TITLE:
Purkinje-neuron-specific down-regulation of p38 protects motoric function from the repeated use of benzodiazepine
AUTHORS:
Marianna Jung, Daniel Metzger
KEYWORDS:
Benzodiazepine; Motoric Deficit; p38; Purkinje Neurons; Mitochondria
JOURNAL NAME:
Advances in Bioscience and Biotechnology,
Vol.4 No.6A,
June
20,
2013
ABSTRACT: Benzodiazepine (BZD) is the most prescribed CNS
depressant in America to treat hyper-excitatory disorders such as anxiety and
insomnia. However, the chronic use of BZD often creates adverse effects including
psychomotor deficit. In this study, we investigated a novel mechanism by
which chronic BZD impedes motoric function in female mice. We used female mice
because BZD use is much more prevalent in female than male populations. We
tested the hypothesis that the accumulation of p38 (stress-activated
protein) in cerebellar Purkinje neurons mediates motoric deficit induced by
chronic BZD. To test this hypothesis, we generated transgenic mice that lack p38 incerebellar Purkinje neurons by
crossing Pcp2 (Purkinje cell protein 2)-Cre
mice with p38loxP/loxP mice. p38-knockdown mice
and wild-type mice received BZD (lorazepam, 0.5 mg/kg) for 14 days. During
this period, they were tested for motoric performance using Rotarod assay in
which a quicker fall from rotating rod indicates poorer motoric performance. Cerebellum
was then collected to detect p38 inPurkinje neurons and to measure mitochondrial respiration using
immunohistochemistry and real-time XF respirometry, respectively. Compared to
vehicletreated mice, BZD-treated mice showed poorer motoric performance, a
higher number of Purkinje neurons containing p38, and lower mitochondrial
respiration. These effects of BZD were much smaller in p38-knockdown mice. These
results suggest that the excessive accumulation of p38 incerebellar Purkinje neurons contributes to
motoric deficit associated with chronic BZD. They also suggest that Purkinje
neuronal p38 mediates BZD-induced mitochondrial respiratory inhibition in
cerebellum. Our findings may provide a new mechanistic insight into chronic
BZD-induced motoric deficit.