Differential effects of in vivo HDAC inhibitors on PPN oscillatory activity

BISAGNO V; BERNARDI MA; SANZ-BLASCO, S; URBANO FJ; GARCIA-RILL E

NEUROPHARMACOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2020

0028-3908

The pedunculopontine nucleus (PPN) has long been known to bepart of the reticular activating system (RAS) in charge of arousal andREM sleep. We previously showed that in vitro exposure to a HDAC Class Iand II mixed inhibitor (TSA), or a specific HDAC class IIa inhibitor (MC1568), decreased PPN gamma oscillations. Given the lack of information onsystemic in vivo treatments on neuronal synaptic properties, the presentstudy was designed to investigate the systemic effect of HDAC inhibitors(HDACi) on PPN rhythmicity. Rat pups were injected (acute, single dose)with TSA (4 or 20 mg/Kg), MC1568 (4 or 20 mg/Kg), or MS275 (20 or 100mg/kg). Our results show that MC1568 (20 mg/Kg) reduced mean frequency ofPPN oscillations at gamma band, while increasing mean input resistance(Rm) of PPN neurons. For TSA (4 and 20 mg/kg), we observed reduced meanfrequency of oscillations at gamma band and increased mean Rm of PPNneurons. Systemic administration of 20 mg/Kg MC1568 and TSA effects onRm were washed out after 60 minutes of in vitro incubation of PPN slices,suggesting an underlying functional recovery of PPN calcium-mediatedgamma band oscillations over time. In addition, at a lower dose, 4 mg/Kg,MC1568 and TSA induced higher mean amplitude gamma oscillations. BlockingHDAC class I might not have deleterious effects on gamma activity, but,more importantly, the inhibition of HDAC class I (at 100mg/kg) increasedgamma band oscillations. In conclusion, the present results in vivovalidate our previous findings in vitro and further expand information onthe effects of HDAC inhibition on PPN rhythmicity. PPN neurons requirenormal activity of HDAC class IIa in order to oscillate at gamma band.