Our long-term objective is to understand how neuromodulation and synaptic integration shape informationprocessing in the olfactory system. This objective is addressed in the main olfactory bulb (MOB), the firstcentral relay station for olfactory information. The endocannabinoid system is an important neuromodulatorysystem, which involves cannabinoid receptors, CB1R, and their endogenous activators, endocannabinoids(eCBs). In the MOB, neurons express high levels of CB1R, but its cellular and network functions areunknown. Our new preliminary data shows that CB1R agonists and antagonists alter the membrane potentialand response to synaptic input of GABAergic interneurons, granule cells, and the membrane potential andfiring pattern of principal neurons, mitral cells. Based on our preliminary data, the hypothesis is that eCBsprominently modulate membrane properties of MOB neurons, change the response to synaptic input, andregulate the neural network of the MOB. Consequently, the overall aim of this proposal is to determine therole of eCBs and CB1R for neural signaling in the MOB.
In Specific Aim 1, the hypothesis will be tested thatCB1R directly regulates the excitability of mitral cells and granule cells in a slice preparation of the mouseMOB. Do eCBs mediate self-inhibition of mitral cells and granule cells, i.e., are eCBs released by a neuronand target CBIRs on the same neuron? In Specific Aim 2, the hypothesis will be tested that CB1R regulatessynaptic responsiveness of mitral cells and granule cells. Do eCBs serve as retrograde signaling moleculesin the MOB between post- and presynaptic neurons to regulate presynaptic transmitter release? Theinteraction of the eCB system with another modulatory system, the metabotropic glutamate receptor (mGluR)system will be investigated to test the hypothesis that both systems are functionally interrelated. Theexperimental approach includes whole-cell patch-clamp recording and intracellular labeling of MOB neuronsvisualized with near infrared differential interference optics, use of mGluR knockout (KO) mice and CB1R KOmice, and characterization of cellular, membrane, pharmacologic and network properties of eCB-modulatedneural processing in the MOB. Our findings help to explain the properties of marijuana at the cellular levelthrough eCB-mediated synaptic processing in the MOB and eventually lead to a better understanding of drugaddiction and could pave the way for new treatment strategies to prevent the use of drugs.
Showing the most recent 10 out of 152 publications
