Calpain Determines the Propensity of Adult Hippocampal Neural Stem Cells to Autophagic Cell Death Following Insulin Withdrawal

Programmed cell death (PCD) has significant effects on the function of neural stem cells (NSCs) during brain development and degeneration. We have previously reported that adult rat hippocampal neural stem (HCN) cells underwent autophagic cell death (ACD) rather than apoptosis following insulin withdrawal despite their intact apoptotic capabilities. Here, we report a switch in the mode of cell death in HCN cells with calpain as a critical determinant. In HCN cells, calpain 1 expression was barely detectable while calpain 2 was predominant. Inhibition of calpain in insulin-deprived HCN cells further augmented ACD. In contrast, expression of calpain 1 switched ACD to apoptosis. The proteasome inhibitor lactacystin blocked calpain 2 degradation and elevated the intracellular Ca2+ concentration. In combination, these effects potentiated calpain activity and converted the mode of cell death to apoptosis. Our results indicate that low calpain activity, due to absence of calpain 1 and degradation of calpain 2, results in a preference for ACD over apoptosis in insulin-deprived HCN cells. On the other hand, conditions leading to high calpain activity completely switch the mode of cell death to apoptosis. This is the first report on the PCD mode switching mechanism in NSCs. The dynamic change in calpain activity through the proteasome-mediated modulation of the calpain and intracellular Ca2+ levels may be the critical contributor to the demise of NSCs. Our findings provide a novel insight into the complex mechanisms interconnecting autophagy and apoptosis and their roles in the regulation of NSC death. © 2015 AlphaMed Press.

Firefighters, posttraumatic stress disorder, and barriers to treatment: Results from a nationwide total population survey

<div><p>Repeated exposure to traumatic experiences may put professional firefighters at increased risk of developing posttraumatic stress disorder (PTSD). To date, however, the rate of PTSD symptoms, unmet need for mental health treatment, and barriers to treatment have only been investigated in subsamples rather than the total population of firefighters. We conducted a nationwide, total population-based survey of all currently employed South Korean firefighters (n = 39,562). The overall response rate was 93.8% (n = 37,093), with 68.0% (n = 26,887) complete responses for all variables. The rate of current probable PTSD was estimated as 5.4%. Among those with current probable PTSD (n = 1,995), only a small proportion (9.7%) had received mental health treatment during the past month. For those who had not received treatment, perceived barriers of accessibility to treatment (29.3%) and concerns about potential stigma (33.8%) were reasons for not receiving treatment. Although those with higher PTSD symptom severity and functional impairment were more likely to seek treatment, greater symptom severity and functional impairment were most strongly associated with increased concerns about potential stigma. This nationwide study points to the need for new approaches to promote access to mental health treatment in professional firefighters.</p></div

Firefighters, posttraumatic stress disorder, and barriers to treatment: Results from a nationwide total population survey - Fig 2

<p><b>Mental health treatment use during the past month from any professional, among firefighters with current probable posttraumatic stress disorder (n = 1,802), according to the symptom severity (a) and perceived functional impairment (b).</b><i>Note</i>. PTSD = posttraumatic stress disorder.</p

Associations of posttraumatic stress disorder (PTSD) symptom severity and perceived functional impairment with barriers to treatment in firefighters with current probable PTSD but who had not received treatment from any professional (n = 1,802)^a.

<p>Associations of posttraumatic stress disorder (PTSD) symptom severity and perceived functional impairment with barriers to treatment in firefighters with current probable PTSD but who had not received treatment from any professional (n = 1,802)<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0190630#t003fn002" target="_blank">^a</a>.</p

Associations of posttraumatic stress disorder (PTSD) symptom severity and perceived functional impairment with mental health treatment use in firefighters with current probable PTSD (n = 1,995).

<p>Associations of posttraumatic stress disorder (PTSD) symptom severity and perceived functional impairment with mental health treatment use in firefighters with current probable PTSD (n = 1,995).</p

Participant response rate throughout recruitment and data analyses.

<p>^a Excluded individuals who could be faking good, answering randomly, or lying. ^b Imputed datasets were generated using the chained equations approach [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0190630#pone.0190630.ref037" target="_blank">37</a>]. ^c Numbers are expressed in range due to the varying numbers of missing values for each variable. ^d Current probable posttraumatic stress disorder (PTSD) was defined as ≥ 45 on the PTSD checklist. ^e Those who had not received treatment from any professional during the past month.</p