No 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.

The episodic nature of both epilepsy and psychiatric illnesses suggests that the brain switches between healthy and pathological states. The most obvious example of transitions between network states related to epilepsy is the manifestation of ictal events. In addition to seizures, there are more subtle changes in network communication within and between brain regions, which we propose may contribute to psychiatric illnesses associated with the epilepsies. This review will highlight evidence supporting aberrant network activity associated with epilepsy and the contribution to cognitive impairments and comorbid psychiatric illnesses. Further, we discuss potential mechanisms mediating the network dysfunction associated with comorbidities in epilepsy, including interneuron loss and hypothalamic–pituitary–adrenal axis dysfunction. Conceptually, it is necessary to think beyond ictal activity to appreciate the breadth of network dysfunction contributing to the spectrum of symptoms associated with epilepsy, including psychiatric comorbidities.

Corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) are integratory hubs that regulate the endocrine response to stress. GABA inputs provide a basal inhibitory tone that constrains this system and circulating glucocorticoids (CORT) are important feedback controllers of CRH output. Surprisingly little is known about the direct effects of CORT on GABA synapses in PVN. Here we used whole-cell patch clamp recordings from CRH neurons in mouse hypothalamic brain slices to examine the effects of CORT on synaptic and extrasynaptic GABA signalling. We show that GABA transporters (GATs) limit constitutive activation of presynaptic GABA receptors and ensure high release probability at GABA synapses. GATs in combination with GABA receptors also curtail extrasynaptic GABA R signalling. CORT has no effect on synaptic GABA signalling, but increases extrasynaptic GABA tone through upregulation of postsynaptic GABA receptors. These data show that efficient GABA clearance and autoinhibition control the balance between synaptic (phasic) and extrasynaptic (tonic) inhibition in PVN CRH neurons. This balance is shifted towards increased extrasynaptic inhibition by CORT.

GABA synapses in the brain undergo depolarization-induced suppression of inhibition (DSI) that requires activation of presynaptic cannabinoid type 1 receptors (CB 1 Rs). The brevity of DSI, lasting ϳ1 min in most brain regions, has been ascribed to the transient production of 2-arachidonoylglycerol (2-AG). Here, we propose that the duration of DSI is controlled by heterologous interactions between presynaptic mGluRs and CB 1 Rs. By examining GABA synapses on parvocellular corticotropin-releasing hormone-expressing neurons in the paraventricular nucleus of the hypothalamus (PVN) of male and female mice, we show that DSI decays quickly in experimental conditions in which both GABA and glutamate are released from adjacent nerve terminals. Pharmacological inhibition of group I mGluRs prolongs DSI, whereas prior activation of mGluRs inhibits DSI, collectively suggesting that group I mGluRs quench presynaptic CB 1 R signaling. When photostimulation of genetically identified terminals is used to release only GABA, CB 1 R-dependent DSI persists for many minutes. Under the same conditions, activation of group I mGluRs reestablishes classical, transient DSI. The long-lasting DSI observed when GABA synapses are independently recruited functionally uncouples inhibitory input to PVN neurons. These observations suggest that heterologous interactions between mGluRs and CB 1 Rs control the temporal window of DSI at GABA synapses, providing evidence for a powerful new way to affect functional circuit connectivity in the brain.