Toward a Therapy for Autism Spectrum Disorder: The Formyl Peptide Receptor 2 Agonist MR-39 Supports Synaptic Health in the BTBR Mouse and Features a Favorable Safety Profile.

In vivo imaging of synaptic density in psychotropic-free adults with autism spectrum disorder: a [¹¹C]UCB-J PET study.

PT320, a GLP-1 receptor agonist, mitigates nucleus accumbens–associated depression- and anxiety-like behaviors in MitoPark mice of Parkinson's disease

Background Neuropsychiatric symptoms such as anxiety and depression substantially impair quality of life in Parkinson's disease (PD), yet the underlying neural circuits remain poorly defined. The MitoPark (MP) mouse, a dopaminergic mitochondrial dysfunction model, recapitulates both motor and non-motor features of PD. Objective To determine whether the sustained-release GLP-1 receptor agonist PT320 (exenatide) alleviates anxiety- and depression-like behaviors in MP mice and to identify the involved neural substrates. Methods The temporal progression of anxiety- and depression-like behaviors was characterized in MP mice. PT320 was administered biweekly starting at either 5 weeks (early treatment) or 15 weeks (late treatment), with longitudinal evaluation until 20 weeks. Behavioral outcomes were correlated with molecular, transcriptomic, and neurochemical analyses in the nucleus accumbens (NAc), including Western blotting, bulk RNA sequencing, fast-scan cyclic voltammetry, and tyrosine hydroxylase immunostaining. Results Early PT320 treatment effectively prevented the emergence of anxiety- and depression-like phenotypes in MP mice. Behavioral improvement was associated with restoration of BDNF signaling and activation of the Akt–CREB pathway in the NAc. Transcriptomic analysis revealed increased expression of Akt3, CREB, BDNF, and TrkB, along with modulation of genes related to mitochondrial homeostasis. Late PT320 treatment partially ameliorated neuropsychiatric deficits, coinciding with enhanced phasic dopamine release and recovery of tyrosine hydroxylase expression in the NAc. Conclusions These findings identify the NAc as a critical regulator of affective disturbances in this PD model. By restoring neurotrophic signaling and dopaminergic function, PT320 represents a promising therapeutic strategy for PD-related anxiety and depression.

Cellular, electrophysiological and behavioral improvements in a mouse model of Rett syndrome following gene therapy combined with focused ultrasound-mediated blood-brain barrier opening.

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder due to pathogenic variants in the methyl CpG binding protein 2 gene (MECP2). The discovery that deficits resulting from Mecp2 loss are reversible in mice has increased interest in gene therapy as a potential cure for RTT. We have previously evaluated the efficacy of a self-complementary AAV9 vector expressing a codon-optimized version of Mecp2 (scAAV9-MCO) delivered via a systemic approach in early symptomatic Mecp2-knock-out male (KO) mice. In the present study, focused ultrasound (FUS) was used to transiently disrupt the blood-brain barrier (BBB) in a RTT mouse model, thereby facilitating enhanced AAV delivery to the central nervous system (CNS). Our findings demonstrate that scAAV9-MCO administration, when combined with FUS, significantly improves survival, body weight, respiratory function, and locomotor activity, while restoring the excitatory-inhibitory synaptic balance in hippocampal neurons in treated KO mice relative to untreated animals. Quantification of the brain infection level revealed that 20-40% of cells are Mecp2-positive in the brain of KO mice following the treatment with scAAV9-MCO and FUS. This is a significant improvement compared to prior results without FUS. The evaluation of the protein levels indicates a possible overdose of Mecp2 protein in the brain cells. Nevertheless, these results demonstrate that using FUS following systemic administration of an AAV9 vector represents a significant improvement over classical gene therapy protocol for RTT.

Trigonelline attenuates valproic acid-induced autism-like behaviours in rats: histopathological changes of the hippocampus, modulation of gene expressions related to neuroinflammation and blood-brain barrier permeability.

BACKGROUND Autism spectrum disorders (ASD) is a neurodevelopmental disorder. Neuroinflammation and bloodbrain barrier (BBB) dysfunction have role in the pathophysiology of ASD. Trigonelline (TRI) exerted neuroprotective effects. We aimed to investigate TRI's effects on autistic phenotype, gene expression of tight junction proteins associated with BBB integrity, neuroinflammation and histopathological changes in the hippocampus in valproic acid (VPA) - induced autism in rats. METHODS Pregnant Wistar rats received single subcutaneous injection of VPA (600mg/kg) on day 12 of gestation. Animals were treated with normal saline or TRI for one week. Repetitive behaviours, anxiety-like behaviour, memory function, and social interactions were assessed. The thickness and dark neurons of the CA1 and CA3 regions of hippocampus were examined. The inflammatory genes, including Tlr4, Tnf-α, and Il-1β, along with claudins (Cldn -3, Cldn-5, and Cldn-12), were measured in the hippocampus. RESULTS TRI significantly attenuated autistic behaviors. TRI reduced the expression of inflammatory markers and modulated the expression of claudins. TRI increased the thickness and decreased the number of dark neurons in the CA1 and CA3 regions. CONCLUSIONS TRI reduced autistic behaviours probably through attenuation of neuroinflammation, preservation of the hippocampus, and modulation of gene expressions of tight junction proteins associated with the BBB permeability.

Long-term effects of adolescent risperidone treatment on the mouse cortex

Since the introduction of second-generation antipsychotics, antipsychotics have been increasingly prescribed for children and adolescents, raising concerns about their long-term impact on neurodevelopment. Antipsychotics block dopaminergic and serotonergic receptors, potentially disrupting the maturation of neurocognitive processes, which is a public health concern. Previous studies have reported that adolescent antipsychotic treatment can cause persistent neurocognitive dysfunction in rodents, yet the neurobiological underpinnings remain unknown. To address this, we administered risperidone, a commonly used antipsychotic, to C57BL/6 mice during adolescence (3 to 6 weeks of age) and examined behavioral and neurobiological outcomes nine weeks post-treatment. Risperidone-treated mice exhibited subtle deficits in behavioral correlates of anxiety-like behavior. In vivo, two-photon calcium imaging of cortical neurons revealed a remarkable increase in the amplitude of calcium events with subtle sex-specific changes in the frequency, consistent with increased neuronal excitability. Single-nucleus RNA-sequencing (snRNA-seq) analyses showed widespread reductions in transcripts for voltage-sensitive and inwardly rectifying potassium channels in both pyramidal neurons and interneurons. Additionally, both cell types exhibited reduced Grin2a and Grin2b, as well as scaffolding proteins, indicative of weakened synaptic connectivity between excitatory and inhibitory neurons. Interestingly, we observed sex-dependent differences in the directionality of correlation between certain gene co-expression modules and risperidone treatment. Our results suggest that adolescent risperidone treatment induces lasting transcriptomic and functional changes associated with altered excitatory-inhibitory neuronal interactions that may underline cognitive and behavioral dysregulations.

Neuromodulatory roles of the sigma-1 receptor in behavior and drug sensitization during development.