CCDC88C variants are associated with focal epilepsy and genotype-phenotype correlation.

CCDC88C gene, which encodes coiled-coil domain containing 88C, is essential for cell communication during neural development. Variants in the CCDC88C caused congenital hydrocephalus, some accompanied by seizures. In patients with epilepsy without acquired etiologies, we performed whole-exome sequencing (trio-based). Two de novo and two biallelic CCDC88C variants were identified in four cases with focal (partial) epilepsy. These variants did not present or had low frequencies in the gnomAD populations and were predicted to be damaging by multiple computational algorithms. Patients with de novo variants presented with adult-onset epilepsy, whereas patients with biallelic variants displayed infant-onset epilepsy. They all responded well to anti-seizure medications and were seizure-free. Further analysis showed that de novo variants were located at crucial domains, whereas one paired biallelic variants were located outside the crucial domains, and the other paired variant had a non-classical splicing and a variant located at crucial domain, suggesting a sub-molecular effect. CCDC88C variants associated with congenital hydrocephalus were all truncated, whereas epilepsy-associated variants were mainly missense, the proportion of which was significantly higher than that of congenital hydrocephalus-associated variants. CCDC88C is potentially associated with focal epilepsy with favorable outcome. The underlying mechanisms of phenotypic variation may correlation between genotype and phenotype.

[Analysis of CNNM2 gene variant in a child with Hypomagnesemia, seizures, and mental retardation syndrome].

OBJECTIVE: To explore the genetic etiology of a child with Hypomagnesemia, epilepsy and mental retardation syndrome (HSMR). METHODS: A child who was admitted to the Children's Hospital of Shandong University on July 9, 2021 due to repeated convulsions for 2 months was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples of the child and his pedigree members were collected for the extraction of genomic DNA. Whole exome sequencing was carried out, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. RESULTS: The child, a 1-year-and-7-month-old male, had presented with epilepsy and global developmental delay. Serological testing revealed that he has low serum magnesium. Genetic testing showed that the child has harbored a heterozygous c.1448delT (p.Val483GlyfsTer29) variant of the CNNM2 gene, which was de novo in origin. The variant has caused substitution of the Valine at position 483 by Glycine and formation of a termination codon after 29 amino acids at downstream. As predicted by Swiss-Model online software, the variant may alter the protein structure, resulting in a truncation. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.1448delT (p.Val483GlyfsTer29) was predicted as a pathogenic variant (PVS1+PS2+PM2_Supporting+PP4). CONCLUSION: The heterozygous c.1448delT variant of the CNNM2 gene probably underlay the HSMR in this child. Above finding has enriched the phenotype-genotype spectrum of the CNNM2 gene.

Effects of curcumin on chronic, unpredictable, mild, stress-induced depressive-like behaviour and structural plasticity in the lateral amygdala of rats.

Depression is a neuropsychiatric disease associated with wide ranging disruptions in neuronal plasticity throughout the brain. Curcumin, a natural polyphenolic compound of curcuma loga, has been demonstrated to be effective in the treatment of depressive-like disorders. The present study aimed to investigate the mechanisms underlying the antidepressant-like effects of curcumin in a rat model of chronic, unpredictable, mild, stress (CUMS) -induced depression. The results showed that CUMS produced depressive-like behaviours in rats, which were associated with ultra-structural changes in neurons within the lateral amygdala (LA). In addition, the expression of synapse-associated proteins such as brain-derived neurotrophic factor (BDNF), PSD-95 and synaptophysin were significantly decreased in the LA of CUMS-treated rats. Chronic administration of curcumin (40 mg/kg, i.p. 6 wk) before stress exposure significantly prevented these neuronal and biochemical alterations induced by CUMS, and suppressed depressive-like behaviours, suggesting that this neuronal dysregulation may be related to the depressive-like behaviours caused by CUMS. Together with our previous results, the current findings demonstrate that curcumin exhibits neuroprotection and antidepressant-like effects in the CUMS-induced depression model. Furthermore, this antidepressant-like action of curcumin appears to be mediated by modulating synapse-associated proteins within the LA. These findings provide new insights into the underlying mechanisms leading to neural dysfunction in depression and reveal the therapeutic potential for curcumin use in clinical trials.

Recessive LAMA5 Variants Associated With Partial Epilepsy and Spasms in Infancy.

Objective: The LAMA5 gene encodes the laminin subunit α5, the most abundant laminin α subunit in the human brain. It forms heterotrimers with the subunit ß1/ß2 and γ1/γ3 and regulates neurodevelopmental processes. Genes encoding subunits of the laminin heterotrimers containing subunit α5 have been reported to be associated with human diseases. Among LAMAs encoding the laminin α subunit, LAMA1-4 have also been reported to be associated with human disease. In this study, we investigated the association between LAMA5 and epilepsy. Methods: Trios-based whole-exome sequencing was performed in a cohort of 118 infants suffering from focal seizures with or without spasms. Protein modeling was used to assess the damaging effects of variations. The LAMAs expression was analyzed with data from the GTEX and VarCards databases. Results: Six pairs of compound heterozygous missense variants in LAMA5 were identified in six unrelated patients. All affected individuals suffered from focal seizures with mild developmental delay, and three patients presented also spasms. These variants had no or low allele frequencies in controls and presented statistically higher frequency in the case cohort than in controls. The recessive burden analysis showed that recessive LAMA5 variants identified in this cohort were significantly more than the expected number in the East Asian population. Protein modeling showed that at least one variant in each pair of biallelic variants affected hydrogen bonds with surrounding amino acids. Among the biallelic variants in cases with only focal seizures, two variants of each pair were located in different structural domains or domains/links, whereas in the cases with spasms, the biallelic variants were constituted by two variants in the identical functional domains or both with hydrogen bond changes. Conclusion: Recessive LAMA5 variants were potentially associated with infant epilepsy. The establishment of the association between LAMA5 and epilepsy will facilitate the genetic diagnosis and management in patients with infant epilepsy.

Curcumin ameliorates ethanol-induced memory deficits and enhanced brain nitric oxide synthase activity in mice.

Ethanol consumption has well-known deleterious effects on memory. However, the mechanism by which ethanol exerts its effects on memory has received little attention, which has retarded the identification and development of effective therapeutic strategies against ethanol toxicity. The aim of this study was to explore the neuronal mechanisms underlying the protective action of curcumin, a natural polyphenolic compound of Curcuma longa, against ethanol-induced memory deficits. Adult mice were pretreated with curcumin (40 mg/kg, i.p.) before administration of ethanol (1 g/kg, i.p.) for the memory acquisition measurement, or were sacrificed 30 min later for evaluation of regional brain differences in the nitric oxide synthase (NOS) activity and nitric oxide (NO) concentration. The results showed that pretreatment with curcumin significantly ameliorated the memory deficits resulting from acute ethanol administration to mice in the novel object recognition and inhibitory avoidance tasks. Furthermore, acute ethanol treatment increased the NOS activity and NO production in brain regions associated with memory including prefrontal cortex (PFC), amygdala and hippocampus, while this enhancement was suppressed by pretreatment with curcumin. Taken together, these results suggest that the protective effects of curcumin on acute ethanol-induced memory deficits are mediated, at least in part, by suppressing NOS activity in the brain of mice. Thus, manipulation of the NOS/NO signaling pathway might be beneficial for the prevention of ethanol toxicity.

Curcumin ameliorates memory deficits via neuronal nitric oxide synthase in aged mice.

A number of neuroprotective effects of curcumin have been demonstrated in recent years. However, whether curcumin exerts any beneficial effects on age-related impaired cognition and memory has not been well characterized; nor was there any detailed data on the molecular pathways activated by curcumin. The present study attempts to investigate the effects of curcumin on memory decline of aged mice with a focus upon the possible contribution of the neuronal nitric oxide synthase (nNOS)/nitric oxide (NO) pathway in the memory amelioration effect of curcumin. The results showed that chronic administration of curcumin (50mg/kg, i.p., 21 days) significantly ameliorated the memory acquisition ability of aged male mice in the novel object recognition and passive avoidance tasks. Immunoblotting revealed that chronic treatment of curcumin increased nNOS expression in the prefrontal cortex, amygdala and hippocampus, as well as the enhancement of nNOS activity and NO concentration. This enhancement was suppressed by pre-treatment with 7-nitroindazole (7-NI), a specific inhibitor of neuronal nitric oxide synthase (nNOS). Furthermore, inhibition of nNOS synthase by 7-NI also prevented the memory improvement effects of curcumin in aged mice. Taken together, the results of the present study suggest that the amelioration of memory deficits by curcumin in aged mice was mediated, at least in part, by activating the nNOS activity in specific brain regions. These findings reveal the therapeutic potential of curcumin as a preventive agent upon the deterioration of cognitive faculties.

Neotrofin reverses the effects of chronic unpredictable mild stress on behavior via regulating BDNF, PSD-95 and synaptophysin expression in rat.

Depression is one of the most common neuropsychiatric disorders and has been associated with a wide range of neuronal structural changes in brain regions. Neotrofin, a neurotrophin agonist, has been demonstrated to exhibit neuroprotection in various in vivo and in vitro studies. The present study aimed to investigate the neuroprotective and ameliorating effects of neotrofin treatment in a rat model of chronic unpredictable mild stress (CUMS) induced depression. The results showed that CUMS was effective in producing depression-like behavior in rats as indicated by decreased responses in the sucrose preference test, and locomotor activity in the open-field test. Moreover, the expression of brain-derived neurotrophic factor (BDNF), PSD-95 and synaptophysin were decreased in the amygdala of CUMS rats. Chronic administration of neotrofin (60mg/kg, i.p., 5 weeks) significantly ameliorated all these behavioral and biochemical alterations associated with CUMS induced depression, which demonstrated that the expression changes of BDNF, PSD-95 and synaptophysin were correlated with the depression-like behaviors of CUMS rats. Taken together, the results of the present study highlight that neotrofin exhibits neuroprotective and antidepressant-like effects against CUMS induced depression, and suggest a possible mechanism for this protection via changes in synaptic plasticity within the amygdala. These findings reveal the therapeutic potential of neotrofin for use in clinical trials in the treatment of neuronal deterioration in depression.