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A dual role for poly‐ADP‐ribosylation in spatial memory acquisition after traumatic brain injury in mice involving NAD + depletion and ribosylation of 14‐3‐3γ
Author(s) -
Satchell Margaret A.,
Zhang Xiaopeng,
Kochanek Patrick M.,
Dixon C. Edward,
Jenkins Larry W.,
Melick John,
Szabó Csaba,
Clark Robert S. B.
Publication year - 2003
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2003.01707.x
Subject(s) - nad+ kinase , nicotinamide adenine dinucleotide , poly adp ribose polymerase , traumatic brain injury , morris water navigation task , genetically modified mouse , chemistry , neuroscience , biology , biochemistry , medicine , transgene , enzyme , polymerase , cognition , psychiatry , gene
Poly(ADP‐ribose) polymerase‐1 (PARP‐1) is a homeostatic enzyme that paradoxically contributes to disturbances in spatial memory acquisition after traumatic brain injury (TBI) in transgenic mice, thought to be related to depletion of its substrate nicotinamide adenine dinucleotide (NAD + ). In this study, systemic administration of the PARP‐1 inhibitor 5‐iodo‐6‐amino‐1,2‐benzopyrone (INH2BP) after TBI preserved brain NAD + levels and dose‐dependently reduced poly‐ADP‐ribosylation 24 h after injury. While moderate‐dose INH2BP improved spatial memory acquisition after TBI; strikingly, both injured‐ and sham‐mice receiving high‐dose INH2BP were unable to learn in the Morris‐water maze. Poly‐ADP‐ribosylated peptides identified using a proteomics approach yielded several proteins potentially associated with memory, including structural proteins (tubulin α and β, γ‐actin, and α‐internexin neuronal intermediate filament protein) and 14‐3‐3γ. Nuclear poly‐ADP‐ribosylation of 14‐3‐3γ was completely inhibited by the dose of INH2BP that produced profound memory disturbances. Thus, partial inhibition of poly‐ADP‐ribosylation preserves NAD + and improves functional outcome after TBI, whereas more complete inhibition impairs spatial memory acquisition independent of injury, and is associated with ribosylation of 14‐3‐3γ.