No abstract

Acid-sensing ion channel-1a (ASIC1a) contributes to multiple fear behaviors, however the site of ASIC1a action in behavior is not known. To explore a specific location of ASIC1a action, we expressed ASIC1a in the basolateral amygdala of ASIC1a-/-mice using viral vectormediated gene transfer. This rescued context-dependent fear memory, but not the freezing deficit during training or the unconditioned fear response to predator odor. These data pinpoint the basolateral amygdala as the site where ASIC1a contributes to fear memory. They also discriminate fear memory from fear expressed during training and from unconditioned fear. Furthermore, this work illustrates a strategy for identifying discrete brain regions where specific genes contribute to complex behaviors.

No animal models replicate the complexity of human depression. However, a number of behavioral tests in rodents are sensitive to antidepressants and may thus tap important underlying biological factors. Such models may also offer the best opportunity to discover novel treatments. Here, we used several of these models to test the hypothesis that the acid-sensing ion channel-1a (ASIC1a) might be targeted to reduce depression. Genetically disrupting ASIC1a in mice produced antidepressant-like effects in the forced swim test, the tail suspension test, and following unpredictable mild stress. Pharmacologically inhibiting ASIC1a also had antidepressant-like effects in the forced swim test. The effects of ASIC1a disruption in the forced swim test were independent of and additive to those of several commonly used antidepressants. Furthermore, ASIC1a disruption interfered with an important biochemical marker of depression, the ability of stress to reduce BDNF in the hippocampus. Restoring ASIC1a to the amygdala of ASIC1a Ϫ/Ϫ mice with a viral vector reversed the forced swim test effects, suggesting that the amygdala is a key site of ASIC1a action in depression-related behavior. These data are consistent with clinical studies emphasizing the importance of the amygdala in mood regulation, and suggest that ASIC1a antagonists may effectively combat depression.

Repeat-associated non-AUG translation of expanded CGG repeats (CGG RAN) from the FMR1 5’ UTR produces toxic proteins that contribute to neurodegeneration in Fragile X-associated Tremor/Ataxia Syndrome (FXTAS). Here we describe how unexpanded CGG repeats and their translation play conserved roles in regulating FMRP synthesis. In neurons, CGG RAN acts as an inhibitory upstream open reading frame to suppress basal FMRP production. Activation of mGluR5 receptors enhances FMRP synthesis. This enhancement requires both the CGG repeat and CGG RAN initiation sites. Using non-cleaving antisense oligonucleotides (ASOs), we selectively blocked RAN translation. This ASO blockade enhanced endogenous human neuronal FMRP expression. In human and rodent neurons, RAN blocking ASOs suppressed repeat toxicity and prolonged survival. These findings delineate a native function for CGG repeats and RAN translation in regulating basal and activity-dependent FMRP synthesis and demonstrate the therapeutic potential of modulating CGG RAN translation in fragile X-associated disorders.

A dynamic balance between stem cell maintenance and differentiation paces generation of post-mitotic progeny during normal development and maintenance of homeostasis. Recent studies show that Notch plays a key role in regulating the identity of neuroepithelial stem cells, which generate terminally differentiated neurons that populate the adult optic lobe via the intermediate progenitor cell type called neuroblast. Thus, understanding how Notch controls neuroepithelial cell maintenance and neuroblast formation will provide critical insight into the intricate regulation of stem cell function during tissue morphogenesis. Here, we showed that a low level of Notch signaling functions to maintain the neuroepithelial cell identity by suppressing the expression of pointedP1 gene through the transcriptional repressor Anterior open. Increased Notch signaling, which coincides with transient cell cycle arrest but precedes the expression of PointedP1 in cells near the medial edge of neuroepithelia, defines transitioning neuroepithelial cells that are in the process of acquiring the neuroblast identity. Transient up-regulation of Notch signaling in transitioning neuroepithelial cells decreases their sensitivity to PointedP1 and prevents them from becoming converted into neuroblasts prematurely. Down-regulation of Notch signaling combined with a high level of PointedP1 trigger a synchronous conversion from transitioning neuroepithelial cells to immature neuroblasts at the medial edge of neuroepithelia. Thus, changes in Notch signaling orchestrate a dynamic balance between maintenance and conversion of neuroepithelial cells during optic lobe neurogenesis.