Smoking is not only associated with NPC risk in individuals from China but is also associated with EBV seropositivity in healthy males and is involved in EBV activation.

Heterozygous reeler mice (HRM) haploinsufficient for reelin express Ϸ50% of the brain reelin content of wild-type mice, but are phenotypically different from both wild-type mice and homozygous reeler mice. They exhibit, (i) a down-regulation of glutamic acid decarboxylase 67 (GAD67)-positive neurons in some but not every cortical layer of frontoparietal cortex (FPC), (ii) an increase of neuronal packing density and a decrease of cortical thickness because of neuropil hypoplasia, (iii) a decrease of dendritic spine expression density on basal and apical dendritic branches of motor FPC layer III pyramidal neurons, and (iv) a similar decrease in dendritic spines expressed on the basal dendrite branches of CA1 pyramidal neurons of the hippocampus. To establish whether the defect of GAD67 down-regulation observed in HRM is responsible for neuropil hypoplasia and decreased dendritic spine density, we studied heterozygous GAD67 knockout mice (HG67M). These mice exhibited a down-regulation of GAD 67 mRNA expression in FPC (about 50%), but they expressed normal amounts of reelin and had no neuropil hypoplasia or down-regulation of dendritic spine expression. These findings, coupled with electron-microscopic observations that reelin colocalizes with integrin receptors on dendritic spines, suggest that reelin may be a factor in the dynamic expression of cortical dendritic spines perhaps by promoting integrin receptor clustering. These findings are interesting because the brain neurochemical and neuroanatomical phenotypic traits exhibited by the HRM are in several ways similar to those found in postmortem brains of psychotic patients. B rain postmortem studies from patients with schizophrenia reveal a characteristic pattern of neuroanatomical and neurochemical abnormalities including: (i) enlarged cerebral ventricles (1, 2), (ii) altered cortical distribution of NADPHdiaphorase positive cells (3), (iii) decreased cortical thickness (4), (iv) increased cell-packing density associated with a neuropil hypoplasia in absence of gliosis (5), (v) decreased expression of dendritic spine in frontal, temporal, and subicular cortex (5-7), and (v) decreased expression of glutamic acid decarboxylase 67 (GAD 67 ) mRNA in prefrontal cortex neurons, particularly evident in layers II and III (8-11).Patients with schizophrenia or bipolar disorder with psychosis express about 50% of the normal brain reelin mRNA levels in every cortical structure so far investigated, as well as in hippocampus, cerebellum, and caudate nucleus (9, 10). Although the number of GABAergic neurons that express reelin in prefrontal and temporal cortices (9, 10) and in the hippocampus (12) of these patients is reduced, the number of these interneurons is unchanged (8). Thus, it has been suggested that the decrease of reelin in neurons is probably because of the downregulation in the expression of GAD 67 mRNA and protein in neurons rather than a reduction of the number of neurons per se (9, 10, 12). To evaluate whether the down-regulation of GAD 67 mRNA expression is as...

Reelin (Reln) is a protein with some structural analogies with other extracellular matrix proteins that functions in the regulation of neuronal migration during the development of cortical laminated structures. In the cortex of adult animals, Reln is expressed primarily in ␥-aminobutyric acid (GABA)ergic neurons and is secreted into perineuronal nets. However, only 50-60% of GABAergic interneurons express Reln. We have characterized this subpopulation of cortical GABAergic neurons that expresses Reln by using two strategies: ( Reln is secreted by GABAergic neurons, its target are not the GABA receptors, but rather may be extrasynaptically located in perineuronal nets and concerned with the modulation of neuronal plasticity. Dab1, the target adapter protein that presumably mediates transcription regulation via the extrasynaptic actions of Reln, is expressed predominantly in pyramidal neurons, but it can also be detected in a small population of GABAergic neurons that are neither horizontal nor bitufted neurons.

Reelin is synthesized and secreted into extracellular matrix by cortical ␥-aminobutyric acid (GABA)ergic interneurons and binds with high affinity to the extracellular domain of integrin receptors expressed in dendritic shaft and spine postsynaptic densities (DSPSD) of pyramidal neurons. In heterozygous reeler mice, reelin bound to DSPSD, and the expression of Arc (activity-regulated cytoskeletal protein) is lower than in wild-type mice. We studied the effect of reelin on Arc and total protein synthesis in synaptoneurosomes ( I n mammalian cortex, reelin is selectively synthesized by ␥-aminobutyric acid (GABA)ergic interneurons, which constitutively secrete this protein in the extracellular matrix (ECM) very likely in proximity of dendritic spine postsynaptic densities (DSPSD) of pyramidal neurons (1-3). Immunoelectron microscopy shows that reelin preferentially localizes around the extracellular domain of integrin receptors highly expressed in DSPSD of cortical pyramidal neurons (1, 3). In the embryonic rodent brain, reelin not only binds to the very low density lipoprotein and apoliprotein E2 receptors (4) but also to ␣ 3 ,␤ 1 integrin receptors with high affinity (5) thereby activating a signal transduction pathway that induces the adapter function of the DAB1 protein (4-6). It is therefore possible that in the adult mammalian brain integrin receptors initiate a signal transduction cascade between ECM reelin and pyramidal neuron DSPSD.In rat hippocampal slices, integrin receptors may contribute to synapse maturation (7) or to long-term potentiation (LTP) consolidation by transducing ECM signals, leading to a cytoskeleton reorganization via the activation of extrasomal mRNA translation (8-10). This view is supported by inhibition of LTP consolidation by the addition of function-blocking antibodies to ␣5͞␤1 or ␣3͞␤1 integrin receptors or by integrin receptor antagonists including an RGD (Arg-Gly-Asp) motif (9, 10). Hence, an integrin-mediated signal transduction may be critical to the stabilization of the LTP-induced plasticity at central excitatory synapses.The application of reelin to adult rat hippocampal slices enhances LTP induction (11). Moreover, in heterozygous reeler mice (HRM) that contain reduced reelin gene dosage, cortical neuropil and dendritic spine density are reduced (12). These considerations suggest that reelin, acting at integrin receptors, could stabilize DSPSD, providing a molecular scaffold for the assembly of cytoskeletal proteins that facilitate dendrite resident mRNA translation and provide the increased protein synthesis required for LTP consolidation and memory trace formation. This hypothesis is consistent with the deficit in memory acquisition and the increased dizocilpine amnestic action characteristic of HRM (13, ‡).The synthesis of activity-regulated cytoskeletal protein (Arc) is encoded by dendritic resident mRNAs. This rapidly inducible protein (14) functions as an immediate early gene product that very likely is involved in spine skeleton formation during LTP stabilization (1...