Serotonergic regulation of neuronal excitability and glutamatergic synaptic transmission in rat claustrum

The claustrum (CLA) receives dense serotonergic innervation from dorsal raphe nucleus (DRN) serotonin (5-HT) neurons, which are implicated in regulating sleep and stress homeostasis. However, the mechanisms by which 5-HT regulates the excitability of CLA neurons remain poorly defined. In the present study, we combined whole-cell patch-clamp recordings, 5-HT uncaging, and receptor pharmacology to examine the effects of 5-HT on the excitability of CLA neurons and their glutamatergic synapses. We found that 5-HT consistently induced membrane hyperpolarization or depolarization in regular-spiking type I and type II neurons, whereas it predominantly induced hyperpolarization in strongly adapting CLA neurons. The 5-HT-induced membrane hyperpolarization and depolarization were mediated by 5-HT1A receptors (5-HT1ARs) and 5-HT2A receptors (5-HT2ARs), respectively. Furthermore, we showed that activation of presynaptic 5-HT2ARs inhibits glutamatergic synaptic transmission in the CLA by reducing glutamate release. This effect was not mediated by the canonical phospholipase C (PLC) signaling cascade. Collectively, these findings reveal cell type-specific and multifaceted serotonergic modulation of the intrinsic excitability and synaptic transmission in the claustrum.