No abstract

γ-frequency oscillations (30-120 Hz) in cortical networks influence neuronal encoding and information transfer, and are disrupted in multiple brain disorders. While synaptic inhibition is important for synchronization across the γ-frequency range, the role of distinct interneuronal subtypes in slow (<60 Hz) and fast γ states remains unclear. Here, we used optogenetics to examine the involvement of parvalbumin-expressing (PV + ) and somatostatin-expressing (SST + ) interneurons in γ oscillations in the mouse hippocampal CA3 ex vivo , using animals of either sex. Disrupting either PV + or SST + interneuron activity, via either photoinhibition or photoexcitation, led to a decrease in the power of cholinergically induced slow γ oscillations. Furthermore, photoexcitation of SST + interneurons induced fast γ oscillations, which depended on both synaptic excitation and inhibition. Our findings support a critical role for both PV + and SST + interneurons in slow hippocampal γ oscillations, and further suggest that intense activation of SST + interneurons can enable the CA3 circuit to generate fast γ oscillations. SIGNIFICANCE STATEMENT The generation of hippocampal γ oscillations depends on synchronized inhibition provided by GABAergic interneurons. Parvalbumin-expressing (PV + ) interneurons are thought to play the key role in coordinating the spike timing of excitatory pyramidal neurons, but the role distinct inhibitory circuits in network synchronization remains unresolved. Here, we show, for the first time, that causal disruption of either PV + or somatostatin-expressing (SST + ) interneuron activity impairs the generation of slow γ oscillations in the ventral hippocampus ex vivo . We further show that SST + interneuron activation along with general network excitation is sufficient to generate high-frequency γ oscillations in the same preparation. These results affirm a crucial role for both PV + and SST + interneurons in hippocampal γ oscillation generation.

Advances in membrane cell biology are hampered by the relatively high proportion of proteins with no known function. Such proteins are largely or entirely devoid of structurally significant domain annotations. Structural bioinformaticians have developed profile‐profile tools such as HHsearch (online version called HHpred), which can detect remote homologies that are missed by tools used to annotate databases. Here we have applied HHsearch to study a single structural fold in a single model organism as proof of principle. In the entire clan of protein domains sharing the pleckstrin homology domain fold in yeast, systematic application of HHsearch accurately identified known PH‐like domains. It also predicted 16 new domains in 13 yeast proteins many of which are implicated in intracellular traffic. One of these was Vps13p, where we confirmed the functional importance of the predicted PH‐like domain. Even though such predictions require considerable work to be corroborated, they are useful first steps. HHsearch should be applied more widely, particularly across entire proteomes of model organisms, to significantly improve database annotations.

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.

No abstract