Ketosis often occurs during the postpartum transition period in dairy cows, leading to economic and welfare problems. Previously, ketosis was reported to be associated with hematological and serum ...biochemical parameters. However, the association between the parameters on the calving date and ketosis during the postpartum transition period remains unclear. This study aimed to investigate this association. Blood samples were collected from the jugular vein of Holstein cows on the calving date and β-hydroxybutyrate was tested once every 3 days (8 times in 21 days). The cows were divided into three groups: non-ketosis, subclinical ketosis, and clinical ketosis. The clinical ketosis group significantly had the highest values of mean corpuscular volume, mean corpuscular hemoglobin, β-hydroxybutyrate, non-esterified fatty acids, and total bilirubin, but the lowest values of red cell distribution width, the counts of white blood cell, monocyte, and eosinophil, albumin, alanine transaminase, lactate dehydrogenase, and amylase. In contrast, the non-ketosis group showed the opposite results (p < 0.05). In conclusion, these parameters are associated with the development and severity of ketosis. Our findings suggest that these parameters on the calving date may be useful indicators to identify dairy Holstein cow susceptible to ketosis during the transition period.
Autism spectrum disorder (ASD) is a group of conditions characterized by impaired social interaction and communication, and restricted and repetitive behaviours. ASD is a highly heritable disorder ...involving various genetic determinants. Shank2 (also known as ProSAP1) is a multi-domain scaffolding protein and signalling adaptor enriched at excitatory neuronal synapses, and mutations in the human SHANK2 gene have recently been associated with ASD and intellectual disability. Although ASD-associated genes are being increasingly identified and studied using various approaches, including mouse genetics, further efforts are required to delineate important causal mechanisms with the potential for therapeutic application. Here we show that Shank2-mutant (Shank2(-/-)) mice carrying a mutation identical to the ASD-associated microdeletion in the human SHANK2 gene exhibit ASD-like behaviours including reduced social interaction, reduced social communication by ultrasonic vocalizations, and repetitive jumping. These mice show a marked decrease in NMDA (N-methyl-D-aspartate) glutamate receptor (NMDAR) function. Direct stimulation of NMDARs with D-cycloserine, a partial agonist of NMDARs, normalizes NMDAR function and improves social interaction in Shank2(-/-) mice. Furthermore, treatment of Shank2(-/-) mice with a positive allosteric modulator of metabotropic glutamate receptor 5 (mGluR5), which enhances NMDAR function via mGluR5 activation, also normalizes NMDAR function and markedly enhances social interaction. These results suggest that reduced NMDAR function may contribute to the development of ASD-like phenotypes in Shank2(-/-) mice, and mGluR modulation of NMDARs offers a potential strategy to treat ASD.
Abstract
NMDA receptor (NMDAR) and GABA neuronal dysfunctions are observed in animal models of autism spectrum disorders, but how these dysfunctions impair social cognition and behavior remains ...unclear. We report here that NMDARs in cortical parvalbumin (Pv)-positive interneurons cooperate with gap junctions to promote high-frequency (>80 Hz) Pv neuronal burst firing and social cognition.
Shank2
–/–
mice, displaying improved sociability upon NMDAR activation, show impaired cortical social representation and inhibitory neuronal burst firing. Cortical
Shank2
–/–
Pv neurons show decreased NMDAR activity, which suppresses the cooperation between NMDARs and gap junctions (GJs) for normal burst firing.
Shank2
–/–
Pv neurons show compensatory increases in GJ activity that are not sufficient for social rescue. However, optogenetic boosting of Pv neuronal bursts, requiring GJs, rescues cortical social cognition in
Shank2
–/–
mice, similar to the NMDAR-dependent social rescue. Therefore, NMDARs and gap junctions cooperate to promote cortical Pv neuronal bursts and social cognition.
Autism spectrum disorders (ASDs) are four times more common in males than in females, but the underlying mechanisms are poorly understood. We characterized sexually dimorphic changes in mice carrying ...a heterozygous mutation in Chd8 (Chd8
) that was first identified in human CHD8 (Asn2373LysfsX2), a strong ASD-risk gene that encodes a chromatin remodeler. Notably, although male mutant mice displayed a range of abnormal behaviors during pup, juvenile, and adult stages, including enhanced mother-seeking ultrasonic vocalization, enhanced attachment to reunited mothers, and isolation-induced self-grooming, their female counterparts do not. This behavioral divergence was associated with sexually dimorphic changes in neuronal activity, synaptic transmission, and transcriptomic profiles. Specifically, female mice displayed suppressed baseline neuronal excitation, enhanced inhibitory synaptic transmission and neuronal firing, and increased expression of genes associated with extracellular vesicles and the extracellular matrix. Our results suggest that a human CHD8 mutation leads to sexually dimorphic changes ranging from transcription to behavior in mice.
Shank2 is a multidomain scaffolding protein implicated in the structural and functional coordination of multiprotein complexes at excitatory postsynaptic sites as well as in psychiatric disorders, ...including autism spectrum disorders. While Shank2 is strongly expressed in the cerebellum, whether Shank2 regulates cerebellar excitatory synapses, or contributes to the behavioral abnormalities observed in Shank2
mice, remains unexplored. Here we show that Shank2
mice show reduced excitatory synapse density in cerebellar Purkinje cells in association with reduced levels of excitatory postsynaptic proteins, including GluD2 and PSD-93, and impaired motor coordination in the Erasmus test. Shank2 deletion restricted to Purkinje cells (Pcp2-Cre;Shank2
mice) leads to similar reductions in excitatory synapse density, synaptic protein levels, and motor coordination. Pcp2-Cre;Shank2
mice do not recapitulate autistic-like behaviors observed in Shank2
mice, such as social interaction deficits, altered ultrasonic vocalizations, repetitive behaviors, and hyperactivity. However, Pcp2-Cre;Shank2
mice display enhanced repetitive behavior in the hole-board test and anxiety-like behavior in the light-dark test, which are not observed in Shank2
mice. These results implicate Shank2 in the regulation of cerebellar excitatory synapse density, motor coordination, and specific repetitive and anxiety-like behaviors.
The postsynaptic side of excitatory synapses contains multiprotein complexes, termed the postsynaptic density, which contains receptors, scaffolding/adaptor proteins, and signaling molecules. Shank2 is an excitatory postsynaptic scaffolding protein implicated in the formation and functional coordination of the postsynaptic density and has been linked to autism spectrum disorders. Using Shank2-null mice and Shank2-conditional knock-out mice with a gene deletion restricted to cerebellar Purkinje cells, we explored functions of Shank2 in the cerebellum. We found that Shank2 regulates excitatory synapse density, motor coordination, and specific repetitive and anxiety-like behaviors, but is not associated with autistic-like social deficits or repetitive behaviors.
The diversity of bacteria and their function in cattle gastrointestinal tracts can influence animal welfare. Next-generation sequencing (NGS) was used to investigate microbial diversity in the feces ...of Hanwoo steers reared under natural grazing (GS) and housing (HS) systems. Additionally, serum metabolic parameters, such as liver and kidney markers and mineral and lipid content changes, as well as their correlation with pyrotags, were studied. A total of 6468 ± 87.86 operational taxonomic units (OTUs) were identified in both steer groups, of which 3538 ± 38.17 OTUs were from grazing steer and 2930 ± 94.06 OTUs were from GS. Chao1 index analysis revealed a higher bacterial richness in GS. The dominant bacterial taxa were Bacteroidetes and Firmicutes. GS showed lower Bacteroidetes and higher Firmicutes abundance than HS. The serum of HS showed consistent increases in gamma-glutamyl transpeptidase (γGTP), glucose (GLU), total cholesterol (T-CHO), and triglyceride (TG) levels. The impact of GS on animal health and serum metabolic markers was strongly correlated with microbiota. As shown in this study, grazing has a significant impact on the fecal microbiota at the phylum and family levels, as well as the serum biochemical metabolites of Hanwoo steers.
Autism spectrum disorder involves neurodevelopmental dysregulations that lead to visible symptoms at early stages of life. Many autism spectrum disorder–related mechanisms suggested by animal studies ...are supported by demonstrated improvement in autistic-like phenotypes in adult animals following experimental reversal of dysregulated mechanisms. However, whether such mechanisms also act at earlier stages to cause autistic-like phenotypes is unclear.
We used Shank2−/− mice carrying a mutation identified in human autism spectrum disorder (exons 6 and 7 deletion) and combined electrophysiological and behavioral analyses to see whether early pathophysiology at pup stages is different from late pathophysiology at juvenile and adult stages and whether correcting early pathophysiology can normalize late pathophysiology and abnormal behaviors in juvenile and adult mice.
Early correction of a dysregulated mechanism in young mice prevents manifestation of autistic-like social behaviors in adult mice. Shank2−/− mice, known to display N-methyl-D-aspartate receptor (NMDAR) hypofunction and autistic-like behaviors at postweaning stages after postnatal day 21 (P21), show the opposite synaptic phenotype—NMDAR hyperfunction—at an earlier preweaning stage (∼P14). Moreover, this NMDAR hyperfunction at P14 rapidly shifts to NMDAR hypofunction after weaning (∼P24). Chronic suppression of the early NMDAR hyperfunction by the NMDAR antagonist memantine (P7–P21) prevents NMDAR hypofunction and autistic-like social behaviors from manifesting at later stages (∼P28 and P56).
Early NMDAR hyperfunction leads to late NMDAR hypofunction and autistic-like social behaviors in Shank2−/− mice, and early correction of NMDAR dysfunction has the long-lasting effect of preventing autistic-like social behaviors from developing at later stages.
Netrin-G ligand 2 (NGL-2)/LRRC4, implicated in autism spectrum disorders and schizophrenia, is a leucine-rich repeat-containing postsynaptic adhesion molecule that interacts intracellularly with the ...excitatory postsynaptic scaffolding protein PSD-95 and trans-synaptically with the presynaptic adhesion molecule netrin-G2. Functionally, NGL-2 regulates excitatory synapse development and synaptic transmission. However, whether it regulates synaptic plasticity and disease-related specific behaviors is not known. Here, we report that mice lacking NGL-2 (Lrrc4−/− mice) show suppressed N-Methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity in the hippocampus. NGL-2 associates with NMDARs through both PSD-95-dependent and -independent mechanisms. Moreover, Lrrc4−/− mice display mild social interaction deficits and repetitive behaviors that are rapidly improved by pharmacological NMDAR activation. These results suggest that NGL-2 promotes synaptic stabilization of NMDARs, regulates NMDAR-dependent synaptic plasticity, and prevents autistic-like behaviors from developing in mice, supporting the hypothesis that NMDAR dysfunction contributes to autism spectrum disorders.
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•NGL-2 associates with and clusters NMDA receptors•NGL-2 deletion in mice suppresses synaptic NMDAR function•NGL-2 deletion in mice leads to autistic-like behaviors•Pharmacological NMDAR activation improves autistic-like behaviors
NGL-2 is a postsynaptic adhesion molecule known to regulate synaptic transmission, but whether NGL-2 regulates synaptic plasticity and specific behaviors remains unknown. Um et al. find that mice lacking NGL-2 display suppressed NMDA receptor-dependent synaptic plasticity and autistic-like social deficits and repetitive behaviors that are responsive to NMDA receptor activation.
Background
Ketosis is a common metabolic disorder during the post‐partum transition period of dairy cattle. How the method of reproduction, parturition time, and calf birth weight affect the ...occurrence of ketosis on dairy herds remains elusive.
Objectives
This study investigated factors associated with the severity of ketosis.
Methods
We divided 186 Holstein cows into three classifications based on the highest β‐hydroxybutyrate (BHBA) concentration during the post‐partum transition period, namely non‐ketosis (<1.2 mmol/L, n = 94), subclinical ketosis (1.2–2.9 mmol/L, n = 58), and clinical ketosis (≥3.0 mmol/L, n = 34). We evaluated characteristics of cows associated with the severity of ketosis.
Results
Ketosis was not associated with the method of reproduction, parturition time, pregnancy wastage, premature delivery, retained placenta, and type of calf. Cows calving in spring and especially summer were at higher risk of severe ketosis (p < 0.01). Cows with increased body condition score (BCS) at parturition, age, lactation number, and calving interval were more likely to develop severe ketosis (p < 0.05). Cows with clinical ketosis produced most milk (29.9 ± 1.0 kg) from days four to six, whereas cows without ketosis produced the least (21.3 ± 0.8 kg) (p < 0.001). Heavier calf birth weight resulted in high risk of severe ketosis (p < 0.01), due to increased milk yield during the early lactation.
Conclusions
The severity of ketosis is associated with the calving season, BCS at parturition, age, lactation number, calving interval, milk yield in the early lactation period, and calf birth weight. Nonetheless, it was not associated with the method of reproduction, parturition time, pregnancy wastage, premature delivery, retained placenta, and type of calf. This study is the first to investigate the associations between ketosis and calf birth weight. Our findings could help predict cows at risk of ketosis and take precautions.
This study investigated characteristics of Holstein cows associated with the severity of ketosis during the post‐partum transition period. The severity of ketosis is associated with the calving season, BCS at parturition, age, lactation number, calving interval, milk yield in the early lactation period, and calf birth weight. This study is the first to investigate the associations between ketosis and calf birth weight.
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