Background Consistent with postmortem findings in patients, most animal models for schizophrenia (SCZ) present abnormal levels of parvalbumin (PV), a marker of fast-spiking GABAergic interneurons, in the prefrontal cortex (PFC) and hippocampus (HIP). However, there are discrepancies in the literature. PV reductions lead to a functional loss of PV interneurons, which is proposed to underly SCZ symptoms. Given its complex etiology, different categories of animal models have been developed to study SCZ, which may distinctly impact PV levels in rodent brain areas. Study Design We performed a quantitative meta-analysis on PV-positive cell number/density and expression levels in the PFC and HIP of animal models for SCZ based on pharmacological, neurodevelopmental, and genetic manipulations. Results Our results confirmed that PV levels are significantly reduced in the PFC and HIP regardless of the animal model. By categorizing into subgroups, we found that all pharmacological models based on NMDA receptor antagonism decreased PV-positive cell number/density or PV expression levels in both brain areas examined. In neurodevelopmental models, abnormal PV levels were confirmed in both brain areas in maternal immune activation models and HIP of the methylazoxymethanol acetate model. In genetic models, negative effects were found in neuregulin 1 and ERBB4 mutant mice in both brain regions and the PFC of dysbindin mutant mice. Regarding sex differences, male rodents exhibited PV reductions in both brain regions only in pharmacological models, while few studies have been conducted in females. Conclusion Overall, our findings support deficits in prefrontal and hippocampal PV interneurons in animal models for SCZ.

Background and Hypothesis Stress during adolescence is a major risk factor for schizophrenia. We have found previously in rats that adolescent stress caused, in adulthood, behavioral changes and enhanced ventral tegmental area (VTA) dopamine system activity, which were associated with dysregulation of the excitatory-inhibitory (E/I) balance in the ventral hippocampus (vHip). Levetiracetam, an anticonvulsant drug, regulates the release of neurotransmitters, including glutamate, via SV2A inhibition. It also modulates parvalbumin interneuron activity via Kv3.1 channels. Therefore, levetiracetam could ameliorate deficits in the E/I balance. We tested whether levetiracetam attenuate the adolescent stress-induced behavioral changes, vHip hyperactivity, and enhanced VTA dopamine system activity in adult rats. Study Design Male Sprague-Dawley rats were subjected to a combination of daily footshock (postnatal day [PD] 31–40), and three 1 h-restraint stress sessions (at PD31, 32, and 40). In adulthood (PD62), animals were tested for anxiety responses (elevated plus-maze and light-dark box), social interaction, and cognitive function (novel object recognition test). The activity of vHip pyramidal neurons and VTA dopamine neurons was also recorded. Study Results Adolescent stress produced anxiety-like responses and impaired sociability and cognitive function. Levetiracetam (10 mg/kg) reversed these changes. Levetiracetam also reversed the increased VTA dopamine neuron population activity and the enhanced firing rate of vHip pyramidal neurons induced by adolescent stress. Conclusions These findings suggest that levetiracetam attenuates the adverse outcomes associated with schizophrenia caused by stress during adolescence.

Higher levels of interleukin (IL)-6 and elevated neutrophil counts are consistently reported in the blood of patients with schizophrenia. Stressors during childhood and/or adolescence are major socioenvironmental risk factors for schizophrenia and may contribute to immune dysregulation. Previous studies using blood cytokines to stratify patients with schizophrenia suggest that only a subset presents a low-grade inflammatory state. However, these studies have not addressed whether environmental factors such as childhood maltreatment contributed to identifying inflammatory clusters. Moreover, a neutrophil-related mechanism (Neutrophil Extracellular Traps; NETs) central to both the initiation and chronicity of autoimmune and inflammatory diseases has never been investigated in psychiatry. Elevated NETs in schizophrenia may predispose patients to inflammatory and autoimmune diseases resulting in reduced life expectancy. We, therefore, investigated NETs as a novel mechanism and biological target in early schizophrenia and their role together with IL-6 and childhood maltreatment in identifying cluster subgroups. We found increased NETs in the plasma of patients with early schizophrenia (n = 78) compared to both their unaffected siblings (n = 25) and community controls (n = 78), irrespective of sex, body mass index, psychoactive drug use, or tobacco smoking. Increased NETs in patients were unrelated to antipsychotic treatment, which was further tested in vitro using fresh neutrophils. By applying unsupervised two-step clustering analysis, we integrated values of NETs, IL-6, and childhood maltreatment scores. We identified two main clusters; childhood maltreatment scores and NETs were the most important variables contributing to cluster separation (high-CL1 and low-CL2), while IL-6 was the least contributor. Patients allocated in the high-CL1 (61.5%) had significantly higher childhood maltreatment scores, NETs, and IL-6 levels than the remaining groups (patients low-CL2, siblings, and controls high-CL1 and low-CL2). We complemented these findings with a rat model based on stress exposure during adolescence that results in several schizophrenia-like changes in adulthood. We found that adolescent stressed rats had higher NETs and IL-6 levels in serum compared to non-stressed rats with a tendency to produce more NETs from the bone marrow. Altogether, this study brings a novel cellular-based mechanism in schizophrenia that, combined with early-stress, could be useful to identify subgroups for more personalised treatments.

Pesticides, as Temephos and Roundup, and surfactants, like Sodium Dodecyl Sulfate (SDS), when discharged into the environment, are harmful to non-target wildlife, especially fish. To evaluate the effects of those chemicals alone and their binary combinations, we assessed the histological alterations in Danio rerio gills after 15 days of exposure to Temephos (1ppm), Roundup (10ppm), SDS (2ppm), SDS plus Temephos (2ppm+1ppm), SDS plus Roundup (2ppm+10ppm) and Temephos plus Roundup (1ppm+10ppm). Hyperplasia, a regressive change, was significant in all exposed groups. The progressive change, complete fusion of lamellae, was significantly intensive in Roundup plus Temephos group. Regarding circulatory disturbances, vascular congestion was significant intensive in SDS group, while severe aneurysm was observed in Roundup group. Although xenobiotics in the blend are biologically complex, mainly for long periods, combinatorial exposure incremented only complete fusion of lamellae. Our results reinforce the rationalization of indiscriminate use of those compounds alone or in combination.

Alpha-adrenergic receptors are crucial regulators of vascular hemodynamics and essential pharmacological targets for cardiovascular diseases. With aging, there is an increase in sympathetic activation, which could contribute to the progression of aging-associated cardiovascular dysfunction, including stroke. Nevertheless, there is little information directly associating adrenergic receptor dysfunction in the blood vessels of aged females. This study determined the role of a-adrenergic receptors in carotid dysfunction of senescent female mice (accelerated-senescence prone, SAMP8), compared to a non-senescent (accelerated-senescence prone, SAMR1). Vasoconstriction to phenylephrine (Phe) were markedly increased in common carotid artery of SAMP8 (AUC: 527±53) compared to SAMR1 (AUC: 334±30, p= 0.006). There were no changes in vascular responses to the vasoconstrictor agent U46619 or the vasodilators acetylcholine (ACh) and sodium nitroprusside (NPS). Hyperactivity to Phe in female SAMP8 was reduced by cyclooxygenase-1 and cyclooxygenase-2 inhibition and associated with augmented ratio of TXA2/PGI2 release (SAMR1: 1.1±0.1 vs. SAMP8: 2.1±0.3, p= 0.007). However, no changes in cyclooxygenase expression were seen in SAMP8 carotids. Selective a1A receptor antagonism markedly reduced maximal contraction, while a1D antagonism induced a minor shift in Phe contraction in SAMP8 carotids. Ligand binding analysis revealed a 3-fold increase of α-adrenergic receptor density in smooth muscle cells (VSMC) of SAMP8 versus SAMR1. Phe rapidly increased intracellular calcium (iCa+2) in VSMC via the a1A receptor, with a higher peak in VSMC from SAMP8,. In conclusion, senescence intensifies vasoconstriction mediated by a1A-adrenergic signaling in the carotid of female mice by mechanisms involving increased iCa+2 and release of cyclooxygenase-derived prostanoids.