awake-electrophysiological-profiling-ventromedial-prefrontal-cortex

Awake Electrophysiological Profiling of the Ventromedial Prefrontal Cortex in a Mouse Model of Depression and Parkinson's Disease

While Parkinson's disease (PD) is primarily known as a motor disorder, non-motor symptoms often emerge before motor deficits and significantly impact ...

Spanish National Research Council (CSIC)

August Pi i Sunyer Biomedical Research Institute (IDIBAPS)

Biomedical Research Networking Center for Mental Health (CIBERSAM), ISCIII

University of Valencia

Hyperammonemia contributes to hepatic encephalopathy. In hyperammonemic rats, cognitive function is impaired by altered glutamatergic neurotransmission induced by neuroinflammation. The underlying mechanisms remain unclear. Enhanced sphingosine-1-phosphate receptor 2 (S1PR2) activation in the cerebellum of hyperammonemic rats contributes to neuroinflammation. in In hyperammonemic rats, we assessed if blocking S1PR2 reduced hippocampal neuroinflammation and reversed cognitive impairment and if the signaling pathways were involved. S1PR2 was blocked with intracerebral JTE-013, and cognitive function was evaluated. The signaling pathways inducing neuroinflammation and altered glutamate receptors were analyzed in hippocampal slices. JTE-013 improved cognitive function in the hyperammonemic rats, and hyperammonemia increased S1P. This increased IL-1β, which enhanced Src activity, increased CCL2, activated microglia and increased the membrane expression of the NMDA receptor subunit GLUN2B. This increased p38-MAPK activity, which altered the membrane expression of AMPA receptor subunits and increased BDNF, which activated the TrkB → PI3K → Akt → CREB pathway, inducing sustained neuroinflammation. This report unveils key pathways involved in the induction and maintenance of neuroinflammation in the hippocampus of hyperammonemic rats and supports S1PR2 as a therapeutic target for cognitive impairment.

Enhanced Activation of the S1PR2-IL-1β-Src-BDNF-TrkB Pathway Mediates Neuroinflammation in the Hippocampus and Cognitive Impairment in Hyperammonemic Rats.

Depression is a devastating mood disorder that causes significant disability worldwide. Current knowledge of its pathophysiology remains modest and clear biological markers are lacking. Emerging evidence from human and animal models reveals persistent alterations in endoplasmic reticulum (ER) homeostasis, suggesting that ER stress-related signaling pathways may be targets for prevention and treatment. However, the neurobiological basis linking the pathways involved in depression-related ER stress remains unknown. Here, we report that an induced model of ER stress in mouse serotonin (5-HT) neurons is associated with reduced Egr1-dependent 5-HT cellular activity and 5-HT neurotransmission, resulting in neuroplasticity deficits in forebrain regions and a depressive-like phenotype. Ketamine administration engages downstream eIF2α signaling to trigger rapid neuroplasticity events that rescue the depressive-like effects. Collectively, these data identify ER stress in 5-HT neurons as a cellular pathway involved in the pathophysiology of depression and show that eIF2α is critical in eliciting ketamine's fast antidepressant effects.

ER stress in mouse serotonin neurons triggers a depressive phenotype alleviated by ketamine targeting eIF2α signaling.

Neuropsychiatric and neurodegenerative disorders are frequently associated with gastrointestinal (GI) co-pathologies. Although the central and enteric nervous systems (CNS and ENS, respectively) have been studied separately, there is increasing interest in factors that may contribute to conditions affecting both systems. There is compelling evidence that serotonin (5-HT) may play an important role in several gut-brain disorders. It is well known that 5-HT is essential for the development and functioning of the CNS. However, most of the body's 5-HT is produced in the GI tract. A deeper understanding of the specific effects of enteric 5-HT on gut-brain disorders may provide the basis for the development of new therapeutic targets. This review summarizes current data focusing on the important role of 5-HT in ENS development and motility, with particular emphasis on novel aspects of 5-HT signaling in conditions where CNS and ENS comorbidities are common, such as Parkinson's disease and depressive disorders.

New insights into the effects of serotonin on Parkinson's disease and depression through its role in the gastrointestinal tract.

Major depressive disorder (MDD) is characterized by significant impairment in social, emotional, and cognitive functioning. Its precise pathophysiology remains poorly understood. Alterations in protein homeostasis and some misfolded proteins have been identified within the brains of patients diagnosed with neuropsychiatric disorders. In contrast to neurodegenerative processes such as Parkinson's disease (PD), where the accumulation of aggregated α-synuclein (α-Syn) protein is a primary cause of significant neuronal loss, altered proteostasis in MDD may result in loss-of-function effects by modifying synaptic neuroplasticity. Moreover, aberrant activation of endoplasmic reticulum (ER) pathways may intensify the pathological alterations due to altered proteostasis. In this study, dorsolateral prefrontal cortex (dlPFC) and caudate nucleus from MDD patients and non-psychiatric controls were used. Postmortem samples of same brain areas from PD patients (Braak 2-3 and 5-6) and controls were also included. Protein levels of ER and unfolded protein response (UPR), synucleins (α-, β- and γ-Syn), and brain-derived neurotrophic factor (BDNF) were measured by Western-Blot. Phospho-eIF2α/eIF2α ratio was increased in the dlPFC and caudate nucleus of MDD and PD patients compared to their respective controls. Brain area-dependent changes in BiP and GRP94 levels were also found. We further detected accumulation of immature BDNF precursors and opposite changes in α- and β-Syn levels in the dlPFC of MDD and PD patients compared to controls. Our findings suggest that alterations in proteostasis contribute to the pathophysiology of MDD, as previously described in PD. A deeper understanding of the pathways involved will identify other candidate proteins and new targets with therapeutic potential.

Impaired unfolded protein response, BDNF and synuclein markers in postmortem dorsolateral prefrontal cortex and caudate nucleus of patients with depression and Parkinson's disease.

Hyperammonemia is a main contributor to cognitive impairment in patients with hepatic encephalopathy. Hyperammonemia-induced cognitive impairment is mediated by neuroinflammation and alteration of glutamatergic and GABAergic neurotransmission in hippocampus. Hyperammonemia enhances GABAergic neurotransmission in hippocampus but the role of neuroinflammation remains unknown. In cerebellum of hyperammonemic rats enhanced S1PR2-BDNF-TrkB pathway activation mediates enhancement of GABAergic neurotransmission. In hippocampus of hyperammonemic rats, the increase of IL-1β and Src kinase activation alters glutamatergic neurotransmission. The aims of this work were to assess if neuroinflammation is responsible for the enhanced GABAergic neurotransmission in hippocampus of hyperammonemic rats and to identify the underlying mechanisms. We used ex vivo hippocampal slices from control and hyperammonemic male rats and assessed the effects of blocking the S1PR2, the IL-1 receptor, TrkB or of inhibiting the protein kinases Src or PI3K on glutamate decarboxylases and GABA content and on membrane expression of GABA receptor, GABA transporters and chloride co-transporters. Blocking the S1PR2-IL-1β-Src-BDNF-TrkB-PI3K pathway at any of its steps reversed the reduced membrane expression of GABA transporters, which would increase extracellular GABA, and the increased membrane expression of most of the GABA receptor subunits analyzed, which also enhances GABAergic neurotransmission. This would be mediated by increasing the content of gephyrin and phosphorylation of the β3 subunit of GABA receptors. The identification of this pathway as the origin of the enhanced GABAergic neurotransmission provides several therapeutic targets to reverse cognitive impairment in hyperammonemia and hepatic encephalopathy and, likely, in other pathologies associated to neuroinflammation and enhanced GABAergic neurotransmission.

Article	Year
Enhanced Activation of the S1PR2-IL-1β-Src-BDNF-TrkB Pathway Mediates Neuroinflammation in the Hippocampus and Cognitive Impairment in Hyperammonemic Rats. International journal of molecular sciences\| PubMed ID: 38139078	2023
ER stress in mouse serotonin neurons triggers a depressive phenotype alleviated by ketamine targeting eIF2α signaling. iScience\| PubMed ID: 38711453	2024
New insights into the effects of serotonin on Parkinson's disease and depression through its role in the gastrointestinal tract. Spanish journal of psychiatry and mental health\| PubMed ID: 38992345	2025
Impaired unfolded protein response, BDNF and synuclein markers in postmortem dorsolateral prefrontal cortex and caudate nucleus of patients with depression and Parkinson's disease. Progress in neuro-psychopharmacology & biological psychiatry\| PubMed ID: 40015617	2025
Mechanisms by which neuroinflammation modulates GABAergic neurotransmission in the hippocampus of hyperammonemic rats. Neurotoxicology\| PubMed ID: 41205708	2025

Maria Sancho-Alonso

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