No abstract

Several lines of evidence suggest that genetic factors might contribute to the pathogenesis of eating disorders and that brain-derived neurotrophic factor (BDNF) plays a role in the pathophysiology of eating disorders. To investigate the role of the BDNF gene in the susceptibility to eating disorders, we analyzed the BDNF 196G/A gene polymorphism in female patients with eating disorders and female normal controls. The difference in the genotype frequency between patients (n = 198) and normal controls (n = 222) was statistically significant (P = 0.029). Interestingly, a significant (P = 0.015) difference in the genotype frequency between normal controls and bulimia nervosa patients (n = 101) with binge-purging type was detected. This study suggests that the BDNF 196G/A gene polymorphism might be associated with a susceptibility to eating disorders.

Synaptic scaffolding molecule (S-SCAM) interacts with a wide variety of molecules at excitatory and inhibitory synapses. It comprises three alternative splicing variants, S-SCAM␣, -␤, and -␥. We generated mutant mice lacking specifically S-SCAM␣. S-SCAM␣-deficient mice breathe and feed normally but die withinVarious scaffold proteins, such as PSD-95 and gephyrin, play an important role at excitatory and inhibitory synapses in the brain. The physiological importance of these proteins is underscored by the results of studies using mutant mice. PSD-95 mutant mice show impaired learning and lack of neuropathic sensitization (9, 28). Gephyrin-deficient mice fail to suckle and die within 1 day of birth (6). Glycine receptor clustering is disrupted in these mice. Synaptic scaffolding molecule (S-SCAM)/membrane-associated guanylate kinase inverted-2 (MAGI-2) was originally characterized as a scaffold protein interacting with N-methyl-D-aspartate (NMDA) receptors at excitatory synapses (16). The protein comprises a guanylate kinase domain, two WW domains, and PSD-95/Discs large/ Zonula Occludens-1 (PDZ) domains. S-SCAM interacts with various components of excitatory synapses (4). Moreover, we have recently reported that S-SCAM interacts with neuroligin 2 and ␤-dystroglycan at inhibitory synapses in rat hippocampal neurons (42). These interactions of S-SCAM with a wide variety of synaptic molecules lead us to speculate that S-SCAM plays an important role as a scaffold at both excitatory and inhibitory synapses. However, direct evidence that S-SCAM is a critical component of synapses is missing. To address this question, we generated mice lacking S-SCAM.The S-SCAM gene is located on human chromosome 7 and mouse chromosome 5. It spans more than 1.4 Mb. There are three alternative splicing variants, S-SCAM␣, -␤, and -␥, which start with different initiation methionines. S-SCAM␣ is the longest and has an additional N-terminal PDZ domain (17). S-SCAM␤ and -␥ start in the guanylate kinase domain. The exon coding the initiation methionine of S-SCAM␣ is separated by more than 1,000 kb from the first noncoding exon of S-SCAM␤. We replaced the first exon of the coding region of S-SCAM␣ with a neomycin resistance (neo R ) gene cassette

The findings of the present study suggest that glycine and D: -serine but not D: -cycloserine could attenuate PPI deficits associated with NMDA receptor hypofunction via NMDA glycine sites in the brain.

Neuropeptide S (NPS) and its cognate receptor were reported to mediate anxiolytic-like and arousal effects. NPS receptors are predominantly expressed in the brain, especially in limbic structures, including amygdala, olfactory nucleus, subiculum and retrosplenial cortex. In contrast, the NPS precursor is expressed in only a few brainstem nuclei where it is co-expressed with various excitatory transmitters, including glutamate. The current study investigates interactions of the NPS system with glutamatergic neurotransmission. It has been suggested that dysfunctions in glutamatergic neurotransmission via N-methyl-D-aspartate (NMDA) receptors might be involved in the pathophysiology of schizophrenia since NMDA receptor antagonists, such as MK-801, have been shown to induce psychotic-like behavior in humans and animal models. Also, MK-801 is known to produce histological changes such as cytoplasmic vacuoles in retrosplenial cortex neurons where NPS receptors are highly expressed. In this study we show that NPS is able to alleviate neuropathological, neurochemical and behavioral changes produced by NMDA receptor antagonists. NPS treatment attenuated MK-801-induced vacuolization in the rat retrosplenial cortex in a dose dependent manner that can be blocked by an NPS receptor-selective antagonist. NPS also suppressed MK-801-induced increases of extracellular acetylcholine levels in the retrosplenial cortex. In the prepulse inhibition (PPI) assay, animals pretreated with NPS recovered significantly from MK-801-induced disruption of PPI. Our study suggests that NPS may have protective effects against the neurotoxic and behavioral changes produced by NMDA receptor antagonists and that NPS receptor agonists may elicit antipsychotic effects.