Mood is governed by the actions of a complex, anatomically dispersed circuit comprised of specific subpopulations of neurons arranged into functional units. Functional imaging studies of patients suffering from major depressive disorder (MDD), bipolar disorder and anxiety indicate that a fundamental neural circuit controls emotion, with different elements of the circuit contributing to specific aspects of emotive behavior (Drevets et al., 2008
; Mayberg, 2009
). For example, fMRI and PET imaging of patients suffering from MDD has consistently demonstrated decreased prefrontal cortex function, and alterations in the activity of subcortical structures that include the basal ganglia, amygdala and thalamus (Drevets, 2000
; Mayberg et al., 1999
). There is general agreement that in MDD, disease and treatment mechanisms impact the same basic circuitry controlling emotional state. However it is evident from deep brain stimulation studies in a number of neurological and psychiatric disorders that the pathological mechanisms causing dysfunction and the immediate targets of clinical interventions most effective in alleviating symptoms may involve different brain structures. Given this realization, our understanding of the pathophysiology of depression as well as the development of improved therapies for this disorder will be advanced by identification of cell types and molecular mechanisms responsible for generating depression-like phenotypes, as well as those mediating responses to antidepressant treatment.
Recently, p11 (the protein product of the S100a10
gene) was found to be an important factor mediating antidepressant responses and depression-like states (Svenningsson et al., 2006
). P11 is an adaptor protein that is expressed specifically in the CNS (Egeland et al., 2011
). It regulates serotonin signaling by binding to serotonin receptors (Htrs) 1b, 1d, and 4 and stabilizing the localization of these receptors at the cell surface (Svenningsson et al., 2006
; Warner-Schmidt et al., 2009
). Decreased p11 levels were found in the cortex of MDD patients, suicide victims, and a mouse model of depression (Anisman et al., 2008
; Svenningsson et al., 2006
). Chronic antidepressant treatment, electroconvulsive therapy, and BDNF treatment all result in increased p11 expression in the cerebral cortex (Svenningsson et al., 2006
; Warner-Schmidt et al., 2010
). Importantly, mice lacking p11 exhibit depressive-like behaviors, increased anxiety, and a blunted behavioral response to antidepressant treatment (Svenningsson et al., 2006
; Warner-Schmidt et al., 2009
Antidepressant drugs target neuromodulatory systems that have widespread effects throughout the CNS, engaging receptors that are broadly expressed in the brain. While the pharmacological effect of these drugs is immediate, there is a therapeutic delay of weeks to months before antidepressant activity is evident. This delay is thought to reflect neuroadaptive changes in pre- and postsynaptic cells, including long-term changes in gene expression and protein translation (Krishnan and Nestler, 2008
). Although the cell types and precise molecular mechanisms mediating the efficacy of antidepressant drugs have not been identified, neuroimaging studies have shown that the clinical effects of antidepressant drug therapy and deep brain stimulation correlate with increased activity in the cerebral cortex (Drevets et al., 2008
; Mayberg, 2009
). Given these observations, and the dramatic regulation of p11 in the frontal cortex of depressed patients, we wished to determine whether p11 expressing cells in the cerebral cortex are critically important for antidepressant action, and to search for beneficial adaptations that may occur in these cells in response to chronic antidepressant treatment.
For this study, we created an S100a10 bacTRAP mouse line to characterize p11 expressing cells and measure their responses to antidepressant treatment (Doyle et al., 2008
; Heiman et al., 2008
). We report that p11 is highly enriched in layer 5 corticostriatal (CStr) projection neurons, that these cells respond preferentially to chronic SSRI treatment by altering serotonergic tone, and that loss of p11 in the cortex results in the inability to respond to an SSRI. Our data demonstrate that the beneficial actions of antidepressant therapy can be mediated by a single cell type in the cerebral cortex, and suggest that development of drugs that specifically target the activity of CStr neurons can result in improved therapies for depression.