It is hypothesized that genetic alterations in oxytocin and vasopressin neurotransmission may account for several features of autism. Oxytocin and vasopressin produced by hypothalamic neurons in the nucleus supraopticus (NSO) and nucleus paraventricularis (NPV) have unique effects on the normal expression of social behavior, attachment behaviors, formation and retention of social memory, communication, and rituals. In autistic subjects the level of oxytocin is reduced (Modahl et al 1998) but the level of C-terminal extended forms of oxytocin is increased which suggests a deficit in oxytocin production and modifications of oxytocin processing (Green et al 2001). Patients with autism spectrum disorders show a significant reduction in repetitive behaviors following oxytocin infusion (Hollander et al 2003).
Objectives:
The aim of this study was to test the hypothesis that development of neurons in the NSO and NPV is modified in autistic subjects and to characterize the type of structural changes by employing unbiased morphometric methods.
Methods:
Brain hemispheres of 13 autistic and 14 control subjects 4 to 64 years of age were fixed in 10% formalin, dehydrated, embedded in celloidin, cut into 200-um-thick serial sections and stained with cresyl violet. Due to incomplete preservation of hypothalamic nuclei the number of examined cases was reduced to 8 autistic (4 to 52 year old) and 10 control (4 to 32 year old) subjects. The fractionator method was used to determine the number of neurons, the Cavalieri method to estimate the volume of the NSO and NPV, and Nucleator method to determine the volume of neurons and neuronal nuclei (Microbrightfield, VT).
Results: The average volume of neuron and neuron nucleus volume in the NSO and NPV were compared in eight autistic and ten control subjects. Ages of autistic subjects ranged from 4 to 52 years (mean 20.2, SD 16.7) and of controls from 4 to 32 years (mean 15.5, SD 10.0). Stepwise regressions on autistic status, age, and their interaction showed neuronal size and nuclear size in the NSO to be significantly smaller in autistic subjects with age controlled. Mean neuronal size in autistic subjects was 3,813 μm3 (SD 1,068 μm3) vs. 4,895 μm3 (SD 1,197 μm3) in controls (t = -2.70, p = .016, controlled for age). Mean nuclear size in autistic subjects was 513 μm3 (SD 164 μm3) vs. 668 μm3 (SD 177 μm3) in controls (t = -2.80, p = .014, controlled for age). Similar pattern was found in the NPV.
Conclusions:
Detected altered trajectory of development of neurons producing oxytocin and vasopressin may contribute to biochemical and behavioral changes observed in autism.
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