Alpar, A. | Search bioRxiv

bioRxiv2026

Astrocytes modulate mitochondrial proteostasis and membrane potential in neurons through S100A6 - calcyclin-binding protein signaling

Calcyclin binding protein (CaCyBp) is an evolutionarily conserved protein that converts S100 protein family-derived signals to protein turnover through an ubiquitin ligase interaction domain within its C-terminus. Despite its predicted roles in cellular differentiation, CaCyBp expression alone and in relation to S100A6, its prototypic ligand, during fetal and postnatal organ development remains incompletely understood. Here, we combined cell-resolved neuroanatomy and biochemistry to reveal not only organ system-level CaCyBp expression but also its region-, circuit-, and neuron-specific distribution in the mouse brain from embryonic day 18.5. We extended these studies to human brains past gestational week 27, corroborating that neurons, but not astrocytes, microglia or oligodendrocytes, harbored CaCyBp. Conversely, S100A6 was detected only in astrocytes and ependymoglia in both species. Ultrastructural studies localized CaCyBp to mitochondria in neurons, with genetic loss-of-function and recombinant S100A6-induced signaling implicating CaCyBp in the regulation of the mitochondrial electrochemical gradient controlling ATP production. Overall, pleiotropic CaCyBp expression in neurons suggests a maintenance receptor-like role impacting cellular respiration, thus affecting proteostasis upon glia-derived S100A6 signals.

cell biology↗

bioRxiv2019

Brain-wide genetic mapping identifies the indusium griseum as a prenatal and shared target of pharmacologically-unrelated psychostimulants

Psychostimulant use is an ever-increasing socioeconomic burden, including a dramatic rise during pregnancy. Nevertheless, brain-wide effects of psychostimulant exposure are incompletely understood. Here, we performed Fos-CreERT2-based activity mapping, correlated for pregnant mouse dams and their fetuses with amphetamine, nicotine and caffeine applied acutely during mid-gestation. While light-sheet microscopy-assisted intact tissue imaging revealed drug- and age-specific neuronal activation, the indusium griseum (IG) appeared indiscriminately affected. By using GAD67gfp/+ mice we subdivided the IG into a dorsolateral domain populated by GABA interneurons and a ventromedial segment containing glutamatergic neurons, many showing drug-induced activation and sequentially expressing Pou3f3/Brn1 and secretagogin (Scgn) during differentiation. We then combined Patch-seq and circuit mapping to show that the ventromedial IG is a quasi-continuum of glutamatergic neurons (IG-Vglut1+) reminiscent to dentate granule cells in both rodents and humans, whose dendrites emanate perpendicularly towards, while their axons course parallel with the superior longitudinal fissure. IG-Vglut1+ neurons receive Vglut1+ and Vglut2+ excitatory afferents that topologically segregate along their somatodendritic axis. In turn, their efferents terminate in the olfactory bulb, thus being integral to a multi-synaptic circuit that could feed information antiparallel to the olfactory-cortical pathway. In IG-Vglut1+ neurons, prenatal psychostimulant exposure delayed the onset of Scgn expression. Genetic ablation of Scgn was then found to sensitize adult mice towards methamphetamine-induced epilepsy, suggesting a role for this Ca2+-binding protein in scaling IG-Vglut1+ neuronal excitability. Overall, our study identifies brain-wide targets of the most common psychostimulants, among which Scgn+/Vglut1+ neurons of the IG link limbic and olfactory circuits.\n\nSignificance statementDrug abuse during pregnancy is a significant socioeconomic problem. The use of psychostimulants is particularly common during pregnancy even though a risk to the developing fetus is significant. Here, we show that short-lived exposure to amphetamine, nicotine and caffeine during pregnancy induces neuronal activation in the fetal brain with the indusium griseum (IG), a brain area situated parallel to the central surface of the cortical hemispheres, becoming indiscriminately activated. By using mouse genetics, we find that psychostimulants preferentially target glutamatergic IG neurons, and delay their differentiation postnatally. Notably, the expressional onset of secretagogin, a Ca2+-sensor amenable for synaptic integration, is deregulated. This is significant because these neurons are integral to a multi-synaptic neuronal pathway that links limbic and olfactory circuits. As such, genetic deletion of secretagogin brings about heightened sensitivity to psychostimulants, manifesting as epileptiform discharges. Cumulatively, we describe a novel psychostimulant-sensitive neuronal subtype and its circuit arrangement whose developmental delay seems critical for behavioral abnormalities in offspring prenatally exposed to the most common psychostimulants.

neuroscience↗