PMID- 21971706
OWN - NLM
STAT- MEDLINE
DCOM- 20120823
LR  - 20211020
IS  - 1097-4547 (Electronic)
IS  - 0360-4012 (Print)
IS  - 0360-4012 (Linking)
VI  - 90
IP  - 2
DP  - 2012 Feb
TI  - Altered glutamate receptor function in the cerebellum of the Ppt1-/- mouse, a 
      murine model of infantile neuronal ceroid lipofuscinosis.
PG  - 367-75
LID - 10.1002/jnr.22763 [doi]
AB  - 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.
CI  - Copyright (c) 2011 Wiley Periodicals, Inc.
FAU - Finn, Rozzy
AU  - Finn R
AD  - Center for Neural Development and Disease, University of Rochester School of 
      Medicine and Dentistry, Rochester, New York, USA.
FAU - Kovacs, Attila D
AU  - Kovacs AD
FAU - Pearce, David A
AU  - Pearce DA
LA  - eng
GR  - R01 NS043310/NS/NINDS NIH HHS/United States
GR  - R01 NS044310/NS/NINDS NIH HHS/United States
GR  - R01 NS044310-04/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20111004
PL  - United States
TA  - J Neurosci Res
JT  - Journal of neuroscience research
JID - 7600111
RN  - 0 (Cross-Linking Reagents)
RN  - 0 (Receptors, AMPA)
RN  - 0 (Receptors, Glutamate)
RN  - 0 (glutamate receptor ionotropic, AMPA 4)
RN  - EC 3.1.2.- (Thiolester Hydrolases)
RN  - EC 3.1.2.22 (palmitoyl-protein thioesterase)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Cells, Cultured
MH  - Cerebellum/enzymology/*metabolism/physiology
MH  - Cross-Linking Reagents/metabolism
MH  - *Disease Models, Animal
MH  - Down-Regulation/genetics
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Neuronal Ceroid-Lipofuscinoses/enzymology/*genetics/metabolism
MH  - Receptors, AMPA/antagonists & inhibitors/*genetics/physiology
MH  - Receptors, Glutamate/genetics/*metabolism
MH  - Thiolester Hydrolases/*deficiency/genetics
PMC - PMC3237775
MID - NIHMS311950
EDAT- 2011/10/06 06:00
MHDA- 2012/08/24 06:00
PMCR- 2013/02/01
CRDT- 2011/10/06 06:00
PHST- 2011/03/20 00:00 [received]
PHST- 2011/05/26 00:00 [revised]
PHST- 2011/07/12 00:00 [accepted]
PHST- 2011/10/06 06:00 [entrez]
PHST- 2011/10/06 06:00 [pubmed]
PHST- 2012/08/24 06:00 [medline]
PHST- 2013/02/01 00:00 [pmc-release]
AID - 10.1002/jnr.22763 [doi]
PST - ppublish
SO  - J Neurosci Res. 2012 Feb;90(2):367-75. doi: 10.1002/jnr.22763. Epub 2011 Oct 4.