Presynaptic plasticity as a hallmark of rat stress susceptibility and antidepressant response.
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.
Synaptic Physiology Laboratory, Department of Biomedicine, Building 1160, Aarhus University, DK-8000, Aarhus C, Denmark.
Jose Luis
JL
Nieto-Gonzalez
Synaptic Physiology Laboratory, Department of Biomedicine, Building 1160, Aarhus University, DK-8000, Aarhus C, Denmark.
Mai Marie
MM
Holm
Synaptic Physiology Laboratory, Department of Biomedicine, Building 1160, Aarhus University, DK-8000, Aarhus C, Denmark.
Irina
I
Vardya
Translational Neuropsychiatry Unit, Aarhus University Hospital, DK-8240, Risskov, Denmark.
Trine
T
Christensen
Translational Neuropsychiatry Unit, Aarhus University Hospital, DK-8240, Risskov, Denmark.
Ove
O
Wiborg
Synaptic Physiology Laboratory, Department of Biomedicine, Building 1160, Aarhus University, DK-8000, Aarhus C, Denmark; Translational Neuropsychiatry Unit, Aarhus University Hospital, DK-8240, Risskov, Denmark; Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
Kimmo
K
Jensen
D000818:Animals; D003863:Depression / Q000503:physiopathology*; D008297:Male; D009473:Neuronal Plasticity; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D005680:gamma-Aminobutyric Acid