Disturbances in the serotonergic system have been recognized in autism. To investigate the association between serotonin and dopamine transporters and autism, we studied 15 children (14 males, one female; mean age 8y 8mo [SD 3y 10mo]) with autism and 10 non-autistic comparison children (five males, five females; mean age 9y 10mo [SD 2y 8mo]) using single-photon emission computed tomography (SPECT) with [ 123 I] nor-b-CIT. The children, with autism were studied during light sedation. They showed reduced serotonin transporter (SERT) binding capacity in the medial frontal cortex, midbrain, and temporal lobe areas. However, after correction due to the estimated effect of sedation, the difference remained significant only in the medial frontal cortex area (p=0.002). In the individuals with autism dopamine transporter (DAT) binding did not differ from that of the comparison group. The results indicate that SERT binding capacity is disturbed in autism. The reduction is more evident in adolescence than in earlier childhood. The low SERT binding reported here and the low serotonin synthesis capacity shown elsewhere may indicate maturation of a lesser number of serotonergic nerve terminals in individuals with autism.

Neuroligins are cell-adhesion molecules located at the postsynaptic side of the synapse. Neuroligins interact with b-neurexins and this interaction is involved in the formation of functional synapses. Mutations in two X-linked neuroligin genes, NLGN3 and NLGN4, have recently been implicated in pathogenesis of autism. The neuroligin gene family consists of five members (NLGN1 at 3q26, NLGN2 at 17p13, NLGN3 at Xq13, NLGN4 at Xp22, and NLGN4Y at Yq11), of which NLGN1 and NLGN3 are located within the best loci observed in our previous genome-wide scan for autism in the Finnish sample. Here, we report a detailed molecular genetic analysis of NLGN1, NLGN3, NLGN4, and NLNG4Y in the Finnish autism sample. Mutation analysis of 30 probands selected from families producing linkage evidence for Xq13 and/or 3q26 loci revealed several polymorphisms, but none of these seemed to be functional. Family-based association analysis in 100 families with autism spectrum disorders yielded only modest associations at NLGN1 (rs1488545, P ¼ 0.002), NLGN3 (DXS7132, P ¼ 0.014), and NLGN4 (DXS996, P ¼ 0.031). We conclude that neuroligin mutations most probably represent rare causes of autism and that it is unlikely that the allelic variants in these genes would be major risk factors for autism.

There has been little exploration of major biologic regulators of cerebral development in autism. We measured insulin-like growth factors (IGF) -1 and -2 from cerebrospinal fluid (CSF) by radio immunoassay in 25 children with autism (median age 5y 5mo; range 1y 11mo-15y 10mo; 20 males, 5 females), and in 16 age-matched comparison children without disability (median age 7y 4mo; range 1y 1mo-15y 2mo; eight males, eight females). IGF-1 and -2 concentrations were further correlated with age of patients and head size. CSF IGF-1 concentration was significantly lower in patients with autism than in the comparison group. The CSF concentrations of children with autism under 5 years of age were significantly lower than their age-matched comparisons. The head circumferences correlated with CSF IGF-1 in children with autism but no such correlation was found in the comparison group. There was no difference between the two groups in CSF IGF-2 concentrations. No patients with autism had macrocephaly. We conclude that low concentrations of CSF IGF-1 at an early age might be linked with the pathogenesis in autism because IGF-1 is important for the survival of Purkinje cells of the cerebellum. The head growth might be explained by the actions of IGF-1 and -2 reflected in CSF concentrations.

There has been little exploration of major biologic regulators of cerebral development in autism. We measured insulin‐like growth factors (IGF) ‐1 and ‐2 from cerebrospinal fluid (CSF) by radio immunoassay in 25 children with autism (median age 5y 5mo; range 1y 11mo‐15y 10mo; 20 males, 5 females), and in 16 age‐matched comparison children without disability (median age 7y 4mo; range 1y 1mo‐15y 2mo; eight males, eight females). IGF‐1 and ‐2 concentrations were further correlated with age of patients and head size. CSF IGF‐1 concentration was significantly lower in patients with autism than in the comparison group. The CSF concentrations of children with autism under 5 years of age were significantly lower than their age‐matched comparisons. The head circumferences correlated with CSF IGF‐1 in children with autism but no such correlation was found in the comparison group. There was no difference between the two groups in CSF IGF‐2 concentrations. No patients with autism had macrocephaly. We conclude that low concentrations of CSF IGF‐1 at an early age might be linked with the pathogenesis in autism because IGF‐1 is important for the survival of Purkinje cells of the cerebellum. The head growth might be explained by the actions of IGF‐1 and ‐2 reflected in CSF concentrations.

A positive effect of fluoxetine has been shown in some children with autism. The present study was undertaken to correlate striatal dopamine transporter (DAT) binding and cerebrospinal fluid insulin-like growth factor-1 (CSF-IGF-1) with clinical response in autistic children (n=13, age 5-16 years) after a 6-month fluoxetine treatment. Good clinical responders (n=6) had a decrease (p=0.031) in DAT binding as assessed using single-photon emission computed tomography with [123I]-nor-β-CIT, whereas poor responders had a trend to an increase. An increase in CSF-IGF-1 (p=0.003) was detected after the treatment period, but no correlation between the clinical response and CSF-IGF-1 was found. In conclusion, fluoxetine decreases DAT binding indicating alleviation of the hyperdopaminergic state and increases CSF-IGF-1 concentration, which may also have a neuroprotective effect against dopamine-induced neurotoxicity in autistic children.