The goal of this project is to establish an approach that will allow us to pharmacologically modulate nAChRs in specific neuronal populations in a wild-type brain, without the need for genetically modified animals. Such an approach is needed to eventually translate the knowledge obtained in (genetically modified) mice to human patients.
When working with animal models in preclinical research, we commonly use Cre-expressing genetically modified mouse lines and Cre-dependent viral vectors to target specific neuronal populations. These models are used to modify the expression of nAChRs and inform us of the effect of nicotinic hypo- or hyper-function in specific neuronal populations. However, the ultimate goal is to take that information obtained in mice and translate it to human patients, modifying nAChRs expressed in specific neurons to reverse pathological behavioral symptoms.
Non-selective AAV vector expressing Cre-recombinase
in the mouse striatum. The vector is labelled by GFP
expression (green). On the left, the GFP expression was
complemented by labeling of the transcription factor
c-Fos (red) and nuclear staining by Hoechst (blue).
In humans, we cannot rely on neuronal-type-specific Cre expression to target specific neuronal populations with viral vectors. Instead, we can use AAV viruses with tropism to specific neuronal types and use them to express enzymes and other proteins in a neuronal-type-specific manner. Then we apply a masked ligand of nAChRs that can be only unmasked and activated by the exogenously expressed enzyme. The neuronal-type-specific expression of the enzyme will ensure that the nicotinic ligand will be selectively activated in the targeted neuronal population and the nAChRs modulation will be neuronal-type-specific.
Besides the small-molecule ligands, nAChRs also interact with various peptides some of which can cross the blood-brain barrier and be administered systemically. Some of these peptides can also represent candidates for masking and neuronal-type-specific unmasking/activation. One of these peptides is the rabies-derived peptide (RDP) that binds to alpha7 nAChRs. Whether the interaction of the RDP with alpha7 nAChRs can increase its entry into alpha7 nAChRs-expressing neurons and what is its role in the rabies-associated behavioral symptoms remains an open and intriguing question.
