Staehr, C. | bioRxiv Science

bioRxiv2023

SorCS2 modulates neurovascular coupling via glutamatergic and calcium signaling in astrocytes

AO_SCPLOWBSTRACTC_SCPLOWSorCS2 is involved in trafficking of membrane receptors and transporters. SorCS2 is implicated in brain disorders, but the mechanism remains uncertain. We hypothesized that SorCS2 expression is important for neurovascular coupling. Brains from P8 and 2-month-old wild type mice were stained for SorCS2 and compared to SorCS2 knockouts (Sorcs2-/-). Changes in cerebral perfusion in response to sensory stimulation, i.e., neurovascular coupling, were compared in vivo. Neurovascular coupling was also assessed ex vivo in brain slices loaded with calcium-sensitive dye. Proteomics of astrocytes was analyzed for ingenuity pathways. SorCS2 was strongly expressed in astrocytic endfeet of P8 mice but only in few astrocytes from 2-month-old brains. Sorcs2-/- mice demonstrated reduced neurovascular coupling. This was associated with reduced astrocytic calcium response to neuronal excitation in Sorcs2-/- mice. No difference in cerebral artery caliber nor in endothelial function was seen between wild type and Sorcs2-/- mice. Proteomics indicated reduced glutamatergic signaling and suppressed calcium signaling in Sorcs2-/- astrocytes. We suggest that SorCS2 expression is important for neurovascular coupling due to modulation of glutamatergic and calcium signaling in astrocytes.

neuroscience↗

bioRxiv2022

Microcirculatory dysfunction associates with neurovascular uncoupling in peri-ischemic brain regions after ischemic stroke

BackgroundDespite recanalization after ischemic stroke, neurovascular coupling, i.e., the local hyperaemic response to neuronal activity, is impaired in peri-ischemic brain regions. Reduced neurovascular coupling may contribute to neurological deterioration over time. The mechanism underlying dysfunctional neurovascular coupling following stroke is largely unknown. MethodsMice implanted with chronic cranial windows were trained for awake head-fixation prior to experiments. One hour occlusion of the anterior middle cerebral artery branch was induced using single vessel photothrombosis. Cerebral perfusion and neurovascular coupling were assessed by optical coherence tomography and laser speckle contrast imaging. Capillaries and pericytes were studied in perfusion-fixed tissue by labelling lectin and platelet-derived growth factor receptor {beta}. ResultsArterial occlusion induced on average 11 spreading depressions over one hour associated with substantially reduced blood flow in the peri-ischemic cortex. Approximately half of the capillaries in the peri-ischemic area were no longer perfused 3 and 24 hours after reperfusion, which was associated with constriction of an equivalent proportion of peri-ischemic capillary pericytes. The capillaries in the peri-ischemic cortex that remained perfused showed increased prevalence of dynamic flow stalling. Whisker stimulation led to reduced neurovascular coupling responses in the sensory cortex corresponding to the peri-ischemic region 3 and 24 hours after reperfusion. ConclusionArterial occlusion led to constriction of pericytes in the peri-ischemic cortex associated with long-lasting microcirculatory failure. This reduced capillary capacity may, at least in part, underlie impaired neurovascular coupling in peri-ischemic brain regions after stroke and reperfusion.

physiology↗