Research

Major depressive disorder is one of the most common and costly of neuropsychiatric syndromes, with a lifetime prevalence of 7-12% in men and 20-25% in women and a multi-billion dollar annual economic burden in the US. The most tragic consequence of untreated depression is suicide, attempted by as many as 8% of severely depressed patients. According to the Centers for Disease Control and Prevention, nearly half a million patients receive emergency care for suicide attempts each year in the United States, and over 38,000 individuals die by intentional self-inflicted injuries - twice as many lives as are lost to homicide.

Stressful life events are a key environmental risk factor for depressive disorders. Our laboratory uses chronic stress to produce changes in the behavior of rats and mice that are analogous to the behavioral symptoms of human depression, such as anhedonia (the inability to derive pleasure from things that should be pleasurable). We can then analyze brain tissue taken from animals whose behavior was affected by stress and use electrophysiological, biochemical, and molecular assays to identify the underlying pathological changes.

Antidepressant medications, such as selective serotonin reuptake inhibitors or SSRIs, raise serotonin concentrations in the brain. SSRIs are fully effective in only half of depressed patients, however. In addition, the 3-8 week latency to achieve a therapeutic effect complicates the optimization of medication and delays symptomatic relief. Better, faster-acting therapeutic approaches are clearly needed.

Building on our evidence that excitatory synapses are weakened in reward circuits after stress, my lab discovered that endogenous serotonin selectively potentiates some, but not all, excitatory synapses in CA1 pyramidal cells via activation of 5-HT_1BRs. We found that this potentiation is expressed postsynaptically by AMPA-type glutamate receptors and requires calmodulin-dependent protein kinase-mediated phosphorylation of GluA1 subunits (Cai et al., 2013). We also showed that SSRIs restore the strength of hippocampal synapses in chronically stressed animals due to increased AMPAR expression (Kallarackal et al., 2013).

Our evidence that restoration of synaptic strength is a property shared by all known antidepressants led us to the discovery of two novel classes of rapidly acting antidepressant compounds: negative allosteric modulators of GABA_ARs containing α5 subunits (Fischell et al., 2015; Troppoli et al., 2022; Thompson, 2023) and metabolites of ketamine (Zanos et al., 2016). We have established that these two classes of compound converge on a common effector mechanism: namely, disinhibition (GABA-NAMs) or increased glutamate release (ketamine metabolites), leading to increased synchronous, oscillatory activity in the gamma frequency range and promotion of endogenous NMDA receptor-dependent synaptic strengthening processes (Zanos et al., 2023). Two patents on the use of GABA receptor modulators as rapid antidepressants have been issued and are licensed to the industry for commercial development.

The regulation of the hypothalamic-pituitary-adrenal axis is altered in several human psychiatric diseases. Evaluation of sensory cues in the forebrain is integrated into the paraventricular nucleus of the hypothalamus (PVN), where corticotrophin-releasing factor (CRF) neurons initiate signaling via the pituitary to stimulate corticosteroid secretion in the adrenal cortex, i.e., a stress response. The stress response is terminated, in part, due to negative feedback mediated upstream of the PVN. We showed that one pathway for feedback inhibition originates in the hippocampus and is relayed to the PVN by inhibitory neurons in the bed nucleus of the stria terminalis (BNST) (Cole et al., 2022). The Bale lab has established that several forms of early life stress can lead to delayed changes in HPA axis reactivity, perhaps contributing to increased susceptibility to psychiatric disease.