Striatal cAMP Is Regulated by a Local Clock-Gene-Dependent Mechanism

Circadian rhythms regulate the timing of major biological functions, including sleep/wake patterns, memory processes, and motor activity. Within cells, circadian oscillations are dictated by rhythmic expression of the “molecular clock” genes Bmal1 , Clock , Per , and Cry . BMAL1 and CLOCK form a heterodimer that promotes Per and Cry transcription. PER and CRY then dimerize to suppress Bmal1 and Clock . As BMAL1-CLOCK levels fall, PER-CRY follows, resuming Bmal1 and Clock expression and resetting the 24 h cycle. This molecular clock regulates the expression of many other genes and serves a vital role throughout the brain. Global Bmal1 knock-out causes motor impairments (Schoettner et al., 2022), but the specific brain regions in which Bmal1 acts to influence motor function are not well understood. Motor execution depends on activity in the basal ganglia, especially the dorsal striatum, where medium spiny neurons integrate cortical and midbrain inputs to influence action selection. Medium spiny neuron activity is influenced by neuromodulators such as dopamine and acetylcholine, and their G-protein-coupled receptors (GPCRs). GPCRs activate or inhibit the enzyme adenylyl cyclase, which produces cyclic adenosine monophosphate (cAMP). In general, GPCR-dependent increases in cAMP increase the probability of medium spiny neuron firing, while GPCR-dependent decreases in cAMP lower firing probability. Because striatal cAMP signaling is critical for motor function and Bmal1 has been shown to regulate cAMP signaling in other brain regions (Wardlaw et al., 2014), Cryan et al. (2025) hypothesized that Bmal1 regulates motor function by modulating cAMP-related signaling in the striatum. The authors first aimed to identify whether Bmal1 regulates circadian expression of cAMP and related proteins in the dorsal striatum. Using Western blot analysis of striatal tissue sampled every 4 h, they found no circadian oscillations of the G-protein subunits Gαi and Gβ or the cAMP degradation enzyme phosphodiesterase 10A (PDE10A) in control or … Correspondence should be addressed to Jordan M. McCarthy at mccartj{at}umich.edu.