Abstract
Two main questions are important for understanding and treating affective disorders: why are certain individuals susceptible or resilient to stress, and what are the features of treatment response and resistance? To address these questions, we used a chronic mild stress (CMS) rat model of depression. When exposed to stress, a fraction of rats develops anhedonic-like behavior, a core symptom of major depression, while another subgroup of rats is resilient to CMS. Furthermore, the anhedonic-like state is reversed in about half the animals in response to chronic escitalopram treatment (responders), while the remaining animals are resistant (non-responder animals). Electrophysiology in hippocampal brain slices was used to identify a synaptic hallmark characterizing these groups of animals. Presynaptic properties were investigated at GABAergic synapses onto single dentate gyrus granule cells. Stress-susceptible rats displayed a reduced probability of GABA release judged by an altered paired-pulse ratio of evoked inhibitory postsynaptic currents (IPSCs) (1.48 ± 0.25) compared with control (0.81 ± 0.05) and stress-resilient rats (0.78 ± 0.03). Spontaneous IPSCs (sIPSCs) occurred less frequently in stress-susceptible rats compared with control and resilient rats. Finally, a subset of stress-susceptible rats responding to selective serotonin reuptake inhibitor (SSRI) treatment showed a normalization of the paired-pulse ratio (0.73 ± 0.06) whereas non-responder rats showed no normalization (1.2 ± 0.2). No changes in the number of parvalbumin-positive interneurons were observed. Thus, we provide evidence for a distinct GABAergic synaptopathy which associates closely with stress-susceptibility and treatment-resistance in an animal model of depression.
Highlights
Understanding stress susceptibility or resilience of individuals is thought to be important in understanding affective disorders, since this may identify factors that determine individualPLOS ONE | DOI:10.1371/journal.pone.0119993 March 5, 2015Synaptic Hallmark of Rat Stress Response risks of progressing into a depressive state
We have previously reported a decreased GABA release probability between control and stress-susceptible rats using electrophysiological recording of dentate gyrus granule cells in brain slices of rat chronic mild stress (CMS) model of depression [20]
Our data show that a GABAergic synaptopathy associates closely with the behavioral state of the animal. We suggest that this synaptopathy has a presynaptic origin and can identify stress-resilient and stress-susceptible individuals, as well as animals not responding to antidepressant treatment
Summary
Understanding stress susceptibility or resilience of individuals is thought to be important in understanding affective disorders, since this may identify factors that determine individualPLOS ONE | DOI:10.1371/journal.pone.0119993 March 5, 2015Synaptic Hallmark of Rat Stress Response risks of progressing into a depressive state. Progress has been made in humans and animals identifying some factors that correlate with stress resilience [1,2,3,4]. Recent data support the hypothesis that stress-resilience is an active process, and not a lack of the changes associated with stress-susceptibility [5]. This type of analysis points to novel pathways, which may be targeted by future antidepressant treatments, in order to shift the balance between resilience and susceptibility [5]. Some factors have been identified, the underlying function of neuronal microcircuits in stress susceptibility and treatment resistance is poorly understood
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