Finn_2012_J.Neurosci.Res_90_367

Reference

Title : Altered glutamate receptor function in the cerebellum of the Ppt1-\/- mouse, a murine model of infantile neuronal ceroid lipofuscinosis - Finn_2012_J.Neurosci.Res_90_367
Author(s) : Finn R , Kovacs AD , Pearce DA
Ref : Journal of Neuroscience Research , 90 :367 , 2012
Abstract :

The neuronal ceroid lipofuscinoses (NCLs) are a family of devastating pediatric neurodegenerative disorders and currently represent the most common form of pediatric-onset neurodegeneration. Infantile NCL (INCL), the most aggressive of these disorders, is caused by mutations in the CLN1 gene that encodes the enzyme palmitoyl protein thioesterase 1 (PPT1). Previous studies have suggested that glutamatergic neurotransmission may be disrupted in INCL, so the present study investigates glutamate receptor function in the Ppt1(-/-) mouse model of INCL by comparing the sensitivity of cultured wild-type (WT) and Ppt1(-/-) cerebellar granule cells to glutamate receptor-mediated toxicity. Ppt1(-/-) neurons were significantly less sensitive to AMPA receptor-mediated toxicity but markedly more vulnerable to NMDA receptor-mediated cell death. Because glutamate receptor function is regulated primarily by the surface expression level of the receptor, the surface level of AMPA and NMDA receptor subunits in the cerebella of WT and Ppt1(-/-) mice was also examined. Western blotting of surface cross-linked cerebellar samples showed a significantly lower surface level of the GluR4 AMPA receptor subunit in Ppt1(-/-) mice, providing a plausible explanation for the decreased vulnerability of Ppt1(-/-) cerebellar neurons to AMPA receptor-mediated cell death. The surface expression of the NR1, NR2A, and NR2B NMDA receptor subunits was similar in the cerebella of WT and Ppt1(-/-) mice, indicating that there is another mechanism behind the increased sensitivity of Ppt1(-/-) cerebellar granule cells to NMDA toxicity. Our results indicate an AMPA receptor hypofunction and NMDA receptor hyperfunction phenotype in Ppt1(-/-) neurons and provide new therapeutic targets for INCL.

PubMedSearch : Finn_2012_J.Neurosci.Res_90_367
PubMedID: 21971706
Gene_locus related to this paper: mouse-ppt

Related information

Gene_locus mouse-ppt

Citations formats

Finn R, Kovacs AD, Pearce DA (2012)
Altered glutamate receptor function in the cerebellum of the Ppt1-\/- mouse, a murine model of infantile neuronal ceroid lipofuscinosis
Journal of Neuroscience Research 90 :367

Finn R, Kovacs AD, Pearce DA (2012)
Journal of Neuroscience Research 90 :367