Chronic Stress Exposure Reduces Parvalbumin Expression in the Rat Hippocampus through an Imbalance of Redox Mechanisms: Restorative Effect of the Antipsychotic Lurasidone

Abstract

BackgroundPsychiatric disorders are associated with altered function of inhibitory neurotransmission within the limbic system, which may be due to the vulnerability of selective neuronal subtypes to challenging environmental conditions, such as stress. In this context, parvalbumin-positive GABAergic interneurons, which are critically involved in processing complex cognitive tasks, are particularly vulnerable to stress exposure, an effect that may be the consequence of dysregulated redox mechanisms.MethodsAdult Male Wistar rats were subjected to the chronic mild stress procedure for 7 weeks. After 2 weeks, both control and stress groups were further divided into matched subgroups to receive chronic administration of vehicle or lurasidone (3 mg/kg/d) for the subsequent 5 weeks. Using real-time RT-PCR and western blot, we investigated the expression of GABAergic interneuron markers and the levels of key mediators of the oxidative balance in the dorsal and ventral hippocampus.ResultsChronic mild stress induced a specific decrease of parvalbumin expression in the dorsal hippocampus, an effect normalized by lurasidone treatment. Interestingly, the regulation of parvalbumin levels was correlated to the modulation of the antioxidant master regulator NRF2 and its chaperon protein KEAP1, which were also modulated by pharmacological intervention.ConclusionsOur findings suggest that the susceptibility of parvalbumin neurons to stress may represent a key mechanism contributing to functional and structural impairments in specific brain regions relevant for psychiatric disorders. Moreover, we provide new insights on the mechanism of action of lurasidone, demonstrating that its chronic treatment normalizes chronic mild stress-induced parvalbumin alterations, possibly by potentiating antioxidant mechanisms, which may ameliorate specific functions that are deteriorated in psychiatric patients.

Anti-stress Properties of Atypical Antipsychotics

“…Moreover, GABAergic interneurons that express parvalbumin (PV) and somatostatin (SST), are extremely vulnerable to the detrimental consequences of stress exposure [ 36 , 37 ]. Indeed, several studies reported that chronic stress decreases Pv and Sst mRNA levels, as well as the number of neurons expressing these markers [ 32 , 36 , 37 , 38 ].…”

“…For instance, we have shown that CMS exposure reduces the expression of neuroplastic proteins [ 114 ] and alters synaptic mechanisms involved in the glutamatergic function and local protein synthesis [ 111 ]. Moreover, exposure to CMS is associated with alterations in the glucocorticoid signaling [ 113 ], enhanced expression of inflammatory markers as well as an imbalance of redox mechanisms [ 38 , 110 ], all of which have been associated with schizophrenia.…”

“…In this regard, GABAergic transmission has been proposed as a potential target of antidepressants and antipsychotic drugs [ 141 , 142 ]. For instance, chronic treatment with lurasidone in rats can normalize the CMS-induced reduction of Parvalbumin gene expression within the dorsal hippocampus, an effect that may depend on its ability in regulating the oxidative balance in this brain region [ 38 ]. In more detail, chronic administration of lurasidone for 5 weeks can counteract the CMS-induced increase of the pro-oxidant enzyme NADPH oxidase 2 (NOX2) levels as well as the reduced levels of antioxidant mediator nuclear factor erythroid 2-related factor 2 (NRF2) in the dorsal hippocampus [ 38 ].…”

“…For instance, chronic treatment with lurasidone in rats can normalize the CMS-induced reduction of Parvalbumin gene expression within the dorsal hippocampus, an effect that may depend on its ability in regulating the oxidative balance in this brain region [ 38 ]. In more detail, chronic administration of lurasidone for 5 weeks can counteract the CMS-induced increase of the pro-oxidant enzyme NADPH oxidase 2 (NOX2) levels as well as the reduced levels of antioxidant mediator nuclear factor erythroid 2-related factor 2 (NRF2) in the dorsal hippocampus [ 38 ]. These results are in line with another report showing that chronic administration of paliperidone regulates the redox machinery by counteracting the reduction of NRF2 in the prefrontal cortex of rats exposed to chronic restraint stress [ 143 ].…”

Differential Neuroinflammatory Response in Male and Female Mice: A Role for BDNF

“…Particularly, the increased levels of peripheral and central inflammatory markers observed in a large subset of MDD subjects (Raison et al, 2006; Howren et al, 2009; Dowlati et al, 2010), the high co-morbidity between MDD and various non-psychiatric illnesses associated with inflammatory conditions (Anisman, 2008; Berge and Riise, 2015; Réus et al, 2017), and the development of MDD in a high percentage of patients under interferon regimen (Raison et al, 2009; Udina et al, 2012) clearly support the relevance of a neuroinflammatory component in MDD. In addition, while changes in immune/inflammatory response have been found in MDD experimental models based on both the genetic and the environmental components of the disease (Chourbaji et al, 2011; Couch et al, 2013; Macchi et al, 2013; Rossetti et al, 2016; Wang et al, 2018), several studies indicate the immune/inflammatory system as a potential target for the pharmacological treatment of MDD (Molteni et al, 2013; Kv et al, 2018; Rossetti et al, 2018a,b; Lu et al, 2019).…”