We propose that neurosteroids, endogenous positive modulators of GABAAR function, and their synthetic analogues, may hold promise as treatments for anxiety disorders. The present study is designed to fill gaps in understanding between cellular-level inquiry and in vivo effects. An important premise of this work is that network studies in simple systems can give us insight into the relevant effects of clinically promising drugs, including aspects of drug actions not easily derived from a receptor-level or cellular-level understanding. A secondary premise of this exploratory proposal is that because natural WT networks in dissociated culture are self-organizing into network topologies reminiscent of in vivo networks, key aspects of network dysfunction in disease may also be reconstituted. Recent work supports the radical idea that dysfunction associated with stress and anxiety can be recapitulated in dissociated culture networks. Our work extends research into this potentially important area.
Aim 1 will test the hypothesis that cellular accumulation reduces the effect of exogenous neurosteroids on network function and accounts for steroid-specific rebound of neuronal activity. These studies use multi-electrode array recordings and are unique in probing the gray area between pharmacokinetics and pharmacodynamics as an important contributor to drug effects on networks.
Aim 2 will explore the nature of network dynamics in models deficient in the GABAA receptor gamma2 subunit. The ability of neurosteroids to correct network dynamics will be assessed. These studies will lend insight into changes in network dynamics induced by receptor changes believed to underlie anxiety disorder. The studies will also provide new information on the effect of therapeutic drugs not easily discernible from previous levels of analysis.
Neuropsychiatric disorders are underappreciated causes of death and disability. New treatments are not forthcoming, in part because of withering support for new pharmacological treatment strategies. Furthermore, psychiatry suffers from a dearth of studies designed to understand functional circuitry changes that underlie pharmacological therapy. These studies will investigate a new class of potential therapeutics, using network analysis tools that will lend insight into network dysfunction related to anxiety and new insights into its pharmacological correction.
|Cao, Lily Q; Montana, Michael C; Germann, Allison L et al. (2018) Enhanced GABAergic actions resulting from the coapplication of the steroid 3?-hydroxy-5?-pregnane-11,20-dione (alfaxalone) with propofol or diazepam. Sci Rep 8:10341|
|Sun, Min-Yu; Shu, Hong-Jin; Benz, Ann et al. (2018) Chemogenetic Isolation Reveals Synaptic Contribution of ? GABAA Receptors in Mouse Dentate Granule Neurons. J Neurosci 38:8128-8145|
|Sobieski, Courtney; Fitzpatrick, Michael J; Mennerick, Steven J (2017) Differential Presynaptic ATP Supply for Basal and High-Demand Transmission. J Neurosci 37:1888-1899|
|Zorumski, Charles F; Izumi, Yukitoshi; Mennerick, Steven (2016) Ketamine: NMDA Receptors and Beyond. J Neurosci 36:11158-11164|
|Sun, Min-Yu; Linsenbardt, Andrew J; Emnett, Christine M et al. (2016) 24(S)-Hydroxycholesterol as a Modulator of Neuronal Signaling and Survival. Neuroscientist 22:132-44|
|Sun, Min-Yu; Izumi, Yukitoshi; Benz, Ann et al. (2016) Endogenous 24S-hydroxycholesterol modulates NMDAR-mediated function in hippocampal slices. J Neurophysiol 115:1263-72|
|Chakrabarti, Sampurna; Qian, Mingxing; Krishnan, Kathiresan et al. (2016) Comparison of Steroid Modulation of Spontaneous Inhibitory Postsynaptic Currents in Cultured Hippocampal Neurons and Steady-State Single-Channel Currents from Heterologously Expressed ?1?2?2L GABA(A) Receptors. Mol Pharmacol 89:399-406|
|Jiang, Xiaoping; Shu, Hong-Jin; Krishnan, Kathiresan et al. (2016) A clickable neurosteroid photolabel reveals selective Golgi compartmentalization with preferential impact on proximal inhibition. Neuropharmacology 108:193-206|
|Emnett, Christine; Li, Hairong; Jiang, Xiaoping et al. (2016) A Clickable Analogue of Ketamine Retains NMDA Receptor Activity, Psychoactivity, and Accumulates in Neurons. Sci Rep 6:38808|
|Zorumski, Charles F; Nagele, Peter; Mennerick, Steven et al. (2015) Treatment-Resistant Major Depression: Rationale for NMDA Receptors as Targets and Nitrous Oxide as Therapy. Front Psychiatry 6:172|
Showing the most recent 10 out of 12 publications