Our mission: to discover the changes that occur in the brain in patients with major depression so that we can identify better therapies to treat depression.

The biological basis of depression: 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.

This work has led us to formulate an Excitatory Synapse Hypothesis of Depression

1. Major depression is caused by a weakening of specific subsets of excitatory synapses in multiple brain regions that are critical in the determination of affect and reward. Chronic hyperactivity of the HPA axis in response to excessive stress is one potential mediator of these changes.
2. Many of the characteristic changes in behavior that define the symptomatology of human depression, such as anhedonia and depressed mood, result because impaired excitatory synaptic transmission leads to reduced activity in the cortico-mesolimbic reward circuitry.
3. Restoration of excitatory synaptic strength is the critical action of effective antidepressants, including both conventional agents, such as SSRIs and ECT, and newer compounds, such as ketamine and psychedelics.

The actions of selective serotonin reuptake inhibitors and serotonin: 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 optimization of medication and delays symptomatic relief. It remains uncertain which downstream events are critical to their therapeutic effects. We have discovered that endogenous serotonin selectively potentiates some, but not all, excitatory synapses in CA1 pyramidal cells via activation of 5-HT1BRs. This potentiation is expressed postsynaptically by AMPA-type glutamate receptors and requires calmodulin-dependent protein kinase-mediated phosphorylation of GluA1 subunits. Most importantly, we observed that serotonin-induced potentiation is quantitatively and qualitatively altered by chronic stress and is restored by chronic antidepressant treatment. We are currently trying to understand the second messenger signaling pathways that underlie the response of excitatory synapses to elevated serotonin and how they are affected by chronic stress. This is important because our work shows that this potentiation is critical to their ability to relieve the symptoms of depression. This work has led us to an examination of the receptor pharmacology underlying the antidepressant actions of psychedelics. We hypothesize that they share many of the same synapse restoring mechanisms as SSRIs, only with a faster mechanism of action. Our recent work has suggested that the beneficial interactions of psychedelics may be independent of their mind-altering properties, potentially increasing their utility and decreasing the costs of psychedelic therapy.

Discovering new antidepressant drugs: The discovery that ketamine exerts a rapid antidepressant action has triggered a reevaluation of the causes of depression and potential targets for antidepressants. A common element linking the therapeutic actions of antidepressants, including SSRIs and ketamine, is their shared effects on excitatory synapses in cortico-mesolimbic reward circuits. Ketamine is thought to exert a rapid antidepressant action by promoting network activity, but it acts throughout the brain, thereby producing bad psychotomimetic side-effects. We tested the antidepressant actions of a novel class of compounds- negative allosteric modulators of GABA-A receptors- because they should also promote coherent network oscillations, and used compounds that are highly selective for receptors containing alpha5 subunits. These compounds should produce few side effects because alpha5 subunits are expressed predominantly in the hippocampus and prefrontal cortex. In several chronic stress-based models of changes in hedonic behavior, we observed that these compounds restored normal behaviors in <24 hrs and that the effects persisted for up to 7 days. Concomitant with restoration of normal behaviors, we observed a restoration of synaptic strength and levels of GluA1 protein at hippocampal excitatory synapses. These compounds, which have been shown to be safe and well tolerated in humans, represent a potentially novel class of fast acting antidepressants.

Hesselgrave, N., Troppoli, T.A., Wulff, A.B., Cole, A.B., Thompson, S.M. (2021) Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proc Natl Acad Science, 118:e2022489118, 2021. PMCID: PMC8092378.

Gould, T.D., Zarate, C.A., Thompson, S.M. (2019)  Molecular pharmacology and neurobiology of rapid-acting antidepressants. Ann. Rev. Pharmacol. Toxicol., 59: 213-236. PMCID: PMC6364552

LeGates, T.A., Kvarta, M.D., Tooley, J.R., Francis, T.C., Lobo, M.K., Creed, M.C., Thompson, S.M. (2018) Reward behavior is regulated by the strength of hippocampus-nucleus accumbens excitatory synapses. Nature, 564: 258-262. PMCID: PMC6292781

Zanos, P., Nelson, M.E., Highland, J.N., Krimmel, S.R., Georgiou, P., Gould, T.D., Thompson, S.M. (2017) A negative allosteric modulator for alpha5 subunit-containing GABA receptors exerts a rapid and persistent antidepressant-like action without the side effects of the NMDA receptor antagonist ketamine in mice. eNeuro, DOI: 10.1523/ENEURO.0285-16.2017.  PMCID: PMC5334634

Zanos, P., Moaddel, R., Morris, P.J., Georgiou, P., Fischell, J., Elmer, G.I., Alkondon, M., Yuan, P., Pribut, H.J., Singh, N.S., Dossou, K.S.S., Fang, Y., Huang, X.-P., Mayo, C.L., Wainer, I.W., Albuquerque, E.X., Thompson, S.M., Thomas, C.J., Zarate, C.A., Gould, T.D. (2016) NMDA receptor inhibition-independent antidepressant actions of a ketamine metabolite. Nature, 533: 481-486.  PMCID: PMC4922311

Thompson, S.M., A.J. Kallarackal, M.D. Kvarta, A.M. Van Dyke, T.A. LeGates, X. Cai.  (2015) An excitatory synapse hypothesis of depression.Trends in Neurosciences, 38: 279–294.  PMCID: PMC4417609

Fischell, J., A.M. Van Dyke, M.D. Kvarta, T.A. LeGates, and S.M. Thompson.  (2015) A benzodiazepine receptor inverse agonist exerts a rapid antidepressant action and restores stress-induced impairment of excitatory synaptic strength. Neuropsychopharmacology, 40: 2499-2509, 2015.

Kallarackal A.J., Kvarta, M.D., Camaratta, E., Jaberi, L., Cai, X., Bailey, A.M. and Thompson, S.M. (2013)  Chronic stress induces a selective decrease in AMPA receptor-mediated synaptic excitation at hippocampal temporoammonic-CA1 synapses. J. Neurosci., 33: 15669 –15674.  PMCID: PMC3787493

Cai, X., Kallarackal, A.J., Kvarta, M. D., Goluskin, S., Gaylor, K., Bailey, A.M., Lee, H.-K., Huganir, R.L. and Thompson, S.M. (2013)  Local potentiation of excitatory synapses by serotonin and antidepressants and its dysregulation in rodent models of depression. Nature Neurosci., 16: 464–472.  PMCID: PMC3609911

Thompson, S. M. (2022) Plasticity of synapses and reward circuit function in the genesis and treatment of depression. Neuropsychopharmacology Reviews. doi: 10.1038/s41386-022-01422-1.

Cole, A.B., Montgomery, K., Bale, T.L., and Thompson, S.M. (2022) What the hippocampus tells the HPA axis: Hippocampal output attenuates acute stress responses via disynaptic inhibition of CRF+ PVN neurons. Neurobiology of Stress, 20: 100473.

Troppoli, T.A., Zanos, P., Georgiou, P., Gould, T.D., Rudolph, U., and Thompson, S.M. (2022) Negative allosteric modulation of GABAARs at α5 subunit-containing benzodiazepine sites reverses stress-induced anhedonia and weakened synaptic function in mice. Biological Psychiatry, 92: 216-226.

Thompson, S.M. (2023) Plasticity of synapses and reward circuit function in the genesis and treatment of depression. Neuropsychopharmacol. Reviews, 48: 90-103.

• optogenetic photostimulation in vitro and in vivo
• behavioral tests of reward and hedonic state
• whole-cell patch-clamp recording
• extracellular field potential recording
• Western blotting
• confocal microscopy
• immunocytochemistry
• rodent survival surgery