Synaptic BMAL1 phosphorylation controls circadian hippocampal plasticity.

Area of Science:

• Chronobiology
• Neuroscience
• Molecular Biology

Background:

• Circadian rhythms significantly impact cognitive functions, including long-term memory.
• The molecular mechanisms linking circadian clocks to synaptic plasticity are not fully understood.
• The core circadian clock relies on a transcription-translation feedback loop (TTFL) involving the BMAL1 transcription factor.

Purpose of the Study:

• To investigate the role of the circadian clock protein BMAL1 in synaptic function and memory.
• To elucidate the molecular mechanisms by which circadian rhythms influence synaptic plasticity.

Main Methods:

• Investigated the rhythmic localization of BMAL1 to hippocampal synapses.
• Examined the role of BMAL1 phosphorylation at Ser42 (pBMAL1(S42)) in synaptic processes.
• Assessed the impact of pBMAL1(S42) on CaMKIIα autophosphorylation and CaMKIIα-dependent molecular interactions and long-term potentiation (LTP).

Main Results:

• BMAL1 rhythmically localizes to hippocampal synapses, dependent on its phosphorylation at Ser42 (pBMAL1(S42)).
• pBMAL1(S42) regulates the autophosphorylation of synaptic CaMKIIα.
• Circadian rhythms of CaMKIIα-dependent molecular interactions and LTP are controlled by pBMAL1(S42), while global rest/activity behavior remains unaffected.

Conclusions:

• The study proposes a model where BMAL1 is repurposed to synapses to locally regulate the circadian timing of synaptic plasticity.
• Synaptic BMAL1, specifically its phosphorylated form, plays a critical role in gating memory formation processes according to the time of day.
• These findings reveal a novel mechanism connecting the central circadian clock to cognitive functions at the synaptic level.