Autism, characterized by profound impairment in social interactions and communicative skills, is the most common neurodevelopmental disorder, and its underlying molecular mechanisms remain unknown. Ca 2+ -dependent activator protein for secretion 2 (CADPS2; also known as CAPS2) mediates the exocytosis of densecore vesicles, and the human CADPS2 is located within the autism susceptibility locus 1 on chromosome 7q. Here we show that Cadps2-knockout mice not only have impaired brain-derived neurotrophic factor release but also show autistic-like cellular and behavioral phenotypes. Moreover, we found an aberrant alternatively spliced CADPS2 mRNA that lacks exon 3 in some autistic patients. Exon 3 was shown to encode the dynactin 1-binding domain and affect axonal CADPS2 protein distribution. Our results suggest that a disturbance in CADPS2-mediated neurotrophin release contributes to autism susceptibility.

Abstract. This study was designed to investigate the therapeutic efficacy of estrogen in female patients with dementia of the Alzheimer type (DAT). Fifteen DAT patients with a mean age of (x ± SE) 71.9 ± 2.4 years were treated with 0.625 mg of conjugated equine estrogens orally twice a day for 6 weeks. Of the 15 DAT patients, 4 were diagnosed as mild, 7 as moderate and 4 as severe. The effects of estrogen on DAT patients were evaluated by psychometric assessments, behavior rating scales, regional cerebral blood flow (rCBF) measurement and quantitative EEG analysis. Psychometric assessments consisted of Mini-Mental State Examination (MMSE) and Hasegawa Dementia Scale (HDS). Dementia syndromes were evaluated by the CBS-Scale (GBSS) and Hamilton Depression Rating Scale (HDRS). During estrogen replacement therapy (ERT), the mean MMSE score (x ± SE) increased significantly from 11.6 ± 1.9 to 13.2 ± 2.0 at 3 weeks (P<0.01) and 13.8 ± 2.0 at 6 weeks (P<0.001). The mean HDS score increased significantly from 8.6 ± 2.1 to 11.5 ± 2.3 at 3 weeks (P<0.001) and 11.6 ± 2.6 at 6 weeks (P<0.01). Significant improvements in the mean scores of the GBSS and HDRS were also observed in the estrogentreated group, but not in the untreated control group with a mean age of 71.2 ± 2.5 years (n=15). The rCBF was measured by single photon emission computed tomography (SPELT). ERT increased the mean rCBF significantly in the lower frontal region (P<0.01) and primary motor area (P<0.02) of the right hemisphere. The mean absolute power delta band values in both left and right frontal EEG (Fp, and Fp2) (P<0.01) and theta1 band values in Fp2 (P<0.05) decreased significantly during ERT. It is inferred that ERT significantly improves cognitive functions, dementia symptoms, regional cerebral blood flow and EEG activity in female patients with DAT.

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