Biology subjects

Leza, J. C.

Publications and source records attributed to Leza, J. C..

4 recordsLinked to original sources

bioRxiv2025

Disruption of Reelin signaling in a dual-hit mouse model of schizophrenia: impact of postnatal Δ9-tetrahydrocannabinol exposure in a maternal immune activation model

Since the discovery of the first antipsychotic, pharmacological treatment of schizophrenia (SCZ) has primarily relied on agents that block D2 dopamine receptors. However, due to variability in patient responses, there is a pressing need to identify new biomarkers and therapeutic strategies. In this context, we have developed a dual-hit mouse model that combines maternal immune activation (MIA) induced by polyinosinic-polycytidylic acid (Poly(I:C)) and postnatal exposure to {Delta}9-tetrahydrocannabinol (THC), the psychoactive component of cannabis. We assessed the face validity of this model and investigated potential alterations in the Reelin signaling pathway. Our findings show a reduction in Reelin levels, a new potential key biomarker of SCZ, in the prefrontal cortex of male mice treated with THC compared to the dual-hit group, and across all treatment groups compared to controls in females. Additionally, a decrease in the number of Reelin+ cells was observed across these groups. The dual-hit model exhibited phenotypes indicative of positive symptoms in males, as well as phenotypes associated with negative symptoms in both sexes. Furthermore, the model demonstrated reduced cortical thickness in THC-treated groups, alongside decreased dendritic spine density in both the prefrontal cortex and hippocampus in the dual-hit group.

neuroscience↗

bioRxiv2024

Sex differences in the impact of nerve injury on Locus Coeruleus function and behaviour in mice

Chronic pain often coexists with stress-related disorders such as anxiety and depression, with a higher prevalence in women. Rodent studies reveal significant sex differences in pain and stress-related behaviours, emphasising the need to explore underlying neurobiological mechanisms. The locus coeruleus (LC), the main noradrenergic nucleus in the brainstem, plays a crucial role in modulating pain and stress responses and exhibits sex-specific characteristics. In this study, we investigated the effects of neuropathic pain on the LC in male and female mice, focusing on sensory thresholds, emotional states, and cognitive function. Nerve injury caused immediate sensory hypersensitivity in both sexes, while depressive-like behaviours and cognitive impairments emerged only after prolonged injury. Interestingly, anxiety-like behaviours and heightened fear conditioning were exclusive to males, which correlated with specific structural and functional changes in the male LC, such as increased noradrenergic cell counts, larger somato-dendritic volume, and greater neuron excitability. In females, however, neuronal excitability was reduced. Chemogenetic inhibition of LC neurons alleviated depressive- and anxiety-like behaviours, as well as fear conditioning, but only in males. Overall, neuropathic pain induces distinct behavioural and neurobiological responses in males and females, challenging traditional views on female vulnerability to pain-induced anxiety and highlighting the need for sex-specific LC-targeted therapies.

neuroscience↗

bioRxiv2021

Kynurenine pathway in post-mortem prefrontal cortex and cerebellum in schizophrenia: relationship with monoamines and symptomatology.

Backgroundthe cortico-cerebellar-thalamic-cortical circuit has been implicated in the emergence of psychotic symptoms in schizophrenia (SZ). The kynurenine pathway (KP) has been linked to alterations in glutamatergic and monoaminergic neurotransmission and to SZ symptomatology through the production of the metabolites quinolinic acid (QA) and kynurenic acid (KYNA). Methodsthis work describes alterations in KP in the post-mortem prefrontal cortex (PFC) and cerebellum (CB) of 15 chronic SZ patients and 14 control subjects in PFC and 13 control subjects in CB using immunoblot for protein levels and ELISA for interleukins and QA and KYNA determinations. Monoamine metabolites were analysed by High Performance Liquid Chromatography and SZ symptomatology was assessed by Positive and Negative Syndrome Scale (PANSS). The association of KP with inflammatory mediators, monoamine metabolism and SZ symptomatology was explored. Resultsin the PFC, the presence of the anti-inflammatory cytokine IL-10 together with IDO2 and KATII enzymes decreased in SZ, while TDO and KMO enzymes expression increased. A network interaction analysis showed that in the PFC IL-10 was coupled to the QA branch of the kynurenine pathway (TDO-KMO-QA), whereas IL-10 associated with KMO in CB. KYNA in the CB inversely correlated with negative and general PANSS psychopathology. Although there were no changes in monoamine metabolites content in the PFC in SZ, a network interaction analysis showed associations between dopamine and methoxyhydroxyphenylglycol degradation metabolite. Direct correlations were found between general PANSS psychopathology and the serotonin degradation metabolite, 5-hydroxyindoleacetic acid. Interestingly, KYNA in the CB inversely correlated with 5-hydroxyindoleacetic acid in the PFC. Conclusionsthus, this work found alterations in KP in two brain areas belonging to the cortico-cerebellar-thalamic-cortical circuit associated with SZ symptomatology, with a possible impact across areas in 5-HT degradation.

neuroscience↗

bioRxiv2021

Analysis Of Molecular Networks In The Cerebellum In Chronic Schizophrenia: Modulation By Early Postnatal Life Stressors In Murine Models

Despite the growing importance of the cortico-cerebellar-thalamo-cortical circuit in schizophrenia, limited information is available regarding altered molecular networks in cerebellum. To identify altered protein networks, we conducted proteomic analysis of grey matter of postmortem cerebellar cortex in chronic schizophrenia subjects (n=12) and healthy individuals (n=14) followed by an extensive bioinformatic analysis. Two double-hit postnatal stress murine models for SZ were used to validate the most robust candidates. The models were maternal deprivation combined with an additional stressor: social isolation or chronic restraint stress. We found that the individual proteomic profile allowed the segregation of most schizophrenia cases from healthy individuals. We found 250 proteins with altered levels. This group was enriched in proteins related to mental disorders, mitochondrial disease, stress, and a number of biological functions including energy, immune response, axonal cytoskeletal organization and vesicle-mediated transport. Network analysis identified three modules: energy metabolism, neutrophil degranulation and a mixed module of mainly axonal-related functions. We analysed the most robust candidates in the networks in two double-hit stress murine models. METTL7A from the degranulation pathway was reduced in both models, while NDUFB9 from the energy network and CLASP1 from the axonal module decreased in only one model. This work provides evidence for altered energy, immune and axonal-related networks in the cerebellum in schizophrenia, suggesting that the accumulation of molecular errors, some by an early postnatal stress exposure, could lead to a failure in the normal cerebellar functions, impairing synaptic response and the defence mechanisms of this region against external harmful injuries in schizophrenia.

neuroscience↗