In the striatum, multiple neuromodulatory systems converge onto spiny projection neurons (SPNs), regulating key aspects of motivated behavior, locomotion, and goal-directed learning. Two critical modulators within the striatum are dopamine and adenosine, which activate distinct G protein coupled receptors (GPCRs) and bidirectionally regulate the activity of a key cellular enzyme, protein kinase A (PKA). Recent experiments have demonstrated that activation of GPCRs regulates the generation of new dendritic spines and synapses on SPNs by increasing PKA activity. This proposal addresses two unknown features of striatal synaptogenesis: 1) the temporal dynamics for the integration of newly generated spines into functional synapses and 2) how convergent modulatory systems in the striatum interact on short temporal and small spatial scales to regulate the probability of spinogenesis.
Aim 1 of this proposal is to understand the functional and structural characteristics of newly generated dendritic spines. De novo spinogenesis will be induced on SPNs, and Ca2+ influx into new, time- stamped spines will be compared to pre-existing neighboring dendritic spines. To address whether and how fast nascent spines become functional synapses, the ultrastructure of newly generated spines will be investigated using electron microscopy.
Aim 2 is to define the spatial and temporal dynamics of G?s and G?i activation in regulating synaptogenesis, as well as to identify any interaction between these two opposing signaling cascades. Co-opting neuromodulatory signaling to control synaptogenesis could be a strategy to correct circuit imbalances in neurodegenerative and neurodevelopmental disorders, relevant to the mission of NINDS.
The generation of new synapses in the brain is essential for circuit wiring during development and learning, and may be co-opted for treating neurodegenerative diseases. Despite the critical nature of this plasticity, its regulation by neuromodulation is poorly understood. This proposal will discover how multiple modulatory systems regulate the genesis of new synapses, and will investigate when and how newly formed synapses become functional.
| Banala, Sambashiva; Arvin, Matthew C; Bannon, Nicholas M et al. (2018) Photoactivatable drugs for nicotinic optopharmacology. Nat Methods 15:347-350 |
