Introduction: Inducible knockout (KO) of the 3 cerebral cavernous malformation (CCM) genes, Krit-1, CCM2 and Pdcd10 has been used to study the functional and structural endothelial cell aberrations associated with CCM and to help elucidate the molecular mechanisms involved in lesion formation in a murine model. Recent studies on middle cerebral artery vessels from Krit-1 and CCM2 KO mice demonstrated a deficiency in endothelial-dependent vasodilation that can be rescued with the superoxide scavenger, Tempol. To date there has been no in-vivo investigation into the neurovascular behavior in CCM knockout mice with cortical and subcortical vascular lesions. Our study evaluates neurovascular coupling in CCM mice using optical intrinsic signaling (OIS) to study cerebral blood volume responses to direct visual and sensory stimulation and to study cortical spreading depression (CSD) induced with increasing concentrations of KCl.
Methods: KO mice induced between postnatal days 1-7 as well as their non-induced control litter mates were subject to a controlled experimental design utilizing optical intrinsic signal imaging of the fronto-parieto-occipital cortex to evaluate for sensory responses to visual and hindpaw stimulation as well as KCl-induced CSD (see figure).
Results: 83.3 % of KO mice had a second CSD versus 20 % of control mice. CSD in KO mice seems to be more often facilitated (4/6 vs 0/5) by sensory input and has a lower propagation velocity compared to control.
Conclusions: A mutation in any one of the 3 CCM genes leads to dysfunctional endothelial cells, which perturbs normal endothelial dependent vascular response. Cortical spreading depression, a well-conserved phenomenon involving neurovascular coupling appears to be different in CCM KO mice versus control mice. KO mice are more likely to have multiple CSDs that are more often facilitated by sensory input with a lower propagation velocity. This may have important clinical and therapeutic implications. receipt
Patient Care: Patients with multiple familial cavernous malformation may be more prone to having cortical spreading depression that may be facilitated by sensory input. This may be exemplified in the instance of an acute hemorrhage causing severe headaches and seizures as well as increased sensory sensitivity such as photo- and phono-phobia. This may help explain post hemorrhagic headaches experienced in this patient population who may be effectively treated with medications used to treat migraine type headaches. In addition, increased oxidative stress may be affecting vascular response to neuronal depolarization in familial CCM patients bringing about recurrent CSDs that are triggered by sensory stimulation. Superoxide inhibitors may be effective in reversing these phenotypes.
Learning Objectives: 1. Understand the difference in CSD characteristics between KO and Control mice.
2. Understand the clinical and therapeutic implications behind the different CSD characteristics.
3. Understand the function and utility of OIS (optical intrinsic signaling) in detecting cerebral blood volume (CBV) changes and mapping functional regions of the brain.