No abstract

Aim To determine whether post‐injury depressive symptoms, and pre‐injury major life stressors and genetic factors (HTR1A C(‐1019)G alleles; rs6295) are more common in children with mild traumatic brain injury (mTBI) who develop postconcussion syndrome (PCS) symptoms compared with children with asymptomatic mTBI. Method This was a cross‐sectional study of 47 symptomatic children (32 males, 15 females; mean age 14y [SD 3y 3mo]) who experienced post‐concussive symptoms for 7 or more days and 42 asymptomatic children (26 males 16 females; mean age 13y 6mo [SD 3y 1mo]) after mTBI. Outcome measures were the Postconcussion Symptoms Inventory (PCSI), the Children's Depression Inventory (CDI), standard questionnaire of previous life events, and buccal DNA analysis to determine genotype and allele frequencies for the HTR1A C(‐1019)G polymorphism. Results Depressive symptoms were uncommon. CDI scores did not differ between groups. Allelic and genotypic frequencies for HTR1A C(‐1019)G were similar in both groups. Symptomatic children continued to have elevated PCS scores compared with asymptomatic children 1.72 (SD 0.69) years later and had experienced significantly more life stressors (Wald (1)=8.51, p=0.004). Interpretation HTR1A polymorphisms do not differ in children with PCS. Children who have experienced more significant life stresses are more likely to develop PCS symptoms after mTBI.

There may be a pediatric syndrome of indomethacin-responsive headache without autonomic symptoms that does not fit well within current diagnostic classifications. More research is needed to determine appropriate dosage and duration of treatment in pediatric indomethacin-responsive headache. Once secondary causes have been ruled out, a trial of indomethacin should be considered in pediatric patients presenting with severe paroxysmal headaches, even if no autonomic symptoms are present.

Neuroligins (NLGNs) are a class of postsynaptic cell adhesion molecules that interact with presynaptic neurexins (NRXNs) and regulate synapse function. NLGN4 is a member of the NLGN family and consists of a unique amino acid sequence in humans that is not evolutionarily well conserved in rodents. The human-specific NLGN4 gene has been reported to be mutated in many patients with autism and other neurodevelopmental disorders. However, it remained unclear how these mutations might alter the molecular properties of NLGN4 and affect synaptic transmission in human neurons. Here, we describe a severely autistic male patient carrying a single amino acid substitution (R101Q) in the NLGN4 gene. When expressed in HEK293 cells, the R101Q mutation in NLGN4 did not affect its binding affinity for NRXNs or its capacity to form homodimers. This mutation, however, impaired the maturation of NLGN4 protein by inhibiting N-linked glycosylation at an adjacent residue (N102), which is conserved in all NLGNs. As a result, the R101Q substitution significantly decreased the surface trafficking of NLGN4 and increased its retention in the endoplasmic reticulum and Golgi apparatus. In human neurons derived from male stem cell lines, the R101Q mutation also similarly reduced the synaptic localization of NLGN4, resulting in a loss-of-function phenotype. This mutation-induced trafficking defect substantially diminished the ability of NLGN4 to form excitatory synapses and modulate their functional properties. Viewed together, our findings suggest that the R101Q mutation is pathogenic for NLGN4 and can lead to synaptic dysfunction in autism.

Lymnaea stagnalis were exposed to hypoxic and chemical challenges while ventilation, heart rate and metabolism were monitored. Hypoxia increased ventilatory behavior, but this response was eliminated by immersion in 0.75 mM nitric oxide synthase (NOS) inhibitor, 7-nitroindazole (7 NI). 7 NI also suppressed ventilatory behavior under normoxia. 10.0 mM L-arginine (ARG, the NOS substrate) increased ventilatory behavior under normoxia, but dampened the hypoxic response. The heart-rate response to NOS inhibition exhibited dose-dependent contradictory characteristics. Under both normoxia and hypoxia 0.25 mM 7 NI increased heart rate, while 0.75 mM 7 NI suppressed it. The effect of 0.50 mM 7 NI depended on whether normoxia or hypoxia was coincident; under normoxia 0.50 mM 7 NI increased heart rate, while under hypoxia this concentration suppressed heart rate. Exposure to ARG did not elicit dose-dependent contradictory responses. Heart rate increased when treated with 10.0 mM ARG under normoxia and hypoxia, while 1.0 mM ARG increased heart rate only under hypoxia. Metabolic responses to NOS inhibition also exhibited dose-dependent contradictory changes. V.O2 decreased over 60% in response to 0.75 mM 7 NI, and baseline V.O2 was restored when exposure ceased. In contrast, 0.25 mM 7 NI increased V.O2 10%, and the increase continued after exposure ceased. 0.50 mM 7 NI decreased V.O2 40%, but V.O2 increased when exposure ceased. ARG had only the effect of increasing V.O2, and only at 10.0 mM concentration. Based on these results and on NO's known role as a neuromodulator, we conclude that the cardio-respiratory responses to hypoxia are, in part, mediated by NO.