SUMMARY Adult brain function and behavior are influenced by neuronal network formation during development. Genetic susceptibility factors for adult psychiatric illnesses, such as Neuregulin-1 and Disrupted-in-Schizophrenia-1 (DISC1), influence adult high brain functions, including cognition and information processing. These factors have roles during neurodevelopment and are likely to cooperate, forming “pathways” or “signalosomes.” Here we report the potential to generate an animal model via in utero gene transfer in order to address an important question of how nonlethal deficits in early development may affect postnatal brain maturation and high brain functions in adulthood, which are impaired in various psychiatric illnesses, such as schizophrenia. We show that transient knockdown of DISC1 in the pre- and peri-natal stages, specifically in a lineage of pyramidal neurons mainly in the prefrontal cortex, leads to selective abnormalities in postnatal mesocortical dopaminergic maturation and behavioral abnormalities associated with disturbed cortical neurocircuitry after puberty.

A new gene, termed klotho, is associated with the suppression of several aging phenotypes. Because high expression of klotho gene was detected in the brain, it would be plausible that klotho gene is involved in the regulation of brain aging. We investigated the changes in mnemonic function accompanying aging in klotho mutant mice. Cognitive function measured by novel-object recognition and conditioned-fear tests in klotho mutant mice was normal at the age of 6 wk, but markedly impaired at the age of 7 wk. Lipid (malondialdehyde) and DNA (8-hydroxy-2'-deoxyguanosine) peroxide levels in the hippocampus of klotho mutant mice increased at the age of 5 wk, 2 wk before the development of cognition deficits. Pro-death Bax increased, whereas anti-death Bcl-2 and Bcl-XL decreased, and apoptotic TUNEL-positive cells were detected in the hippocampus of klotho mutant mice at the age of 7 wk. A potent antioxidant, a-tocopherol, prevented cognition impairment and lipid peroxide accumulation and decreased the number of apoptotic cells in klotho mutant mice. These results suggest that oxidative stress has a crucial role in the aging-associated cognition impairment in klotho mutant mice. Klotho protein may be involved in the regulation of antioxidative defense.

The peptide nociceptin (also named orphanin FQ) acts in the brain to produce various pharmacological effects, including hyperalgesia and hypolocomotion. The nociceptin receptor uses guanine-nucleotide-binding proteins to mediate the inhibition of adenylyl cyclase, the activation of potassium channels and inhibition of calcium channels. It has been shown using knock-out mice that the nociceptin receptor is not required for regulation of nociceptive responses or locomotion activity, but modulates the auditory function. Here we show that mice lacking the nociceptin receptor possess greater learning ability and have better memory than control mice. Histological analysis revealed the expression of both the nociceptin precursor and the nociceptin receptor in the hippocampus, thought to take part in aspects of learning and memory. Moreover, the receptor-deficient mice showed larger long-term potentiation in the hippocampal CA1 region than control mice, without apparent changes in presynaptic or postsynaptic electrophysiological properties. These results show that the loss of the nociceptin receptor results in a gain-of-function mutation in both the memory process and the long-term potentiation mechanism in CA1, perhaps as a result of altered intracellular signal transduction systems in neurons.

A subtle but chronic alteration in metabolic balance between amyloid-␤ peptide (A␤) anabolic and catabolic activities is thought to cause A␤ accumulation, leading to a decade-long pathological cascade of Alzheimer disease. However, it is still unclear whether a reduction of the catabolic activity of A␤ in the brain causes neuronal dysfunction in vivo. In the present study, to clarify a possible connection between a reduction in neprilysin activity and impairment of synaptic and cognitive functions, we cross-bred amyloid precursor protein (APP) transgenic mice (APP23) with neprilysin-deficient mice and biochemically and immunoelectron-microscopically analyzed A␤ accumulation in the brain. We also examined hippocampal synaptic plasticity using an in vivo recording technique and cognitive function using a battery of learning and memory behavior tests, including Y-maze, novel-object recognition, Morris water maze, and contextual fear conditioning tests at the age of 13-16 weeks. We present direct experimental evidence that reduced activity of neprilysin, the major A␤-degrading enzyme, in the brain elevates oligomeric forms of A␤ at the synapses and leads to impaired hippocampal synaptic plasticity and cognitive function before the appearance of amyloid plaque load. Thus, reduced neprilysin activity appears to be a causative event that is at least partly responsible for the memory-associated symptoms of Alzheimer disease. This supports the idea that a strategy to reduce A␤ oligomers in the brain by up-regulating neprilysin activity would contribute to alleviation of these symptoms. Accumulation of amyloid-␤ peptide (A␤)4 is a triggering event leading to a decade-long pathological cascade of Alzheimer disease (AD) (1, 2). A subtle but chronic alteration in metabolic balance between A␤ anabolic and catabolic activities could result in A␤ accumulation and change monomeric A␤ to pathogenic forms (3,4). Neprilysin is an A␤-degrading enzyme first identified as a major in vivo peptidase capable of hydrolyzing synthetic multiple-radiolabeled A␤ injected into rat hippocampus (5). A genetic deficiency in neprilysin results in an elevation of A␤ levels in the mouse brain (6). Transgenic or viral expression of neprilysin in the brains of amyloid precursor protein (APP) transgenic mice consistently leads to marked attenuation of A␤ pathology (7-9). The exposure of APP transgenic mice to an enriched environment is reported to result in pronounced deceleration in cerebral A␤ levels and amyloid deposits with a concomitant elevation of brain neprilysin activity (10). Neprilysin is a presynaptic membrane-associated ectoenzyme with an extracellular active site, and it is involved in A␤ degradation at presynaptic sites (9,11,12). A recent study showed that somatostatin causes selective reduction of A␤ 42 by promoting the surface appearance of neprilysin on the presynaptic membrane (13). Down-regulation of neprilysin in the hippocampus and cerebral cortex with aging (14,15) and at an early stage of AD development (15-17) suggests a cl...