Professor Pat DohertyThe main interest of my lab is endocannabinoid (eCB) signalling in the nervous system, and this stems from our interest in regeneration, and in particular the role that adhesion molecules play in promoting axonal growth. Relevant contributions include the first report that polysialic acid is required for NCAM stimulated axonal growth, the observation that threshold levels and alternative splicing regulates NCAM function, the observation that signalling rather than adhesion accounts for the neurite outgrowth response stimulated by at least three adhesion molecules (CAMs, NCAM, L1 and N-cadherin); the consequent development of the CAM/FGF receptor hypothesis which identified a completely novel signalling axis in neurons. More recent work has identified cross-talk between the FGFR and eCB signalling in axonal growth and guidance.
Our current focus is on the role of endocannabinoid (eCB) signalling in adult neurogenesis. eCB signalling, driven by activation of the CB1 and/or CB2 cannabinoid receptors, has widespread functions during development and in the adult. Conditions that might benefit from intervention include pain, obesity, liver disease, spastic disorders, epilepsy, various psychiatric conditions as well as Parkinson’s and Alzheimer’s. As some drugs have been approved for use in man, with many others in clinical trials, it is important to fully understand the role of eCB signalling in adult neurogenesis. Our major contributions to this field to date have been: - (1) To use a bioinformatics approach to identify and then clone the diacyglycerol lipases (DAGL alpha and DAGL Beta) that synthesis 2-AG, one of the two well characterised eCBs (2) To generate the first knockout animals for each enzyme and provided conclusive evidence that these enzymes are responsible for the synthesis of 2-AG, and that DAGL beta function is required the best studied eCB function in the adult brain, namely retrograde synaptic signalling. (3) To provide both pharmacological, and more recently genetic, evidence that DAGL alpha and DAGL beta play a substantial role in the generation of new neurons in both the hippocampus and olfactory bulb in adult animals.One fascinating aspect of neurogenesis is the dramatic decline that is seen during aging. We have shown that this can be circumvented by (a) preventing the degradation of eCBs and/or (b) direct activation of CB2 receptors. This suggests that the machinery to make eCBs and respond to them is intact, and leads us to hypothesis that the reduced neurogenesis seen in older animals most probably stems from a loss of “drive” upstream from the DAGLs. To be able to fully test this hypothesis we need to understand the factors that normally activate DAGLs in NSCs, as well as the actual mechanism that results in enzyme activation. The study of the structure and function of the DAGLs, and the pathways that regulate their activity, will open up new avenues for developing agents that can modulate enzyme activity in either a positive or negative manner – and perhaps lead to novel therapeutic tools.
Full details of all Doherty lab publications can be accessed at: -