An excitatory synapse hypothesis of depression

Abstract

Depression is a common cause of mortality and morbidity, but the biological bases of the deficits in emotional and cognitive processing remain incompletely understood. Current antidepressant therapies are effective in only some patients and act slowly. Here, we propose an excitatory synapse hypothesis of depression in which chronic stress and genetic susceptibility cause changes in the strength of subsets of glutamatergic synapses at multiple locations, including the prefrontal cortex (PFC), hippocampus, and nucleus accumbens (NAc), leading to a dysfunction of corticomesolimbic reward circuitry that underlies many of the symptoms of depression. This hypothesis accounts for current depression treatments and suggests an updated framework for the development of better therapeutic compounds.

Keywords: glutamate; hippocampus; ketamine; nucleus accumbens; reward; stress.

Figure 1. Stress induced internalization of AMPARs in D1R-expressing medium spiny neurons in the NAc underlies some stress-induced depression-like behavioral changes

A. Whole-cell recording of evoked excitatory synaptic currents from D1R-expressing MSNs at −70 mV and +40 mV for analysis of AMPAR- and NMDAR-mediated components in slices from control and chronically stressed mice. Chronic stress decreased the AMPAR component, but not the NMDAR component. B,C. Transfection of D1R-expressing cells with a peptide that prevents stress-induced AMPAR internalization prevented the stress-induced loss of sucrose preference (B), but not stress-induced immobility in the forced swim test (C). Modified with permission from Lim et al., 2012 [29].

Figure 2. Stress-induced internalization of AMPARs and NMDARs in the prefrontal cortex is mediated by ubiquitination and proteosomal degradation

AMPAR-mediated (A, −70 mV, representative currents at right) and NMDAR-mediated (B, +60 mV) excitatory currents recorded from layer V pyramidal cells in response to a range of stimulation intensities in slices from unstressed control rats (open circle) and rats subjected to chronic restraint stress (filled triangle) or chronic unpredictable stress (filled square). Stress depressed both components regardless of stimulation intensity. C. Chronic restraint stress decreased both expression and plasma membrane surface insertion of GluA1 and GluN1 receptor subunits. D. Pharmacological inhibition of proteosomal degradation prevented decreases in AMPAR-mediated synaptic currents in response to chronic stress, but had no effect in unstressed animals. Representative currents shown at right. Modified with permission from Yuen et al., 2012 [49].

Figure 3. Stress decreases AMPAR-mediated excitation and GluA1 expression at temporoammonic to CA1 cell synapses and chronic fluoxetine reverses these effects

A. Field excitatory postsynaptic potentials (fEPSPs) are recorded in stratum lacunosum moleculare in response to stimulation of the temporoammonic (TA) pathway in Mg²⁺-free saline, allowing dissection of AMPAR- and NMDAR-mediated components. AMPAR-mediated transmission was reduced over a range of stimulation intensities after chronic unpredictable stress (red) compared to unstressed rats (blue). Quantification of AMPA:NMDA ratios (B) and GluA1 protein (C) reveals that the selective decrease in AMPAR-mediated transmission is due to decreased GluA1 expression. Administration of fluoxetine for three weeks to stressed rats restored both AMPA:NMDA ratios and GluA1 expression. Modified with permission from Kallarackal et al., 2013 [72].

Figure 4. Serotonin causes a 5-HT_1BR-dependent potentiation of TA-CA1 synapses and this potentiation is altered by chronic stress

A. fEPSPs are recorded in stratum lacunosum moleculare in response to stimulation of the TA pathway during application of the tricyclic antidepressant imipramine in control saline (black) or saline containing the 5-HT_1BR antagonist isamoltane. Elevation of endogenous serotonin produces a doubling of synaptic strength. B. Activation of 5-HT_1BRs with the selective agonist anpirtoline promotes action potential discharge in CA1 cells. C. Anpirtoline produces a robust and reversible potentiation of TA-CA1 excitatory postsynaptic currents in slices from unstressed control animals, but produces an enhanced and persistent potentiation in slices from rats subjected to chronic unpredictable stress. Modified with permission from Cai et al., 2013 [76].

Figure 5. The hypothesized impact of stress-induced changes in excitatory synaptic transmission on the reward circuitry and the mechanisms of antidepressant action

The hippocampus and PFC send glutamatergic projections (red) to the NAc where they excite D1R-expressing GABAergic MSNs. These cells inhibit a population of interneurons within the VTA that form GABAergic inhibitory synapses (blue) onto dopaminergic VTA cells (green) projecting back to the NAc, hippocampus, and PFC. When the hippocampus or PFC are active, they excite D1R cells, thereby disinhibiting VTA dopaminergic cells and promoting dopamine release (left panel). There is a distinct circuit mediating responses to negative stimuli in which glutamatergic cells in the LHb project to GABAergic neurons in the rostromedial tegmentum (RMTg), which in turn inhibit dopaminergic neurons in the VTA. Chronic stress induces anhedonia and other reward-related symptoms of depression because of a weakening of excitatory synapses in the hippocampus and PFC and because of a weakening of excitatory synapses on D1R MSNs. There is also a potentiation of excitatory inputs onto LHb neurons, resulting in an increase in the excitation of RMTg neurons and subsequent increase in the inhibition of VTA cells. These changes synergistically increase the inhibition of VTA dopaminergic cells thereby impairing dopamine release (center panel). Effective antidepressant therapies (SSRIs, ketamine, DBS, or ECT) can all trigger an activity- and/or serotonin-dependent strengthening of excitatory synapses in the hippocampus, PFC, and NAc, thereby restoring the normal release of dopamine in response to rewarding stimuli (right panel). Evidence of changes in synaptic excitation: 1. (Lim et al., 2012 [29]); 2. (Yuen et al., 2012; Li et al., 2011; Liston et al., 2006; Radley et al., 2008; Liu and Aghajanian, 2008 [–49,53,104]); 3. (Kallarackal et al., 2013; Alfarez et al., 2003; Schmidt et al., 2010; Watanabe et al., 1992; Sousa et al., 2000 [69,70,72,172,178]). 4. (Li et al., 2011 [60]); 5. (Stamatkis and Stuber, 2012 [179]). Evidence of synaptic strengthening by ADs: 6. (Cai et al., 2013, SSRI [76]; Conrad et al., 1996, tricyclic [180]). 7. (Li et al., 2011, ketamine [104]); 8. (Covington et al., 2010, LTP? [42]).