Autism spectrum disorder (ASD) is characterized by deficits in communication, social interaction, and repetitive and stereotyped behaviors, with no specific drug therapy available. Studies have found that cannabidiol (CBD) can improve hyperactive and cognitive symptoms in children with ASD. However, little is known about the effect of CBD in combination with other medications, such as risperidone (RISP). This study aimed to evaluate the behavioral and biochemical effects of CBD in animals using a valproic acid (VPA)-induced ASD animal model. VPA was administered in pregnant Wistar rats on Day 12.5 of gestation to induce the ASD model. From the 10th to the 16th postnatal day (PND), the neurodevelopment of the animals was assessed through eye-opening, olfactory discrimination, and negative geotaxis behavioral tests. From PNDs 9 to 54, the animals were weighed. They were treated for 21 days with CBD alone (100mg/kg, by gavage, twice a day) or in combination with RISP (0.1mg/kg, by gavage, once a day). At PND 55, the animals were evaluated in social interaction and locomotor activity experiments. Finally, after behavioral assessment, the animals were euthanized, the brain was isolated, and oxidative stress parameters were evaluated in the hippocampus and cortex posterior. Animals exposed to VPA showed neurodevelopmental delays in opening their eyes, difficulties in turning around their axis, and took longer time to find the original nest when compared to control animals. They also exhibited impaired sociability and reduced exploratory activity, which indicates model impairments. Interestingly, animals exposed to VPA treated with CBD+RISP significantly improved sociability parameters, whereas isolated CBD did not affect this parameter. In the biochemical analysis, a significant decrease in the hippocampal sulfhydryl content was noted in the CT+CBD group and an increase in the VPA+CBD group. In conclusion, these results suggest that CBD, in combination with RISP, may be an interesting pharmacological approach to reducing ASD-related symptoms. Summary: Besides the increased prevalence of ASD cases in recent years, there are no medications to improve the central symptoms of autism. Numerous studies discuss CBD as an important medication for improving ASD symptoms; however, it is not known how CBD interacts with commonly used drugs in ASD individuals, such as RISP. This study demonstrated that CBD therapy, only when combined with RISP, improved sociability in a VPA-induced ASD animal model.

The term "neurodiversity" refers to the natural heterogeneity in human neurological functioning, which includes neurodevelopmental differences and other mental health conditions (e.g., autism spectrum disorder [ASD], attention-deficit hyperactivity disorder [ADHD], dyslexia, bipolar disorder, schizophrenia, and depression). This new viewpoint has significant consequences for the future of medicine, specifically in psychiatry, neurology, and neurodevelopmental medicine, as it undermines established notions of these conditions as disorders/diseases that may be healed or corrected. The neurodiversity approach, on the other hand, acknowledges these divergences as natural variations, calling for tailored support and interventions that accommodate individual needs. Neurodiversity could impact current medical perspectives by supporting a shift from pathology to identity. Rather than focusing on the difficulties associated with a specific ailment, the neurodiversity approach stresses the strengths and distinct perspectives that come with neurodivergent identities. This shift has significant consequences for research and therapy by fostering the development of innovative treatments aimed at increasing quality of life and improving functional results. This new perspective advocates including neurodivergent people in all sectors of society, including research, clinical practice, and policymaking, by recognizing, accepting, and integrating natural variances in brain functioning. In this article, we review the development of the neurodiversity movement and propose "The Neurodiversity Framework in Medicine," which challenges traditional views by recognizing neurological differences as natural variations, advocating for inclusive, person-centered approaches in healthcare.

Advanced maternal age (AMA) negatively influences the development and cognitive functions of offspring. However, the underlying mechanism remains to be elucidated. As hippocampal autophagy and primary cilia play a crucial role in learning and memory abilities, this study aimed to investigate the effects of AMA on hippocampal autophagy and primary cilia, and to explore their relationship with the changes of LKB1/AMPK signaling pathway in offspring rats. The whole brains and hippocampus of offspring born to 12-month-old (AMA) and 3-month-old (control) Sprague-Dawley (SD) female rats were collected on post-natal days (P) 14, 28, and 60. Transmission electron microscopy was employed to count the number of autophagosomes. The quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting were used to quantify gene expression, and immunofluorescence was used to measure primary cilia. The results revealed that autophagic activity was inhibited from childhood to adulthood in the AMA group. Furthermore, in the early developmental stage, primary ciliogenesis and growth in the hippocampus in the AMA group were impaired, with astrocytes being more severely affected. In addition, the AMA group exhibited an abnormal activation of the LKB1/AMPK signaling pathway. Thus, in offspring born to mothers of AMA, impaired hippocampal primary ciliary function and aberrant activation of the LKB1/AMPK signaling pathway are associated with inhibited autophagic activity.

Observational studies have found that elevated serum homocysteine (Hcy) levels during pregnancy may be associated with the occurrence of neural tube defects (NTDs). However, the effect of Hcy on fetal neural development and its underlying molecular mechanisms remains unclear. To uncover the molecular mechanism, we analyzed the serum Hcy concentration in pregnant women with normal and abnormal pregnancy outcomes and treated zebrafish model embryos with high Hcy. Our findings indicate that elevated serum Hcy levels during pregnancy are associated with adverse pregnancy outcomes. Using the zebrafish model and transcriptome analysis, we found that high Hcy levels led to developmental neural malformations in embryos and affected the expression of key genes at various stages of neural development. Interestingly, deep transcriptome analysis showed that dysregulated heat shock proteins (HSP) might play a key role in high Hcy-mediated alterations in neural development. Importantly, the inhibition of HSP significantly restored the embryonic neuroteratogenic effects induced by high Hcy levels in the zebrafish model. In summary, our findings provide a novel molecular pathogenic mechanism in which ectopic HSP is associated with neural development defects caused by high Hcy levels, suggesting potential prevention and targeted therapies for high Hcy level-related NTDs during pregnancy.

Owing to the high prevalence of gastrointestinal dysfunction in patients, the gut-brain axis is considered to play a vital role in neurodevelopment diseases. Recent pieces of evidence have pointed to the usage of antibiotics at an early developmental stage to be a causative factor in autism due to its ability to induce critical changes in the gut microbiota. The purpose of the study is to determine the neuroprotective effect of capric acid (CA) on autism in antibiotic-induced gut dysbiosis in rodents. In this study, the effect of CA was observed in penicillin V (31mg/kg, p.o.) exposed animals by evaluating their autism-like behavioral and biochemical parameters. The establishment of gut dysbiosis was confirmed by 16 RNA sequencing, and behavioral tests were performed. Subsequently, oxidative stress, cytokine levels, and mitochondrial complex activities in the hippocampus and prefrontal cortex were analyzed. It was observed that the administration of penicillin V during the perinatal period produced gut dysbiosis and long-lasting changes in social behavior with symptoms of anxiety and depression and impaired learning and memory. Treatment with penicillin V also produced oxidative stress, mitochondrial dysfunction, and inflammation in the hippocampus and prefrontal cortex. Treatment with CA produced a positive effect on the alterations with maximum effects evident at 400mg/kg, p.o. through amelioration of behavioral as well as biochemical changes. The current study concluded that CA could act as a likely candidate for the treatment and management of autism via modulation of gut dysbiosis-induced neurobehavioral parameters, oxidative stress, mitochondrial dysfunction, and inflammatory markers.

Growth differentiation factor 15 (GDF15) can be induced under various stress conditions. This study aimed to explore the role of GDF15 in oxygen-glucose deprivation/reoxygenation (OGD/R)-induced HT22 cells. OGD/R was employed to induce the HT22 cell model, and GDF15 expression was upregulated via transfection. Subsequently, the effects on inflammatory factors, oxidative stress markers, apoptosis-related proteins, and ferroptosis markers were detected. Relevant indicators were evaluated using techniques such as ELISA, probes, flow cytometry, and western blotting. Furthermore, changes in these phenotypes under the influence of the endoplasmic reticulum (ER) stress agonist tunicamycin (TM) were evaluated. The result showed that GDF15 was significantly up-regulated in OGD/R-treated HT22 cells. Overexpression of GDF15 significantly reduced the levels of inflammatory factors tumor necrosis factor-α, IL (interleukin)-1β, and IL-6, inhibited the production of reactive oxygen species and MDA, and improved activity of superoxide dismutase and GSH-Px. Flow cytometry and western blotting results showed that GDF15 overexpression significantly reduced cell apoptosis, reduced caspase3 activity, and regulated the expression of Bcl2 and Bax. In addition, overexpression of GDF15 reduces the levels of ferroptosis markers by inhibiting ER stress. ER stress inducer TM can reverse the protective effects of GDF15 overexpression and promote inflammation, oxidative stress, and apoptosis. This study shows that overexpression of GDF15 reduces OGD/R-induced HT22 cell damage, and ER stress-mediated ferroptosis is included in the regulatory mechanisms. This provides a theoretical basis for GDF15 as a new target for the treatment of cerebral ischemia-reperfusion injury.

Acetylcholine (ACh), a vital neurotransmitter for both the peripheral (PNS) and central nervous systems (CNS), signals through nicotinic ACh receptors (nAChRs) and muscarinic ACh receptors (mAChR). Here, we explore the expression patterns of three nAChR subunits, chrna3, chrnb4, and chrna5, which are located in an evolutionary conserved cluster. This close genomic positioning, in a range of vertebrates, may indicate co-functionality and/or co-expression. Through novel transgenic zebrafish lines, we observe widespread expression within both the PNS and CNS. In the PNS, we observed expression of chrna3tdTomato, chrnb4eGFP, and chrna5tdTomato in the intestinal enteric nervous system; chrna5tdTomato and chrnb4eGFP in sensory ganglia of the lateral line; and chrnb4eGFP in the ear. In the CNS, the expression of chrnb4eGFP and chrna5tdTomato was found in the retina, all three expressed in diverse regions of the brain, where a portion of chrna3tdTomato and chrnb4eGFP cells were found to be inhibitory efferent neurons projecting to the lateral line. Within the spinal cord, we identify distinct populations of chrna3tdTomato-, chrnb4eGFP-, and chrna5tdTomato-expressing neurons within the locomotor network, including dmrt3a-expressing interneurons and mnx1-expressing motor neurons. Notably, three to four primary motor neurons per hemisegment were labeled by both chrna3tdTomato and chrnb4eGFP. Interestingly, we identified an sl-type secondary motor neuron per hemisegement that strongly expressed chrna5tdTomato and co-expressed chrnb4eGFP. These transgenic lines provide insights into the potential roles of nAChRs within the locomotor network and open avenues for exploring their role in nicotine exposure and addiction in a range of tissues throughout the nervous system.