Adenylyl cyclase type 5 as an essential component of striatum -dependent learning

The striatum is implicated in motor control, motor learning and reinforcement learning. My thesis aims to elucidate the role of adenylyl cyclase (AC) AC5 and the cAMP pathway in mediating corticostriatal plasticity and striatum dependent learning.;Unlike the rest of the forebrain that expresses AC1, the adult striatum expresses AC5. AC1 is stimulated by calcium and calmodulin (CaCaM) and essential for LTP as it couples glutamate mediated increases in calcium with cAMP production. In contrast, AC5 is regulated mainly by G protein coupled receptors, not stimulated by CaCaM, and inhibited by PKA. Consistent with these known regulatory properties of AC5, I found that CaCaM could not stimulate cAMP production from adult striatal membranes and PKA inhibited dopamine (DA) D1 receptor stimulation of cAMP production. During early postnatal development, however, the striatum transiently expresses AC1 and CaCaM stimulated cAMP activity. These data suggest that AC5 may play a central role in DA-dependent cAMP modulation and corticostriatal plasticity in adults. Work in my collaborators lab demonstrates that AC5 is required for normal corticostriatal LTD.;The behavioral consequence of altering the AC5-cAMP pathway in the striatum was investigated. Mice with genetic deletion of AC5 (AC5KO) were tested in a number of striatum-dependent learning tasks. AC5KO mice exhibited severe deficits in motor learning in the accelerated rotarod as well as response learning in the cross maze. Mice expressing ectopic AC1 in the adult striatum, bypassing DA-dependent cAMP modulation, also showed deficits in acquisition of response learning in the cross maze.;In appetitive Pavlovian and instrumental paradigms, AC5KO mice acquired the instrumental response and their responding was sensitive to changes in outcome value. When overtrained, their responding became habitual as wild-type mice did. Yet, AC5KO mice were impaired in using Pavlovian cues to predict reward delivery in both simple Pavlovian learning and in instrumental learning with a Pavlovian component. This was not a global deficit in Pavlovian conditioning as AC5KO mice learned an aversive conditioning task. These studies provide the first evidence for a molecular pathway underlying specific aspects of striatum dependent learning.