Scott M. Thompson, PhD

Aungst, S., England, P.M. and Thompson, S.M.  (2013)  Critical role of trkB receptors in reactive axonal sprouting and hyperexcitability after axonal injury. J. Neurophysiol., 109: 813-824. (Editor’s Choice selection).  PMCID: PMC3567381

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

Wang, G., and Thompson S.M. (2008) Maladaptive homeostatic plasticity in a rodent model of central pain syndrome: Thalamic hyperexcitability after spinothalamic tract lesions. Journal of Neuroscience, 28: 11959 –11969.  PMCID: PMC2627563

Cai X., Wei D.-S., Gallagher S.E., Bagal A., Mei Y.-A., Kao J. P. Y., Thompson S. M., and Tang C.-M. (2007) Hyperexcitability of distal dendrites in hippocampal pyramidal cells following chronic partial deafferentation. Journal of Neuroscience 27: 59-68.

Dinocourt, C., Gallagher S.E., and Thompson S.M. (2006) Injury-induced axonal sprouting in the hippocampus is initiated by activation of trkB receptors. European Journal of Neuroscience 24: 1857-1866.

Bagal A., Kao J. P. Y., Tang C.-M., and Thompson S.M. (2005) Long-term potentiation of exogenous glutamate responses at single dendritic spines. Proceedings of the National Academy of Science USA 102: 14434-14439.

Cai X., Liang C.W., Muralidharan S., Kao J.P.Y., Tang C-M, and Thompson S.M. (2004) Unique roles of SK and Kv4.2 potassium channels in dendritic integration. Neuron 44: 351-364, 2004.

Wei D.-S., Mei Y.-A., Bagal A., Kao J.P.Y., Thompson S.M., and Tang C.-M. (2001) Compartmentalized and binary behavior of terminal apical dendrites in hippocampal pyramidal neurons. Science 293: 2271-2275.

McKinney R.A., Debanne D., Gahwiler B.H., and Thompson S.M. (1997) Lesion-induced axonal sprouting and hyperexcitability in the hippocampus in vitro: implications for the genesis of posttraumatic epilepsy. Nature Medicine 3: 990-996.

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.

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.

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.

• 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

Click Here to Support New Treatments for Depression

• Anthony Cole, MD/PhD student - stress and HPA axis regulation
• Natalie Hesselgrave, MD/PhD student - stress and depression
• Tara LeGates, Research Associate – Plasticity of hippocampal-NAc synapses
• Timothy Troppoli, PhD student – fast acting antidepressants
• Andreas Wulff, predoctoral student – synaptic plasticity in depression and antidepressant drug response