Autism spectrum disorder (ASD) is a group of developmental pathologies that impair social communication and cause repetitive behaviors. The suggested roles of noncoding RNAs in pathology led us to perform a comparative analysis of the microRNAs expressed in the serum of human ASD patients. The analysis of a cohort of 45 children with ASD revealed that six microRNAs (miR-19a-3p, miR-361-5p, miR-3613-3p, miR-150-5p, miR-126-3p, and miR-499a-5p) were expressed at low to very low levels compared to those in healthy controls. A similar but less pronounced decrease was registered in the clinically unaffected parents of the sick children and in their siblings but never in any genetically unrelated control. Results consistent with these observations were obtained in the blood, hypothalamus and sperm of two of the established mouse models of ASD: valproic acid-treated animals and Cc2d1a +/− heterozygotes. In both instances, the same characteristic miRNA profile was evidenced in the affected individuals and inherited together with disease symptoms in the progeny of crosses with healthy animals. The consistent association of these genetic regulatory changes with the disease provides a starting point for evaluating the changes in the activity of the target genes and, thus, the underlying mechanism(s). From the applied societal and medical perspectives, once properly confirmed in large cohorts, these observations provide tools for the very early identification of affected children and progenitors. Autism spectrum disorders (ASDs) encompass a range of disorders characterized by impaired social interactions and communications, together with repetitive stereotypic behaviors (refs. 1-5 for recent reviews). The genetic architecture underlying the range of ASD symptoms has been investigated (reviewed by Iakoucheva et al. 1). Mutations in more than 100 genes involved in brain development and neural activity have been identified in patients and are thought to confer a risk for ASD 2,3 , but a constant association that would suggest a causal relationship has not been observed. The same conclusion was recently reached from a large-scale exon sequencing analysis 4. Hence, mouse models that reproduce characteristic elements of the disease have been developed 5. As in other instances, attention has recently been focused on a peculiar class of regulatory alterations that modifies noncoding (nc) RNAs 6 with putative regulatory functions in the synthesis of proteins. One class of these alterations comprises the genes encoding 22 nt-long RNA (often abbreviated miRNAs) that regulate the expression of homologous target genes by blocking translation and inducing the degradation of the mRNAs 7. Among the miRNA genes in the mammalian genome (several hundred in the human genome), a large subset is expressed in the brain 8 , and dysfunctions of particular miRNAs have been tentatively associated with neuropathological conditions, including ASD 9,10 , with however diverging patterns of expression. They may reflect still unknown complexities of the dis...

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Manipulations of thyroid hormones have been shown to influence learning and memory. Although a large body of literature is available on the effect of thyroid hormone deficiency on learning and memory functions during the developmental stage, electrophysiological and behavioural findings, particularly on propylthiouracil administration to adult normothyroid animals, are not satisfactory. The experiments in the present study were carried out on 12 adult male Wistar rats aged 6-7 months. Hypothyroidism was induced by administering 6-n-propyl-2-thiouracil in their drinking water for 21 days at a concentration of 0.05%. The spatial learning performance of hypothyroid and control rats was studied on a Y-maze. The rats were then placed in a stereotaxic frame under urethane anaesthesia. A bipolar tungsten electrode was used to stimulate the medial perforant path. A glass micropipette was inserted into the granule cell layer of the ipsilateral dentate gyrus to record field excitatory post-synaptic potentials. After a 15-min baseline recording of field potentials, long-term potentiation was induced by four sets of tetanic trains. The propylthiouracil-treated rats showed a significantly attenuated input-output (I/O) relationship when population spike (PS) amplitudes and field excitatory post-synaptic potentials (fEPSP) were compared. fEPSP and PS latencies were found to be longer in the hypothyroid group than in the control group. The PS amplitude and fEPSP slope potentiations in the hypothyroid rats were not statistically different from those in the control rats, except for the field EPSP slope measured in the post-tetanic and maintenance phases. The hypothyroid rats also showed lower thyroxine levels and poor performance in the spatial memory task. The present study provides in vivo evidence for the action of propylthiouracil leading to impaired synaptic plasticity, which might explain deficit in spatial memory tasks in adult hypothyroid rats.

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Background: Manipulating thyroid hormones has been shown to influence learning and memory. Although a large body of literature is available on the effects of thyroid hormone deficiency on learning and memory functions during developmental or adult-onset hypothyroidism, electrophysiological findings are limited. This limitation is especially notable with respect to thyroxine administration in adult, normothyroid animals. Methods: Experiments were carried out on 12 adult male Wistar rats, each 9–10 months of age. Rats were randomly divided into hyperthyroid (0.2 mg/kg/day intraperitoneal thyroxine injection, for 21 days) and control groups (n = 6 animals in each group). Following spatial learning performance tests on hyperthyroid and control groups, rats were anesthetized with urethane and placed in a stereotaxic frame. A bipolar, tungsten electrode was used to stimulate the medial perforant path. A glass micropipette was inserted within the granule cell layer of the ipsilateral dentate gyrus to record field excitatory postsynaptic potentials (fEPSP). Following a 15-min baseline recording of fEPSPs, long-term potentiation (LTP) was induced by four sets of tetanic pulse trains. Results: Thyroxine-treated rats showed significantly worse performance in the spatial memory task and attenuated input-output relationships in the electrophysiological analyses. Treated rats also showed a lower efficacy of LTP induction when compared with controls. Conclusion: The present study provides clear in vivo evidence for the action of L-thyroxine in the impairment of synaptic plasticity and in inducing spatial memory task deficits in adult rats. These findings may explain the complaints of cognitive function reductions in hyperthyroid patients.