Research

To address questions regarding how ion channels modulate neuronal function and ultimately behavioral output, my lab makes and uses transgenic mice that have been genetically engineered to either lack specific genes, over express specific gene products or produce gene products that have been functionally mutated. Using a multidisciplinary approach that combines aspects of modern molecular biology, behavioral neuroscience and electrophysiology, the lab is currently pursuing a number of broad-based research domains:

• L-type voltage-gated calcium channels, CaV1.2 & CaV1.3

Within the millisecond/second time domain, L-VGCCs regulate neuronal excitability in an activity dependent manner by gating the calcium influx that is required for the activation of calcium activated potassium channels. At the other end of the time spectrum, L-VGCCs gate calcium influx that activates transcription factors that regulate gene expression which often has long-term or near permanent consequences. Although a great deal has been learned in the last two decades regarding the role that L-VGCCs play in regulating neuronal function, our knowledge of the fine details is still somewhat lacking. Specifically, for the majority of neuronal functions to which L-VGCCs have been ascribed, it is not know which is the relevant subtype (CaV1.2 or CaV1.3) or if they are both involved, what is the relative contribution of the two different subtypes. This is in large part due to the fact that at present there are no pharmacological agents that are subtype specific. In light of recent data suggesting that CaV1.2 and CaV1.3 are biophysically different and previous work demonstrating significant differences in distribution, it has become increasingly apparent that a better understanding of calcium mediated changed in neuronal function will require us to be able to distinguish the relative contributions of two different subtypes. Therefore my laboratory has been using a multidisciplinary approach to address two broad research domains: age related changes in L-VGCC function and the role that L-VGCCs play in the consolidation and extinction of Pavlovian conditioned fear.

• Alzheimer's Disease

Mounting clinical and experimental data suggest that cardiovascular disease (CVD) risk factors that promote vascular remodeling and dysfunction are associated with cognitive impairment, and are significant risk factors for the development of AD dementia. These studies include observations directly linking pathways associated with vascular injury such as hemostasis, angiogenesis, and hypertension to AD, leading to the hypothesis that CVD risk factors may act via common mechanisms to promote AD development or progression. For example, current data show that plaques, tangles, and CVD risk factors all upregulate expression of plasminogen activator inhibitor 1 (PAI-1), an independent CVD risk factor. Recent studies also suggest that PAI-1 may be a diagnostic biomarker and/or a risk factor for clinical AD, and PAI-1 expression increases with age, the most significant risk factor for AD dementia. PAI-1 is best understood for its role regulating fibrinolysis and wound, and in mouse models of AD PAI-1 deficiency is correlated with improved outcomes. In preliminary data presented here in the 5XFAD amyloidogenic mouse model we find that significant vascular remodeling occurs concurrently with amyloid plaque development and cognitive impairment. These changes are associated with reductions in cortical blood flow and increased PAI-1 expression. RNA-Seq and pathway analysis identify highly significant increases in gene expression in pathways known to be involved in vascular remodeling in the 5XFAD mice compared to Wt littermates, including pathways associated with angiogenesis and cardiovascular development. We also find that pharmacologic inhibition of PAI-1 in 5XFAD mice reduces abnormal vascular remodeling and improves cognition in the 5XFAD mice, without reducing plaque burden; and importantly that expression of genes within the vascular remodeling pathways are dramatically reduced in 5XFAD mice receiving the PAI-1 inhibitor. Based on the current literature and our preliminary data we will test the novel hypothesis that there is a causal relationship between vascular remodeling, and impaired cognition in the context AD, and that PAI-1 plays a critical role promoting pathologic vascular remodeling during AD development and progression.