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- Czeh, B., et al.
(författare)
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Long-Term Stress Disrupts the Structural and Functional Integrity of GABAergic Neuronal Networks in the Medial Prefrontal Cortex of Rats
- 2018
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Ingår i: Frontiers in Cellular Neuroscience. - : Frontiers Media SA. - 1662-5102. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Clinical and experimental data suggest that fronto-cortical GABAergic deficits contribute to the pathophysiology of major depressive disorder (MDD). To further test this hypothesis, we used a well characterized rat model for depression and examined the effect of stress on GABAergic neuron numbers and GABA-mediated synaptic transmission in the medial prefrontal cortex (mPFC) of rats. Adult male Wistar rats were subjected to 9-weeks of chronic mild stress (CMS) and based on their hedonic-anhedonic behavior they were behaviorally phenotyped as being stress-susceptible (anhedonic) or stress-resilient. Post mortem quantitative histopathology was used to examine the effect of stress on parvalbumin (PV)-, calretinin- (CR), calbindin- (CB), cholecystokinin- (CCK), somatostatin-(SST) and neuropeptide Y-positive (NPY+) GABAergic neuron numbers in all cortical subareas of the mPFC (anterior cingulate (Cg1), prelimbic (PrL) and infralimbic (IL) cortexes). In vitro, whole-cell patch-clamp recordings from layer II-III pyramidal neurons of the ventral mPFC was used to examine GABAergic neurotransmission. The cognitive performance of the animals was assessed in a hippocampal-prefrontal-cortical circuit dependent learning task. Stress exposure reduced the number of CCK-, CR- and PV-positive GABAergic neurons in the mPFC, most prominently in the IL cortex. Interestingly, in the stress-resilient animals, we found higher number of neuropeptide Y-positive neurons in the entire mPFC. The electrophysiological analysis revealed reduced frequencies of spontaneous and miniature IPSCs in the anhedonic rats and decreased release probability of perisomatic-targeting GABAergic synapses and alterations in GABA(B) receptor mediated signaling. In turn, pyramidal neurons showed higher excitability. Anhedonic rats were also significantly impaired in the object-place paired-associate learning task. These data demonstrate that long-term stress results in functional and structural deficits of prefrontal GABAergic networks. Our findings support the concept that fronto-limbic GABAergic dysfunctions may contribute to emotional and cognitive symptoms of MDD.
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2. |
- Nieto-Gonzalez, J. L., et al.
(författare)
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Presynaptic Plasticity as a Hallmark of Rat Stress Susceptibility and Antidepressant Response
- 2015
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 10:3
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Tidskriftsartikel (refereegranskat)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.
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