Cortical Gene Expression Research Articles

5-HT2A receptor loss does not alter acute fluoxetine-induced anxiety and exhibit sex-dependent regulation of cortical immediate early gene expression.

Background: Acute treatment with the selective serotonin reuptake inhibitor (SSRI), fluoxetine (Flx), induces anxiety-like behavioral effects. The serotonin2A receptor (5-HT2A) is implicated in the modulation of anxiety-like behavior, however its contribution to the anxiogenic effects of acute Flx remains unclear. Here, we examined the role of the 5-HT2A receptor in the effects of acute Flx on anxiety-like behavior, serum corticosterone levels, neural activation and immediate early gene (IEG) expression in stress-responsive brain regions, using 5-HT2A receptor knockout (5-HT2A−/−) mice of both sexes. Methods: 5-HT2A−/− and wild-type (WT) male and female mice received a single administration of Flx or vehicle, and were examined for anxiety-like behavior, serum corticosterone levels, FBJ murine osteosarcoma viral oncogene homolog peptide (c-Fos) positive cell numbers in stress-responsive brain regions of the hypothalamus and prefrontal cortex (PFC), and PFC IEG expression. Results: The increased anxiety-like behavior and enhanced corticosterone levels evoked by acute Flx were unaltered in 5-HT2A−/− mice of both sexes. 5-HT2A−/− female mice exhibited a diminished neural activation in the hypothalamus in response to acute Flx. Further, 5-HT2A−/− male, but not female, mice displayed altered baseline expression of several IEGs (brain-derived neurotrophic factor (Bdnf), Egr2, Egr4, FBJ osteosarcoma gene (Fos), FBJ murine osteosarcoma viral oncogene homolog B (Fosb), Fos-like antigen 2 (Fosl2), Homer scaffolding protein (Homer) 1-3 (Homer1-3), Jun proto-oncogene (Jun)) in the PFC. Conclusion: Our results indicate that the increased anxiety and serum corticosterone levels evoked by acute Flx are not influenced by 5-HT2A receptor deficiency. However, the loss of function of the 5-HT2A receptor alters the degree of neural activation of the paraventricular nucleus (PVN) of the hypothalamus in response to acute Flx, and baseline expression of several IEGs in the PFC in a sexually dimorphic manner.

P37. Analysis of cortical gene expression variability in a mouse model of x-linked infantile spams syndrome

P37. Analysis of cortical gene expression variability in a mouse model of x-linked infantile spams syndrome

Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor.

Lysergic acid diethylamide (LSD) has agonist activity at various serotonin (5-HT) and dopamine receptors. Despite the therapeutic and scientific interest in LSD, specific receptor contributions to its neurobiological effects remain unknown. We therefore conducted a double-blind, randomized, counterbalanced, cross-over studyduring which 24 healthy human participants received either (i) placebo+placebo, (ii) placebo+LSD (100 µg po), or (iii) Ketanserin, a selective 5-HT2A receptor antagonist,+LSD. We quantified resting-state functional connectivity via a data-driven global brain connectivity method and compared it to cortical gene expression maps. LSD reduced associative, but concurrently increased sensory-somatomotor brain-wide and thalamic connectivity. Ketanserin fully blocked the subjective and neural LSD effects. Whole-brain spatial patterns of LSD effects matched 5-HT2A receptor cortical gene expression in humans. Together, these results strongly implicate the 5-HT2A receptor in LSD’s neuropharmacology. This study therefore pinpoints the critical role of 5-HT2A in LSD’s mechanism, which informs its neurobiology and guides rational development of psychedelic-based therapeutics. Funded by the Swiss National Science Foundation, the Swiss Neuromatrix Foundation, the Usona Institute, the NIH, the NIAA, the NARSAD Independent Investigator Grant, the Yale CTSA grant, and the Slovenian Research Agency. NCT02451072

Sequence Alterations of Cortical Genes Linked to Individual Connectivity of the Human Brain.

Individual differences in humans are driven by unique brain structural and functional profiles, presumably mediated in part through differential cortical gene expression. However, the relationships between cortical gene expression profiles and individual differences in large-scale neural network organization remain poorly understood. In this study, we aimed to investigate whether the magnitude of sequence alterations in regional cortical genes mapped onto brain areas with high degree of functional connectivity variability across individuals. First, human genetic expression data from the Allen Brain Atlas was used to identify protein-coding genes associated with cortical areas, which delineated the regional genetic signature of specific cortical areas based on sequence alteration profiles. Thereafter, we identified brain regions that manifested high degrees of individual variability by using test-retest functional connectivity magnetic resonance imaging and graph-theory analyses in healthy subjects. We found that rates of genetic sequence alterations shared a distinct spatial topography with cortical regions exhibiting individualized (highly-variable) connectivity profiles. Interestingly, gene expression profiles of brain regions with highly individualized connectivity patterns and elevated number of sequence alterations are devoted to neuropeptide-signaling-pathways and chemical-synaptic-transmission. Our findings support that genetic sequence alterations may underlie important aspects of brain connectome individualities in humans. Significance Statement: The neurobiological underpinnings of our individuality as humans are still an unsolved question. Although the notion that genetic variation drives an individual's brain organization has been previously postulated, specific links between neural connectivity and gene expression profiles have remained elusive. In this study, we identified the magnitude of population-based sequence alterations in discrete cortical regions and compared them to the brain topological distribution of functional connectivity variability across an independent human sample. We discovered that brain regions with high degree of connectional individuality are defined by increased rates of genetic sequence alterations; these findings specifically implicated genes involved in neuropeptide-signaling pathways and chemical-synaptic transmission. These observations support that genetic sequence alterations may underlie important aspects of the emergence of the brain individuality across humans.

Transcranial Direct Current Stimulation (tDCS) in Mice.

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique proposed as an alternative or complementary treatment for several neuropsychiatric diseases. The biological effects of tDCS are not fully understood, which is in part explained due to the difficulty in obtaining human brain tissue. This protocol describes a tDCS mouse model that uses a chronically implanted electrode allowing the study of the long-lasting biological effects of tDCS. In this experimental model, tDCS changes the cortical gene expression and offers a prominent contribution to the understanding of the rationale for its therapeutic use.

Long-Lasting Effects of Prenatal Ethanol Exposure on Fear Learning and Development of the Amygdala

Prenatal ethanol exposure (PrEE) produces developmental abnormalities in brain and behavior that often persist into adulthood. We have previously reported abnormal cortical gene expression, disorganized neural circuitry along with deficits in sensorimotor function and anxiety in our CD-1 murine model of fetal alcohol spectrum disorders, or FASD (El Shawa et al., 2013; Abbott et al., 2016). We have proposed that these phenotypes may underlie learning, memory, and behavioral deficits in humans with FASD. Here, we evaluate the impact of PrEE on fear memory learning, recall and amygdala development at two adult timepoints. PrEE alters learning and memory of aversive stimuli; specifically, PrEE mice, fear conditioned at postnatal day (P) 50, showed deficits in fear acquisition and memory retrieval when tested at P52 and later at P70–P72. Interestingly, this deficit in fear acquisition observed during young adulthood was not present when PrEE mice were conditioned later, at P80. These mice displayed similar levels of fear expression as controls when tested on fear memory recall. To test whether PrEE alters development of brain circuitry associated with fear conditioning and fear memory recall, we histologically examined subdivisions of the amygdala in PrEE and control mice and found long-term effects of PrEE on fear memory circuitry. Thus, results from this study will provide insight on the neurobiological and behavioral effects of PrEE and provide new information on developmental trajectories of brain dysfunction in people prenatally exposed to ethanol.

Abnormalities in Prefrontal Cortical Gene Expression Profiles Relevant to Schizophrenia in MK-801-Exposed C57BL/6 Mice

MK-801, a non-competitive NMDA receptor (NMDAR) antagonist, disturbs NMDAR function in rodents and induces psychological and behavioral changes similar to schizophrenia (SCZ). However, the effects of MK-801 treatment on gene expression are largely unknown. Here we performed RNA-sequencing on the prefrontal cortex of MK-801-exposed male mice in order to analyze gene expression and co-expression patterns related to SCZ and to identify mechanisms that underlie the molecular etiology of this disorder. Transcriptome analysis revealed that the differentially expressed genes were more often associated with biological processes that included postsynaptic transmission, immune system process, response to external stimulus and hemostasis. In order to extract comprehensive biological information, we used an approach for biclustering, called FABIA, to simultaneously cluster transcriptomic data across genes and conditions. When combined with analyses using DAVID and STRING databases, we found that co-expression patterns were altered in synapse-related genes and genes central to the mitochondrial network. Abnormal co-expression of genes mediating synaptic vesicle cycling could disturb release, uptake and reuptake of glutamate, and the perturbation in co-expression patterns for mitochondrial respiratory chain complexes was extensive. Our study supports the hypothesis that research using MK-801-exposed male mice as an animal model of SCZ offers important insights into the pathogenesis of SCZ.

Abnormalities in behaviour, histology and prefrontal cortical gene expression profiles relevant to schizophrenia in embryonic day 17 MAM-Exposed C57BL/6 mice

Gestational and perinatal disruption of neural development increases the risk of developing schizophrenia (SCZ) later in life. Embryonic day 17 (E17) methylazoxymethanol (MAM) treatment leads to histological, physiological and behavioural abnormalities in post-puberty rats that model the neuropathological and cognitive deficits reported in SCZ patients. However, the validity of E17 MAM-exposed mice to model SCZ has not been explored. Here we treated E17 C57BL/6 mouse dams with various dosages of MAM. We found that this mouse strain was more vulnerable to MAM treatment than rats and there were gender differences in behavioural abnormalities, histological changes and prefrontal cortical gene expression profiles in MAM (7.5 mg/kg)-exposed mice. Both male and female MAM-exposed mice had deficits in prepulse inhibition. Female MAM-exposed mice exhibited mildly increased spontaneous locomotion activity and social recognition deficits, while male mice were normal. Consistently, only female MAM-exposed mice exhibited reduced brain weight, decreased size of prefrontal cortex (PFC) and enlarged lateral ventricles. Transcriptome analysis of the PFC revealed that there were more differentially expressed genes in female MAM-exposed mice than those in male mice. Moreover, expression of Pvalb, Arc and genes in their association networks were downregulated in the PFC of female MAM-exposed mice. These results indicate that E17 MAM-exposure in C57BL/6 mice leads to behavioural changes that model certain deficits reported in SCZ patients. MAM-exposed female mice may be used to study gene expression changes, inhibitory neural circuit dysfunction and glutamatergic synaptic plasticity deficits with a possible relation to those in the brains of SCZ patients.

Differential Effects of Statins on Motor and Sensory Compared with Cortical Gene Expression Patterns (P1.465)

Differential Effects of Statins on Motor and Sensory Compared with Cortical Gene Expression Patterns (P1.465)

Aged Mouse Cortical Microglia Display an Activation Profile Suggesting Immunotolerogenic Functions.

Microglia are the resident immune cells of the central nervous system (CNS) and participate in physiological and pathological processes. Their unique developmental nature suggests age-dependent structural and functional impairments that might contribute to neurodegenerative diseases. In the present study, we addressed the age-dependent changes in cortical microglia gene expression patterns and the expression of M1- and M2-like activation markers. Iba1 immunohistochemistry, isolation of cortical microglia followed by fluorescence-activated cell sorting and RNA isolation to analyze transcriptional changes in aged cortical microglia was performed. We provide evidence that aging is associated with decreased numbers of cortical microglia and the establishment of a distinct microglia activation profile including upregulation of Ifi204, Lilrb4, Arhgap, Oas1a, Cd244 and Ildr2. Moreover, flow cytometry revealed that aged cortical microglia express increased levels of Cd206 and Cd36. The data presented in the current study indicate that aged mouse cortical microglia adopt a distinct activation profile, which suggests immunosuppressive and immuno-tolerogenic functions.

Synaptic and transcriptionally downregulated genes are associated with cortical thickness differences in autism

Differences in cortical morphology—in particular, cortical volume, thickness and surface area—have been reported in individuals with autism. However, it is unclear what aspects of genetic and transcriptomic variation are associated with these differences. Here we investigate the genetic correlates of global cortical thickness differences (ΔCT) in children with autism. We used Partial Least Squares Regression (PLSR) on structural MRI data from 548 children (166 with autism, 295 neurotypical children and 87 children with ADHD) and cortical gene expression data from the Allen Institute for Brain Science to identify genetic correlates of ΔCT in autism. We identify that these genes are enriched for synaptic transmission pathways and explain significant variation in ΔCT. These genes are also significantly enriched for genes dysregulated in the autism post-mortem cortex (Odd Ratio (OR) = 1.11, Pcorrected 10−14), driven entirely by downregulated genes (OR = 1.87, Pcorrected 10−15). We validated the enrichment for downregulated genes in two independent data sets: Validation 1 (OR = 1.44, Pcorrected = 0.004) and Validation 2 (OR = 1.30; Pcorrected = 0.001). We conclude that transcriptionally downregulated genes implicated in autism are robustly associated with global changes in cortical thickness variability in children with autism.

Changed frontal pole gene expression suggest altered interplay between neurotransmitter, developmental, and inflammatory pathways in schizophrenia

Schizophrenia (Sz) probably occurs after genetically susceptible individuals encounter a deleterious environmental factor that triggers epigenetic mechanisms to change CNS gene expression. To determine if omnibus changes in CNS gene expression are present in Sz, we compared mRNA levels in the frontal pole (Brodmann’s area (BA) 10), the dorsolateral prefrontal cortex (BA 9) and cingulate cortex (BA 33) from 15 subjects with Sz and 15 controls using the Affymetrix™ Human Exon 1.0 ST Array. Differences in mRNA levels (±≥20%; p < 0.01) were identified (JMP Genomics 5.1) and used to predict pathways and gene x gene interactions that would be affected by the changes in gene expression using Ingenuity Pathway Analysis. There was significant variation in mRNA levels with diagnoses for 566 genes in BA 10, 65 genes in BA 9 and 40 genes in BA 33. In Sz, there was an over-representation of genes with changed expression involved in inflammation and development in BA 10, cell morphology in BA 9 and amino acid metabolism and small molecule biochemistry in BA 33. Using 94 genes with altered levels of expression in BA 10 from subjects with Sz, it was possible to construct an interactome of proven direct gene x gene interactions that was enriched for genes in inflammatory, developmental, oestrogen, serotonergic, cholinergic and NRG1 regulated pathways. Our data shows complex, regionally specific changes in cortical gene expression in Sz that are predicted to affect homeostasis between biochemical pathways already proposed to be important in the pathophysiology of the disorder.

Comparative profiling of cortical gene expression in Alzheimer\u2019s disease patients and mouse models demonstrates a link between amyloidosis and neuroinflammation

Alzheimer’s disease (AD) is the most common form of dementia, characterized by accumulation of amyloid β (Aβ) and neurofibrillary tangles. Oxidative stress and inflammation are considered to play an important role in the development and progression of AD. However, the extent to which these events contribute to the Aβ pathologies remains unclear. We performed inter-species comparative gene expression profiling between AD patient brains and the AppNL-G-F/NL-G-F and 3xTg-AD-H mouse models. Genes commonly altered in AppNL-G-F/NL-G-F and human AD cortices correlated with the inflammatory response or immunological disease. Among them, expression of AD-related genes (C4a/C4b, Cd74, Ctss, Gfap, Nfe2l2, Phyhd1, S100b, Tf, Tgfbr2, and Vim) was increased in the AppNL-G-F/NL-G-F cortex as Aβ amyloidosis progressed with exacerbated gliosis, while genes commonly altered in the 3xTg-AD-H and human AD cortices correlated with neurological disease. The AppNL-G-F/NL-G-F cortex also had altered expression of genes (Abi3, Apoe, Bin2, Cd33, Ctsc, Dock2, Fcer1g, Frmd6, Hck, Inpp5D, Ly86, Plcg2, Trem2, Tyrobp) defined as risk factors for AD by genome-wide association study or identified as genetic nodes in late-onset AD. These results suggest a strong correlation between cortical Aβ amyloidosis and the neuroinflammatory response and provide a better understanding of the involvement of gender effects in the development of AD.

M101. Different Changes in Cortical Gene Expression in Subjects With Schizophrenia, With and Without Low Muscarinic M1 Receptors, Predict Different Pathways are Involved in the Pathophysiologies of the Two Sub-groups

Abstract Background: We tested the hypothesis that changes in gene expression in the dorsolateral prefrontal cortex (DLPFC) from 2 sub-groups of subjects with schizophrenia, one with a marked deficit in muscarinic M1 receptors (MRDS), would identify different biochemical pathways that would be affected by their aetiologies. Methods: We measured levels of mRNA in Brodmann’s area 9 from 15 MRDS, 15 subjects with schizophrenia but without a deficit in muscarinic M1 receptors (non-MRDS) and 15 Controls using Affymetrix Exon 1.0 ST arrays. Results: There were changes in mRNA levels for 65 genes only in the cortex of subjects with MRDS and these changes predicted changes in pathways involved in cellular movement and cell-to-cell signaling. Levels of mRNA for 45 genes were changed non-MRDS and these changes predicted changes in pathways involved in cellular growth and proliferation as well as cellular function and maintenance. At the level of schizophrenia, changes in gene expression predicted effects on pathways involved in amino acid metabolism, molecular transport and small molecule biochemistry in both MRDS and non-MRDS. Conclusion: Our data argues a prominent role for glial function in MRDS and neurodevelopment in non-MRDS. Our study gives new insight into the molecular pathways affected in the cortex of subjects with MRDS and supports the notion that studying sub-groups within the syndrome of schizophrenia is worthwhile.

Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism.

Autism spectrum disorder (ASD) involves substantial genetic contributions. These contributions are profoundly heterogeneous but may converge on common pathways that are not yet well understood. Here, through post-mortem genome-wide transcriptome analysis of the largest cohort of samples analysed so far, to our knowledge, we interrogate the noncoding transcriptome, alternative splicing, and upstream molecular regulators to broaden our understanding of molecular convergence in ASD. Our analysis reveals ASD-associated dysregulation of primate-specific long noncoding RNAs (lncRNAs), downregulation of the alternative splicing of activity-dependent neuron-specific exons, and attenuation of normal differences in gene expression between the frontal and temporal lobes. Our data suggest that SOX5, a transcription factor involved in neuron fate specification, contributes to this reduction in regional differences. We further demonstrate that a genetically defined subtype of ASD, chromosome 15q11.2-13.1 duplication syndrome (dup15q), shares the core transcriptomic signature observed in idiopathic ASD. Co-expression network analysis reveals that individuals with ASD show age-related changes in the trajectory of microglial and synaptic function over the first two decades, and suggests that genetic risk for ASD may influence changes in regional cortical gene expression. Our findings illustrate how diverse genetic perturbations can lead to phenotypic convergence at multiple biological levels in a complex neuropsychiatric disorder.

Differential effects of social isolation in adolescent and adult mice on behavior and cortical gene expression

Intact function of the medial prefrontal cortex (mPFC) function relies on proper development of excitatory and inhibitory neuronal populations and on integral myelination processes. Social isolation (SI) affects behavior and brain circuitry in adulthood, but previous rodent studies typically induced prolonged (post-weaning) exposure and failed to directly compare between the effects of SI in adolescent and adulthood. Here, we assessed the impact of a 3-week SI period, starting in mid-adolescence (around the onset of puberty) or adulthood, on a wide range of behaviors in adult male mice. Additionally, we asked whether adolescent SI would differentially affect the expression of excitatory and inhibitory neuronal markers and myelin-related genes in mPFC. Our findings indicate that mid-adolescent or adult SI increase anxiogenic behavior and locomotor activity. However, SI in adolescence uniquely affects the response to the psychotomimetic drug amphetamine, social and novelty exploration and performance in reversal and attentional set shifting tasks. Furthermore, adolescent but not adult SI increased the expression of glutamate markers in the adult mPFC. Our results imply that adolescent social deprivation is detrimental for normal development and may be particularly relevant to the investigation of developmental psychopathology.

Gonadectomy prevents the increase in blood pressure and glomerular injury in angiotensin-converting enzyme 2 knockout diabetic male mice. Effects on renin-angiotensin system.

Angiotensin-converting enzyme 2 (ACE2) deletion worsens kidney injury, and its amplification ameliorates diabetic nephropathy. Male sex increases the incidence, prevalence, and progression of chronic kidney disease in our environment. Here, we studied the effect of ACE2 deficiency and gonadectomy (GDX) on diabetic nephropathy and its relationship with fibrosis, protein kinase B (Akt) activation, and the expression of several components of the renin-angiotensin system (RAS).Mice were injected with streptozotocin to induce diabetes and followed for 19 weeks. Physiological and renal parameters were studied in wild-type and ACE2 knockout (ACE2KO) male mice with and without GDX. Diabetic ACE2KO showed increased blood pressure (BP), glomerular injury, and renal fibrosis compared with diabetic wild-type. Gonadectomized diabetic ACE2KO presented a decrease in BP. In the absence of ACE2, GDX attenuated albuminuria and renal lesions, such as mesangial matrix expansion and podocyte loss. Both, α-smooth muscle actin accumulation and collagen deposition were significantly decreased in renal cortex of gonadectomized diabetic ACE2KO but not diabetic wild-type mice. GDX also reduced circulating ACE activity in ACE2KO mice. Loss of ACE2 modified the effect of GDX on cortical gene expression of RAS in diabetic mice. Akt phosphorylation in renal cortex was increased by diabetes and loss of ACE2 and decreased by GDX in control and diabetic ACE2KO but not in wild-type mice. Our results suggest that GDX may exert a protective effect within the kidney under pathological conditions of diabetes and ACE2 deficiency. This renoprotection may be ascribed to different mechanisms such as decrease in BP, modulation of RAS, and downregulation of Akt-related pathways.

Connectome Disconnectivity and Cortical Gene Expression in Patients With Schizophrenia

BackgroundGenome-wide association studies have identified several common risk loci for schizophrenia (SCZ). In parallel, neuroimaging studies have shown consistent findings of widespread white matter disconnectivity in patients with SCZ. MethodsWe examined the role of genes in brain connectivity in patients with SCZ by combining transcriptional profiles of 43 SCZ risk genes identified by the recent genome-wide association study of the Schizophrenia Working Group of the Psychiatric Genomics Consortium with data on macroscale connectivity reductions in patients with SCZ. Expression profiles of 43 Psychiatric Genomics Consortium SCZ risk genes were extracted from the Allen Human Brain Atlas, and their average profile across the cortex was correlated to the pattern of cortical disconnectivity as derived from diffusion-weighted magnetic resonance imaging data of patients with SCZ (n = 48) and matched healthy controls (n = 43). ResultsThe expression profile of SCZ risk genes across cortical regions was significantly correlated with the regional macroscale disconnectivity (r = .588; p = .017). In addition, effects were found to be potentially specific to SCZ, with transcriptional profiles not related to cortical disconnectivity in patients with bipolar I disorder (diffusion-weighted magnetic resonance imaging data; 216 patients, 144 controls). Further examination of correlations across all 20,737 genes present in the Allen Human Brain Atlas showed the set of top 100 strongest correlating genes to display significant enrichment for the disorder, potentially identifying new genes involved in the pathophysiology of SCZ. ConclusionsOur results suggest that under disease conditions, cortical areas with pronounced expression of risk genes implicated in SCZ form central areas for white matter disconnectivity.

Postsynaptic density protein transcripts are differentially modulated by minocycline alone or in add-on to haloperidol: Implications for treatment resistant schizophrenia.

In this study, we investigated whether minocycline, a second-generation tetracycline proposed as an add-on to antipsychotics in treatment-resistant schizophrenia (TRS), may affect the expression of Homer and Arc postsynaptic density (PSD) transcripts, implicated in synaptic regulation. Minocycline was administered alone or with haloperidol in rats exposed or not to ketamine, mimicking acute glutamatergic psychosis or naturalistic conditions, respectively. Arc expression was significantly reduced by minocycline compared with controls. Minocycline in combination with haloperidol also significantly reduced Arc expression compared with both controls and haloperidol alone. Moreover, haloperidol/minocycline combination significantly affected Arc expression in cortical regions, while haloperidol alone was ineffective on cortical gene expression. These results suggest that minocycline may strongly affect the expression of Arc as mediated by haloperidol, both in terms of quantitative levels and of topography of haloperidol-related expression. It is noteworthy that no significant pre-treatment effect was found, suggesting that pre-exposure to ketamine did not grossly affect gene expression. Minocycline was not found to significantly affect haloperidol-related Homer1a expression. No significant changes in Homer1b/c expression were observed. These results are consistent with previous observations that minocycline may modulate postsynaptic glutamatergic transmission, affecting distinct downstream pathways initiated by N-methyl-D-aspartate (NMDA) receptor modulation, i.e. Arc-mediated but not Homer1a-mediated pathways.

Angiotensin II type 1 receptor blockade by telmisartan prevents stress-induced impairment of memory via HPA axis deactivation and up-regulation of brain-derived neurotrophic factor gene expression

Physical and psychological aspects of chronic stress continue to be a persistent clinical problem for which new pharmacological treatment strategies are aggressively sought. By the results of our previous work it has been demonstrated that telmisartan (TLM), an angiotensin type 1 receptor (AT1) blocker (ARB) and partial agonist of peroxisome proliferator-activated receptor gamma (PPARγ), alleviates stress-induced cognitive decline. Understanding of mechanistic background of this phenomenon is hampered by both dual binding sites of TLM and limited data on the consequences of central AT1 blockade and PPARγ activation. Therefore, a critical need exists for progress in the characterization of this target for pro-cognitive drug discovery. An unusual ability of novel ARBs to exert various PPARγ binding activities is commonly being viewed as predominant over angiotensin blockade in terms of neuroprotection. Here we aimed to verify this hypothesis using an animal model of chronic psychological stress (Wistar rats restrained 2.5h daily for 21days) with simultaneous oral administration of TLM (1mg/kg), GW9662 — PPARγ receptor antagonist (0.5mg/kg), or both in combination, followed by a battery of behavioral tests (open field, elevated plus maze, inhibitory avoidance — IA, object recognition — OR), quantitative determination of serum corticosterone (CORT) and evaluation of brain-derived neurotrophic factor (BDNF) gene expression in the medial prefrontal cortex (mPFC) and hippocampus (HIP). Stressed animals displayed decreased recall of the IA behavior (p<0.001), decreased OR (p<0.001), substantial CORT increase (p<0.001) and significantly downregulated expression of BDNF in the mPFC (p<0.001), which were attenuated in rats receiving TLM and TLM+GW9662. These data indicate that procognitive effect of ARBs in stressed subjects do not result from PPAR-γ activation, but AT1 blockade and subsequent hypothalamus–pituitary–adrenal axis deactivation associated with changes in primarily cortical gene expression. This study confirms the dual activities of TLM that controls hypertension and cognition through AT1 blockade.