title: Fetal alcohol exposure alters GAP-43 phosphorylation and protein kinase C responses to contextual fear conditioning in the hippocampus of adult rat offspring.
abstract: BACKGROUND
  The growth- and plasticity-associated protein GAP-43 plays a significant role in the establishment and remodeling of neuronal connections. We have previously shown that GAP-43 levels, protein kinase C (PKC) activity, and GAP-43 phosphorylation increase during contextual fear conditioning and that fetal alcohol exposure (FAE) decreases PKC activity and GAP-43 phosphorylation in the hippocampus of adult offspring. Drawing on these observations, we hypothesized that FAE manifests its cognitive impairment by disrupting PKC activation and membrane translocation, thereby decreasing GAP-43 phosphorylation and function.
  
  
  METHODS
  Three groups of pregnant rat dams (FAE and two control diet groups) were placed on different diet regimens. Offspring from each of these groups were placed into each of four test groups, a contextual fear conditioned (CFC) group, a naïve unhandled group, and two nonlearning stress control groups. Hippocampi were dissected, homogenized, and used to prepare a cytosolic and a membrane fraction. These fractions were probed for total GAP-43, PKC-phosphorylated GAP-43, and several PKC subtypes. PKC activity also was measured in total homogenates.
  
  
  RESULTS
  Compared with both control diet groups, FAE animals showed a deficit in the activation of PKC in the hippocampus at 24 hr but not at 1.5 hr after CFC. Likewise, we found that the amount of GAP-43 and its phosphorylation were decreased 24 hr after CFC in FAE rats but not at early times after training. Analysis of the translocation of various PKC isoforms revealed that FAE animals had decreased levels of membrane-bound PKC beta2 and PKC epsilon 24 hr after CFC.
  
  
  CONCLUSIONS
  Considering the role of PKC activation and GAP-43 phosphorylation in synaptic plasticity, our results suggest that deficient translocation of PKC beta2 and PKC epsilon in the hippocampus may mediate the electrophysiological and behavioral deficits observed in fetal alcohol exposed animals.
authors.affiliation: Department of Neurosciences, University of New Mexico, Albuquerque, New Mexico, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Tanner
authors.forename: Ann W
authors.initials: AW
authors.lastname: Githinji
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Young
authors.forename: Karina
authors.initials: K
authors.lastname: Meiri
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Savage
authors.forename: Nora I
authors.initials: NI
authors.lastname: Perrone-Bizzozero
mesh_terms: D000367:Age Factors; D000818:Animals; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D000431:Ethanol / Q000633:toxicity*; D005239:Fear / Q000187:drug effects* / Q000502:physiology; D005260:Female; D019922:GAP-43 Protein / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats
chemical_list: D019922:GAP-43 Protein; D000431:Ethanol; D011493:Protein Kinase C