Elsevier

Neuroscience

Volume 122, Issue 3, 2003, Pages 585-590
Neuroscience

Intermittent hypoxic exposure during light phase induces changes in cAMP response element binding protein activity in the rat CA1 hippocampal region: water maze performance correlates

https://doi.org/10.1016/j.neuroscience.2003.08.054Get rights and content

Abstract

Intermittent hypoxia (IH) during sleep, a characteristic feature of sleep-disordered breathing (SDB) is associated with time-dependent apoptosis and spatial learning deficits in the adult rat. The mechanisms underlying such neurocognitive deficits remain unclear. Activation of the cAMP-response element binding protein (CREB) transcription factor mediates critical components of neuronal survival and memory consolidation in mammals. CREB phosphorylation and DNA binding, as well as the presence of apoptosis in the CA1 region of the hippocampus were examined in Sprague-Dawley male rats exposed to IH. Spatial reference task learning was assessed with the Morris water maze. IH induced significant decreases in Ser-133 phosphorylated CREB (pCREB) without changes in total CREB, starting as early as 1 h IH, peaking at 6 h–3 days, and returning toward normoxic levels by 14–30 days. Double-labeling immunohistochemistry for pCREB and Neu-N (a neuronal marker) confirmed these findings. The expression of cleaved caspase 3 (cC3) in the CA1, a marker of apoptosis, peaked at 3 days and returned to normoxic values at 14 days. Initial IH-induced impairments in spatial learning were followed by partial functional recovery starting at 14 days of IH exposure. We postulate that IH elicits time-dependent changes in CREB phosphorylation and nuclear binding that may account for decreased neuronal survival and spatial learning deficits in the adult rat. We suggest that CREB changes play an important role in the neurocognitive morbidity of SDB patients.

Section snippets

Experimental procedures

Young adult Sprague–Dawley male rats (60–75 days of age; weight: 175–200 g), were purchased from Charles River Laboratories (Wilmington, MA, USA), and used for all experiments. The experimental protocols were approved by the institutional animal use and care committee, and are in close agreement with the National Institutes of Health guide for the care and use of laboratory animals. Every effort was made to minimize the number of animals used and their suffering.

IH and CREB expression in CA1 region of hippocampus

In six separate experiments, IH exposures induced marked and early decreases in pCREB compared with normoxia (Fig. 1). These reductions in pCREB occurred as early as 1 h of IH exposure (P<0.05), and reached their nadir at 6 h to 3 days (P<0.01). Subsequent recovery of pCREB expression developed, such that by 14 and 30 days IH pCREB returned to normoxic levels and beyond. In contrast, the expression of total CREB was not affected throughout the duration of IH exposure (Fig. 1).

To assess whether

Discussion

The present study shows evidence for a biphasic pattern in CREB phosphorylation occurring in the CA1 region of the rat hippocampus following IH exposures, and that the time course of these changes is highly reminiscent of changes in IH-induced neuronal apoptosis within that region. Furthermore, we show that the pattern of pCREB nuclear binding closely resembles that of the changes in spatial reference function following IH exposures, further suggesting that these phenomena may be

Acknowledgements

This study was supported by National Institutes of Health grants NIH HL-63912, HL-69932 to D.G., P20 RR-15576 to E.G., and HD-42395 to B.W.R.

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