Scn1a haploinsufficiency in the prefrontal cortex engages to cognitive impairment and depressive phenotype.

Altered development and function of the prefrontal cortex (PFC) during adolescence is implicated in the origin of mental disorders. Deficits in the GABAergic system prominently contribute to these alterations. Nav1.1 is a voltage-gated Na+ channel critical for normal GABAergic activity. Here, we studied the role of Nav1.1 in PFC function and its potential relationship with the aetiology of mental disorders. Dysfunction of Nav1.1 activity in the medial PFC (mPFC) of adolescent mice enhanced the local excitation/inhibition ratio, resulting in epileptic activity, cognitive deficits and depressive-like behaviour in adulthood, along with a gene expression profile linked to major depressive disorder (MDD). Additionally, it reduced extracellular serotonin concentration in the dorsal raphe nucleus and brain-derived neurotrophic factor expression in the hippocampus, two MDD-related brain areas beyond the PFC. We also observed alterations in oscillatory activity and impaired hippocampal-mPFC coherence during sleep. Finally, we found reduced expression levels of SCN1A, the gene encoding Nav1.1, in post-mortem PFC samples from human MDD subjects. Collectively, our results provide a novel mechanistic framework linking adolescence-specific alterations in Nav1.1 function in the PFC to the pathogenesis of epilepsy and comorbidities such as cognitive impairment and depressive disorders.

[Multicenter cross-sectional study on the prevalence of delirium in orthogeriatric units: «DELFRA 24 study¼ protocol]. / Estudio transversal multicéntrico sobre la prevalencia de delirium en unidades de ortogeriatría: protocolo de «Estudio DELFRA 24¼.

INTRODUCTION: Delirium is the most common perioperative complication in older adults with hip fracture (HF), leading to a catastrophic impact on their functional recovery and cognitive status. Currently, the true prevalence of this syndrome is unknown as its detection and management are not standardized in clinical practice. METHODS: A multicenter observational cross-sectional study will be conducted nationwide, involving different orthogeriatric units in Spain. The prevalence of delirium will be assessed using the 4AT scale, along with its characteristics and its relationship with other geriatric syndromes, sociodemographic variables, surgical characteristics, and laboratory parameters. RESULTS: Data collection is scheduled to take place on World Delirium Day (Wednesday, March 13, 2024), and therefore, the results are expected during the second or third quarter of 2024. CONCLUSIONS: Understanding the real prevalence and characteristics of delirium in older adults with HF could contribute to the development of strategies for its detection and management, reducing the impact of its consequences.

Gi protein coupling to adenosine A1-A2A receptor heteromers in human brain caudate nucleus.

Pharmacological characterization of adenosine A(1) and A(2A) receptors in human brain caudate nucleus membranes led to non-cooperative binding of radiolabelled ligands. In human caudate nucleus but not in cortex, the agonist binding to A(1) receptors was modulated by the agonist binding to A(2A) receptors indicating a functional negative cross-talk. Accordingly, the A(1) receptor-activation-mediated G(i)-dependent guanosine 5'-o-(3-[(35)S]thio-triphosphate) binding was modulated by agonist binding to A(2A) receptors. A(2A) receptors occupation led to a decrease in the potency of A(1) receptor agonists. These results indicate that A(1) but not A(2A) receptors activation, likely occurring at low adenosine concentrations, engages a G(i)-mediated signaling; however, when both receptors are occupied by adenosine, there is an A(2A) receptor-mediated impairment of G(i)-operated transducing units. These findings are relevant to get insight into the complex relationships derived from co-expression of multiple neurotransmitter/neuromodulator receptors subtypes that individually are coupled to different G proteins. A further finding was the demonstration that the A(2A) receptor agonist, CGS 21680, at high concentrations able to significantly bind to the A(1) receptor, behaved as a partial agonist of the later receptor. This fact might be taken into account when characterizing CGS 21680 actions in human cells expressing A(1) receptors when the compound is used at micromolar concentrations.

Dopaminergic control of ADAMTS2 expression through cAMP/CREB and ERK: molecular effects of antipsychotics.

A better understanding of the molecular mechanisms that participate in the development and clinical manifestations of schizophrenia can lead to improve our ability to diagnose and treat this disease. Previous data strongly associated the levels of deregulated ADAMTS2 expression in peripheral blood mononuclear cells (PBMCs) from patients at first episode of psychosis (up) as well as in clinical responders to treatment with antipsychotic drugs (down). In this current work, we performed an independent validation of such data and studied the mechanisms implicated in the control of ADAMTS2 gene expression. Using a new cohort of drug-naïve schizophrenia patients with clinical follow-up, we confirmed that the expression of ADAMTS2 was highly upregulated in PBMCs at the onset (drug-naïve patients) and downregulated, in clinical responders, after treatment with antipsychotics. Mechanistically, ADAMTS2 expression was activated by dopaminergic signalling (D1-class receptors) and downstream by cAMP/CREB and mitogen-activated protein kinase (MAPK)/ERK signalling. Incubation with antipsychotic drugs and selective PKA and MEK inhibitors abrogated D1-mediated activation of ADAMTS2 in neuronal-like cells. Thus, D1 receptors signalling towards CREB activation might participate in the onset and clinical responses to therapy in schizophrenia patients, by controlling ADAMTS2 expression and activity. The unbiased investigation of molecular mechanisms triggered by antipsychotic drugs may provide a new landscape of novel targets potentially associated with clinical efficacy.

Selective up-regulation of cannabinoid CB1 receptor coupling to Go-proteins in suicide victims with mood disorders.

Brain endocannabinoid system is proposed to play a role in the pathogenesis of affective disorders. In the present study, we analyzed the functionality of the cannabinoid receptor type 1 (CB1 receptor) at different transduction levels in prefrontal cortex (PFC) of depressed suicide victims. We examined stimulation of [35S]GTPγS binding, activation of Gα protein subunits and inhibition of adenylyl cyclase by the cannabinoid agonist WIN55,212-2, as well as [3H]CP55,940 binding, in PFC homogenates from suicide victims with major depression (MD) and matched control subjects. CB1 receptor-stimulated [35S]GTPγS binding was significantly greater in the PFC of MD compared with matched controls (23%, p < 0.05). This increase was most evident in the PFC from MD subgroup with negative blood test for antidepressants (AD) at the time of death (AD-free) (38%, p < 0.05), being absent when comparing the AD-treated MD cases with their controls. The density of CB1 receptors and their coupling to adenylyl cyclase were similar between MD and control cases, regardless of the existence of AD intake. Analysis of [35S]GTPγS-labelled Gα subunits allowed for the detection of upregulated CB1 receptor coupling to Gαo, but not to Gαi1, Gαi2, Gαi3, Gαz subunits, in the PFC from AD-free MD suicides. These results suggest that increased CB1 receptor functionality at the Gαi/o protein level in the PFC of MD subjects is due to enhanced coupling to Gαo proteins and might be modulated by AD intake. These data provide new insights into the role of endocannabinoid neurotransmission in the pathobiology of MD and suggest its regulation by ADs.

Biased Agonism of Three Different Cannabinoid Receptor Agonists in Mouse Brain Cortex.

Cannabinoid receptors are able to couple to different families of G proteins when activated by an agonist drug. It has been suggested that different intracellular responses may be activated depending on the ligand. The goal of the present study was to characterize the pattern of G protein subunit stimulation triggered by three different cannabinoid ligands, Δ9-THC, WIN55212-2, and ACEA in mouse brain cortex. Stimulation of the [35S]GTPγS binding coupled to specific immunoprecipitation with antibodies against different subtypes of G proteins (Gαi1, Gαi2, Gαi3, Gαo, Gαz, Gαs, Gαq/11, and Gα12/13), in the presence of Δ9-THC, WIN55212-2 and ACEA (submaximal concentration 10 µM) was determined by scintillation proximity assay (SPA) technique in mouse cortex of wild type, CB1 knock-out, CB2 knock-out and CB1/CB2 double knock-out mice. Results show that, in mouse brain cortex, cannabinoid agonists are able to significantly stimulate not only the classical inhibitory Gαi/o subunits but also other G subunits like Gαz, Gαq/11, and Gα12/13. Moreover, the specific pattern of G protein subunit activation is different depending on the ligand. In conclusion, our results demonstrate that, in mice brain native tissue, different exogenous cannabinoid ligands are able to selectively activate different inhibitory and non-inhibitory Gα protein subtypes, through the activation of CB1 and/or CB2 receptors. Results of the present study may help to understand the specific molecular pathways involved in the pharmacological effects of cannabinoid-derived drugs.