euteneuer et al., 2013, Paratcha et al., 2006). Having ruled out an effect of GDNF on embryonic PC migration, we considered possible direct effects of GFRα1 on NCAM function independently of GDNF.…”

Mouse Brain PSA-NCAM Levels Are Altered by Graded-Controlled Cortical Impact Injury

“…While the present results are one of the first to examine PSA-NCAM alterations after controlled cortical impact, the role of PSA-NCAM in prosurvival pathways initiated during CNS excitotoxicity insult has been investigated [19]. In this study, endoneuraminidase (endoN) removal of PSA from NCAM following hippocampal injection of kainic acid (KA) in mice was used to determine that PSA-NCAM serves as an indispensable coreceptor of GDNF family receptor α 1 (GFR α 1) to mediate prosurvival Ret-independent glial cell-derived neurotrophic factor (GDNF) initiated Fyn-FAK-MAP kinase pathway activation.…”

“…The necessity of polysialylation for efficient function of select NCAM isoforms has recently been appreciated (see Gascon et al [18] for review). In addition to the indispensable role of PSA-NCAM in maintaining synaptic plasticity and health, recent evidence has also demonstrated the fundamental role of PSA-NCAM in preventing neurodegeneration in the face of ongoing insult such as epileptogenic central nervous system disorders [19]. Additionally, repair and recovery following TBI may be critically dependent on the generation, survival, migration, and integration of neurons from postnatal neurogenic niches into damaged circuitry in order to restore function.…”