Chemogenetic Manipulation of Dorsal Hippocampal Astrocytes Protects Against the Development of Stress-enhanced Fear Learning. (15th September 2018) - Jones, Meghan E.
Highlights: Dorsal hippocampal astroglial Gi activation attenuates stress-enhanced fear learning. CNO attenuates cAMP in AAV8-GFAP-hM4Di-mCherry-transduced DH astrocytes. Severe stress does not alter dorsal hippocampal astrocyte surface area or volume. Severe stress attenuates DH PSD95 immunoreactivity colocalized with astrocytes. Abstract: Maladaptive behavioral outcomes following stress have been associated with immune dysregulation. For example, we have previously reported that stress-induced dorsal hippocampal interleukin-1β signaling is critical to the development of stress-enhanced fear learning (SEFL). In parallel, astroglial signaling has been linked to the development of post-traumatic stress disorder (PTSD)-like phenotypes and our most recent studies have revealed astrocytes as the predominant cellular source of stress-induced IL-1β. Here, we used chemogenetic technology and morphological analyses to further explore dorsal hippocampal astrocyte function in the context of SEFL. Using a glial-expressing DREADD construct (AAV8-GFAP-hM4Di(Gi)-mCherry), we show that dorsal hippocampal astroglial Gi activation is sufficient to attenuate SEFL. Furthermore, our data provide the first initial evidence to support the function of the glial-DREADD construct employed. Specifically, we find that CNO (clozapine-n-oxide) significantly attenuated colocalization of the Gi -coupled DREADD receptor and cyclic adenosine monophosphate (cAMP), indicating functional inhibition of cAMP production. Subsequent experiments examined dorsal hippocampal astrocyte volume, surface area, and synaptic contacts (colocalization with postsynaptic density 95 (PSD95)) following exposure to severe stress (capable of inducing SEFL). While severe stress did not alter dorsal hippocampal astrocyte volume or surface area, the severe stressor exposure reduced dorsal hippocampal PSD95 immunoreactivity and the colocalization analysis showed reduced PSD95 colocalized with astrocytes. Collectively, these data provide evidence to support the functional efficacy of the glial-expressing DREADD employed, and suggest that an astrocyte-specific manipulation, activation of astroglial Gi signaling, is sufficient to protect against the development of SEFL, a PTSD-like behavior.