Living or dying in three quarter time: Neonatal orchestration of hippocampal cell death pathways by androgens and excitatory GABA

Abstract

In the immature brain, GABA (γ-aminobutyric acid) is an excitatory neurotransmitter. With development, GABA becomes inhibitory due to the changes in the expression level of chloride transporters, leading to a negative shift in chloride ions. Clinical evidence and studies in animal models indicate greater brain damage in male versus female neonates following a variety of neuronal insults. The recent finding of Nunez and McCarthy suggest a mechanism whereby androgens may endanger male neurons to the possible excitotoxic effects of excitatory GABA in neonates. Given our growing understanding of the excitatory immature GABAergic system and how sex, age and hormone milieu can influence this system, such studies might pave a path for novel clinical treatments to alleviate neonatal risk for brain injury.

A Crucial Role for the Protein Quality Control System in Motor Neuron Diseases

“…ARpolyQ specifically depleted ER Ca 2+ levels and the store-operated Ca 2+ influx (Hetz and Mollereau, 2014 ; Tadic et al, 2014 ), possibly via the reduction of the sarcoendoplasmic reticulum Ca 2+ ATPases (SERCA) 2b pump activity. This pump allows ER Ca 2+ re-uptake (Foradori and Handa, 2008 ), and its dysregulation activates caspase 12 (Montague et al, 2014 ). Thus, ER stress is also involved in SBMA pathogenesis and may represent an additional therapeutic target for this disease.…”

Endoplasmic reticulum stress in spinal and bulbar muscular atrophy: a potential target for therapy

“…Expression of the SERCA pump (SERCA2b isoform) has previously been shown to be regulated downstream of androgen receptor activation ( Foradori and Handa, 2008 ). We therefore examined the expression of the SERCA2b pump protein to establish whether altered expression of SERCA2b may explain the abnormal Ca 2+ handling observed in AR100 motor neurons in the presence of dihydrotestosterone ( Fig.…”

“…One of the downstream effects of androgen receptor activation is transcription of the SERCA pump, which provides a route by which Ca 2+ enters the endoplasmic reticulum lumen ( Foradori and Handa, 2008 ). The SERCA pump may therefore provide a link between the activation of the androgen receptor and offer an explanation for the observed depletion in endoplasmic reticulum Ca 2+ .…”

The Role of the Protein Quality Control System in SBMA

“…The reduction in ER Ca 2+ may in part be explained by the finding that the expression of the SERCA2b pump was significantly lower in AR100 motor neurons than in wildtype motor neurons. SERCA2b belongs to the sarcoendoplasmic reticulum Ca 2+ ATPases (SERCAs) which enable ER Ca 2+ reuptake (Foradori and Handa, 2008). Furthermore, the levels of the ER stress markers BiP, ATF4…”