Submitted on September 11, 2008
Revised on October 17, 2008
Accepted on October 23, 2008
Salubrinal, an inhibitor of protein synthesis, promotes deep slow wave sleep
Melvi M. Methippara1, Tariq Bashir1, Sunil Kumar1, Noor Alam2, Ronald Szymusiak3, and Dennis McGinty4*
1 Sepulveda VA Medical Center, UCLA
2 UCLA
3 VA Greater Los Angeles
4 Sepulveda VA Medical Center
* To whom correspondence should be addressed. E-mail: dmcginty{at}ucla.edu.
Previous work showed that sleep is associated with increased brain protein synthesis and that arrest of protein synthesis facilitates sleep. Arrest of protein synthesis is induced during the endoplasmic reticulum (ER) stress response, through phosphorylation of eukaryotic initiation factor 2 (p-eIF2
). We tested a hypothesis that elevation of p-eIF2 would facilitate sleep. We studied the effects of ICV infusion of Salubrinal (SALUB), which increases p-eIF2 by inhibiting its dephosphorylation. SALUB increased deep slow wave sleep by 255%, while reducing active waking by 49 %. Delta power within NREM sleep was increased while power in the sigma, beta and gamma bands during NREM was reduced. We found that SALUB increased expression of p-eIF2 in the basal forebrain (BF) area, a sleep-wake regulatory brain region. Therefore, we quantified the p-eIF2 immunolabeled neurons in the BF area; SALUB administration increased the number of p-eIF2 expressing non- cholinergic neurons in the caudal BF. In addition, SALUB also increased the intensity of p-eIF2 expression in both cholinergic and non-cholinergic neurons, but this was more widespread among the non-cholinergic neurons. Our findings support a hypothesis that sleep is facilitated by signals associated with the ER stress response.
