Chemogenetic silencing reveals presynaptic G i/o protein-mediated inhibition of developing hippocampal synchrony in vivo .

Recent advances in understanding how neuronal activity shapes developing brain circuits increasingly rely on G _i/o -dependent inhibitory chemogenetic tools (G _i -DREADDs). However, their mechanisms of action and efficacy in neurons with immature G _i/o signaling are elusive. Here, we express the G _i -DREADD hM4Di in glutamatergic telencephalic neurons and analyze its impact on CA1 pyramidal neurons in neonatal mice. Using acousto-optic two-photon Ca ²⁺ imaging, we report that activation of hM4Di leads to a complete arrest of spontaneous synchrony in CA1 in vitro . We demonstrate that hM4Di does not cause somatic hyperpolarization or shunting but rather mediates presynaptic silencing of glutamatergic neurotransmission. In vivo , inhibition through hM4Di potently suppresses early sharp waves (eSPWs) and discontinuous oscillatory network activity in CA1 of head-fixed mice before eye opening. Our findings provide insights into the role of G _i/o signaling in synchronized activity in the neonatal hippocampus and bear relevance for applying chemogenetic silencing at early developmental stages.
Competing Interests: The authors declare no competing interests.
(© 2024 The Author(s).)