Allopregnanolone mediates affective switching through modulation of oscillatory states in the basolateral amygdala

Abstract

Brexanolone (allopregnanolone), was recently approved by the FDA for the treatment of post-partum depression, demonstrating long-lasting antidepressant effects. Despite our understanding of the mechanism of action of neurosteroids as positive allosteric modulators (PAMs) of GABAA receptors, we still do not fully understand how allopregnanolone exerts these persistent antidepressant effects. We demonstrate that allopregnanolone and similar synthetic neuroactive steroid analogs, SGE-516 (tool-compound) and zuranolone (SAGE-217, investigational-compound), modulate oscillations across species. We further demonstrate a critical role for interneurons in generating oscillations in the basolateral amygdala (BLA) and a role for delta-containing GABAARs in mediating the ability of neurosteroids to modulate network and behavioral states. Actions of allopregnanolone in the BLA confer anxiolytic/antidepressant behavior and enhance BLA high-theta oscillations (6-12Hz) through delta-containing GABAA receptors, a mechanism distinct from other GABAA PAMs, such as benzodiazepines. Moreover, treatment with the allopregnanolone analog SGE-516 protects mice from chronic stress-induced disruption of network and behavioral states. Our findings demonstrate a novel molecular and cellular mechanism mediating the well-established anxiolytic and antidepressant effects of neuroactive steroids.

Neuromodulation-induced burst firing in parvalbumin interneurons of the basolateral amygdala mediates transition between fear-associated network and behavioral states

“…The copyright holder for this preprint (which this version posted April 19, 2021. ; https://doi.org/10. 1101/2021 To confirm that the Gq-DREADD-induced IPSC bursts were mediated by the excitation of PV interneurons through Gq signaling, we blocked Gq protein activation with a selective Gα q/11 inhibitor YM-254890 (10 µM), which blocks the switch of Gα q from the GDP-to GTP-bound state (Takasaki et al, 2004). We found that CNO-induced IPSC bursts were completely eliminated with the Gq blocker (Fig.…”

“…Parvalbumin interneurons are critically involved in the generation of gamma-frequency oscillations in the cortex and hippocampus (Bartos et al, 2007;Buzsáki et al, 2012;Cardin et al, 2009;Hájos et al, 2004;Sohal et al, 2009). Mechanistic studies in these structures indicate that tonic PV neuron activity provides inhibitory signaling to principal neurons that drives the local gamma rhythm, demonstrated by phase locking of PV neuron activity to the gamma cycle (Bartos et al, 2007;Hájos et al, 2004) and by optogenetic activation and inhibition of PV neuron activity (Antonoudiou et al, 2021;Cardin et al, 2009;Sohal et al, 2009). Like in cortical structures, PV interneurons in the BLA densely target the perisomatic region of principal neurons to modulate amygdalar output (Davis et al, 2017;Ozawa et al, 2020;Vereczki et al, 2016;Veres et al, 2017).…”

“…Mechanisms of gamma rhythm generation in other limbic regions point to a coordinating role for parvalbumin-expressing (PV) interneurons (Bartos et al, 2007;Buzsáki et al, 2012;Cardin et al, 2009;Hájos et al, 2004;Sohal et al, 2009), and PV interneurons have been shown to play a critical role in the behavioral expression of fear (Davis et al, 2017;Ozawa et al, 2020). Recent evidence demonstrates a critical role for PV interneurons in generating local gamma oscillations in the BLA (Antonoudiou et al, 2021), likely due to their fast-spiking properties and dense perisomatic innervation of hundreds of neighboring principal cells for fast temporal control over synchronous activity (Vereczki et al, 2016;Veres et al, 2017). Parvalbuminexpressing interneurons in cortical areas are also sensitive to neuromodulatory signals (e.g., noradrenergic inputs) that tune PV cell activity via GPCR activation to execute brain statedependent behavioral tasks (Garcia-Junco-Clemente et al, 2019;Polack et al, 2013).…”

Sex differences in the alcohol-mediated modulation of BLA network states

“…LFP recordings were performed as previously described (Antonoudiou et al, 2021) in male and female C57BL/6J and Gabrd -/mice after a week of recovery from implant surgery. LFP recordings were acquired using Lab Chart software (AD Instruments) collected at 4 KHz and amplified 100X.…”

“…LFP recordings were acquired using Lab Chart software (AD Instruments) collected at 4 KHz and amplified 100X. The data were band pass filtered (1-300 Hz) and spectral analysis was performed in MATLAB (Antonoudiou et al, 2021) using MatWAND (https://github.com/pantelisantonoudiou/MatWAND) which utilizes the fast Fourier transform similar to previous reports (Kruse and Eckhorn, 1996;Frigo and Johnson, 1998;Pape et al, 1998;Freeman et al, 2000). Briefly, recordings were divided into 5 second overlapping segments and the power spectral density for a range of frequencies was obtained (Oppenheim et al, 1999).…”