Activation of Gs Signaling in Cortical Astrocytes Does Not Influence Formation of a Persistent Contextual Memory Engram.

Formation and retrieval of remote contextual memory depends on cortical engram neurons that are defined during learning. Manipulation of astrocytic Gq and Gi associated G-protein coupled receptor (GPCR) signaling has been shown to affect memory processing, but little is known about the role of cortical astrocytic Gs-GPCR signaling in remote memory acquisition and the functioning of cortical engram neurons. We assessed this by chemogenetic manipulation of astrocytes in the medial prefrontal cortex (mPFC) of male mice, during either encoding or consolidation of a contextual fear memory, while simultaneously labeling cortical engram neurons. We found that stimulation of astrocytic Gs signaling during memory encoding and consolidation did not alter remote memory expression. In line with this, the size of the mPFC engram population and the recall-induced reactivation of these neurons was unaffected. Hence, our data indicate that activation of Gs-GPCR signaling in cortical astrocytes is not sufficient to alter memory performance and functioning of cortical engram neurons.

Epileptic activity triggers rapid ROCK1-dependent astrocyte morphology changes.

Long-term modifications of astrocyte function and morphology are well known to occur in epilepsy. They are implicated in the development and manifestation of the disease, but the relevant mechanisms and their pathophysiological role are not firmly established. For instance, it is unclear how quickly the onset of epileptic activity triggers astrocyte morphology changes and what the relevant molecular signals are. We therefore used two-photon excitation fluorescence microscopy to monitor astrocyte morphology in parallel to the induction of epileptiform activity. We uncovered astrocyte morphology changes within 10-20 min under various experimental conditions in acute hippocampal slices. In vivo, induction of status epilepticus resulted in similarly altered astrocyte morphology within 30 min. Further analysis in vitro revealed a persistent volume reduction of peripheral astrocyte processes triggered by induction of epileptiform activity. In addition, an impaired diffusion within astrocytes and within the astrocyte network was observed, which most likely is a direct consequence of the astrocyte remodeling. These astrocyte morphology changes were prevented by inhibition of the Rho GTPase RhoA and of the Rho-associated kinase (ROCK). Selective deletion of ROCK1 but not ROCK2 from astrocytes also prevented the morphology change after induction of epileptiform activity and reduced epileptiform activity. Together these observations reveal that epileptic activity triggers a rapid ROCK1-dependent astrocyte morphology change, which is mechanistically linked to the strength of epileptiform activity. This suggests that astrocytic ROCK1 signaling is a maladaptive response of astrocytes to the onset of epileptic activity.

Differential diagnostic performance of a panel of plasma biomarkers for different types of dementia.

Introduction: We explored what combination of blood-based biomarkers (amyloid beta [Aß]1-42/1-40, phosphorylated tau [p-tau]181, neurofilament light [NfL], glial fibrillary acidic protein [GFAP]) differentiates Alzheimer's disease (AD) dementia, frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB). Methods: We measured the biomarkers with Simoa in two separate cohorts (n = 160 and n = 152). In one cohort, Aß1-42/1-40 was also measured with mass spectrometry (MS). We assessed the differential diagnostic value of the markers, by logistic regression with Wald's backward selection. Results: MS and Simoa Aß1-42/1-40 similarly differentiated AD from controls. The Simoa panel that optimally differentiated AD from FTD consisted of NfL and p-tau181 (area under the curve [AUC] = 0.94; cohort 1) or NfL, GFAP, and p-tau181 (AUC = 0.90; cohort 2). For AD from DLB, the panel consisted of NfL, p-tau181, and GFAP (AUC = 0.88; cohort 1), and only p-tau181 (AUC = 0.81; cohort 2). Discussion: A combination of plasma p-tau181, NfL, and GFAP, but not Aß1-42/1-40, might be useful to discriminate AD, FTD, and DLB.