Stress blunts serotonin- and hypocretin-evoked EPSCs in prefrontal cortex: Role of corticosterone-mediated apical dendritic atrophy

Abstract

Morphological studies show that repeated restraint stress leads to selective atrophy in the apical dendritic field of pyramidal cells in the medial prefrontal cortex (mPFC). However, the functional consequence of this selectivity remains unclear. The apical dendrite of layer V pyramidal neurons in the mPFC is a selective locus for the generation of increased excitatory postsynaptic currents (EPSCs) by serotonin (5-HT) and hypocretin (orexin). On that basis, we hypothesized that apical dendritic atrophy might result in a blunting of 5-HT-and hypocretin-induced excitatory responses. Using a combination of whole-cell recording and two-photon imaging in rat mPFC slices, we were able to correlate electrophysiological and morphological changes in the same layer V pyramidal neurons. Repeated mild restraint stress produced a decrement in both 5-HTand hypocretin-induced EPSCs, an effect that was correlated with a decrease in apical tuft dendritic branch length and spine density in the distal tuft branches. Chronic treatment with the stress hormone corticosterone, while reducing 5-HT responses and generally mimicking the morphological effects of stress, failed to produce a significant decrease in hypocretin-induced EPSCs. Accentuating this difference, pretreatment of stressed animals with the glucocorticoid receptor antagonist RU486 blocked reductions in 5-HT-induced EPSCs but not hypocretin-induced EPSCs. We conclude: (i) stress-induced apical dendritic atrophy results in diminished responses to apically targeted excitatory inputs and (ii) corticosterone plays a greater role in stress-induced reductions in EPSCs evoked by 5-HT as compared with hypocretin, possibly reflecting the different pathways activated by the two transmitters.two-photon imaging ͉ apical tuft ͉ slice ͉ spine ͉ rat S tress induces neuronal atrophy in key limbic brain regions such as the hippocampus and medial prefrontal cortex (mPFC) that have been implicated in depressive illness (1). In layer II/III pyramidal neurons of the mPFC, repeated restraint stress has been shown to produce dendritic atrophy (2-5), an effect mimicked by high levels of corticosterone (6). Notably, these atrophic changes are restricted to the apical dendritic field. However, the functional implications at a cellular level of these localized effects of stress in the apical dendritic field are unclear. In a separate line of experiments in brain slices, we found that the apical dendrites are also the selective target of several stress-linked neurotransmitters/modulators, including serotonin (5-HT) and hypocretin/orexin, both of which induce a large increase in nonelectrically evoked (''spontaneous'') excitatory postsynaptic currents (EPSCs) in layer V mPFC pyramidal cells in brain slices (7,8). The effect of 5-HT is mediated by activation of 5-HT 2A receptors (7, 9), which are highly expressed on apical dendrites of layer V pyramidal neurons (10-13), and can be induced rapidly by the focal application of 5-HT to the apical but not basilar dendritic field in layer V pyramidal cells...

A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists

“…This includes decreased number and length of apical dendrites in the CA3 pyramidal cell layer of the hippocampus and layer V pyramidal neurons of the PFC [30,31]. Reductions of dendrites and spines are observed in the PFC after as little as 7 days of restraint stress [32], and have been associated with depressive behaviours after exposure to chronic unpredictable stress (CUS) [33]. These studies support the possibility that decreased dendrite complexity contributes to the reduced volume of hippocampus and PFC reported in depressed patients.…”

GSK-3 Inhibition Potentiates the Synaptogenic and Antidepressant-Like Effects of Subthreshold Doses of Ketamine

“…Here examined if the low-dose combination Ket-1/Li-10 produces effects comparable to the Ket-10 dose on mPFC spine synapses in parallel with behavioral effects. Whole-cell patch-clamp recordings of layer V pyramidal neurons were conducted as previously described (Liu and Aghajanian 2008;Li et al, 2010). Ket-1/Li-10 was found to significantly increase the frequency of excitatory postsynaptic currents (EPSCs) induced by bath application of 5-HT or hypocretin by B70 and 141% above vehicle control levels (Figure 2a and b. po0.05 and po0.01, respectively, one-way analysis of variance þ post-hoc analysis).…”

“…Brain slices were prepared as previously described (Liu and Aghajanian, 2008;Li et al, 2011). Briefly, one day after drug treatments, rats were anesthetized (chloral hydrate, 400 mg/kg, i.p.)…”

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

“…Second, 5-HT2A-Rs localized in the mPFC have been found to be important modulators of executive functions that are known to be impaired in affective as well as psychotic illness, such as working memory, cognitive flexibility and impulse control (Clarke et al, 2004;Stein et al, 2007;Williams et al, 2002;Winstanley et al, 2004). Third, exposure to stress causes dendritic retraction of mPFC pyramidal neurons and blunts 5-HT2A-R-mediated modulation of these neurons (Liu and Aghajanian, 2008), and produces associated deficits in PFC-mediated behaviors such as fear extinction and attentional set-shifting (Izquierdo et al, 2006;Liston et al, 2006). Thus, loss of 5-HT2A-R function in the mPFC could be a mechanism linking stress with some of the cognitive and executive symptoms found in stress-related disease.…”

“…5-HT2A-R are located on the dendrites of glutamatergic pyramidal neurons and interneurons in the rodent mPFC (Aghajanian and Marek, 1997;Cornea-Hebert et al, 1999;Hamada et al, 1998;Jansson et al, 2001;Miner et al, 2003;Willins et al, 1997;Xu and Pandey, 2000). Electrophysiological studies have demonstrated that selectively stimulating 5-HT2A-Rs (typically by co-applying a mixed 5-HT2A-R/5-HT2C-R agonist and a 5-HT2C-R antagonist to isolate 5-HT2A-Rs) can either excite or inhibit the activity of neurons in the rat mPFC, although an excitatory action appears to predominate under most conditions Marek, 1997, 1999;Amargos-Bosch et al, 2007;Araneda and Andrade, 1991;Arvanov et al, 1999;Ashby et al, 1990Ashby et al, , 1994Liu and Aghajanian, 2008;Marek et al, 2006;Puig et al, 2003;Zhou and Hablitz, 1999). On the basis of what appears to be an extrasynaptic localization of 5-HT2A-Rs on mPFC neurons (Jansson et al, 2001), some authors have proposed that the excitatory action of this receptor may be particularly prominent under conditions of high serotonin release .…”