Decreased expression of the GABA synthetic enzyme glutamate decarboxylase 67 (GAD67) in a subset of GABAergic neurons, including parvalbumin (PV)-expressing neurons, has been observed in postmortem brain studies of schizophrenics and in animal models of schizophrenia. However, it is unclear whether and how the perturbations of GAD67-mediated GABA synthesis and signaling contribute to the pathogenesis of schizophrenia. To address this issue, we generated the mice lacking GAD67 primarily in PV neurons and characterized them with focus on schizophrenia-related parameters. We found that heterozygous mutant mice exhibited schizophrenia-related behavioral abnormalities such as deficits in prepulse inhibition, MK-801 sensitivity, and social memory. Furthermore, we observed reduced inhibitory synaptic transmission, altered properties of NMDA receptor-mediated synaptic responses in pyramidal neurons, and increased spine density in hippocampal CA1 apical dendrites, suggesting a possible link between GAD67 deficiency and disturbed glutamatergic excitatory synaptic functions in schizophrenia. Thus, our results indicate that the mice heterozygous for GAD67 deficiency primarily in PV neurons share several neurochemical and behavioral abnormalities with schizophrenia, offering a novel tool for addressing the underlying pathophysiology of schizophrenia.

Cortical interneurons are classified into several subtypes that contribute to cortical oscillatory activity. Parvalbumin (PV)-expressing cells, a type of inhibitory interneuron, are involved in the gamma oscillations of local field potentials (LFPs). Under ketamine-xylazine anesthesia or sleep, mammalian cortical circuits exhibit slow oscillations in which the active-up state and silent-down state alternate at ~1 Hz. The up state is composed of various high-frequency oscillations, including gamma oscillations. However, it is unclear how PV cells and somatostatin (SOM) cells contribute to the slow oscillations and the high-frequency oscillations nested in the up state. To address these questions, we used mice lacking glutamate decarboxylase 67, primarily in PV cells (PV-GAD67 mice) or in SOM cells (SOM-GAD67 mice). We then compared LFPs between PV-GAD67 mice and SOM-GAD67 mice. PV cells target the proximal regions of pyramidal cells, whereas SOM cells are dendrite-preferring interneurons. We found that the up state was shortened in duration in the PV-GAD67 mice, but tended to be longer in SOM-GAD67 mice. Firing rate tended to increase in PV-GAD67 mice, but tended to decrease in SOM-GAD67 mice. We also found that delta oscillations tended to increase in SOM-GAD67 mice, but tended to decrease in PV-GAD67 mice. Current source density and wavelet analyses were performed to determine the depth profiles of various high-frequency oscillations. High gamma and ripple (60–200 Hz) power decreased in the neocortical upper layers specifically in PV-GAD67 mice, but not in SOM-GAD67. In addition, beta power (15–30 Hz) increased in the deep layers, specifically in PV-GAD67 mice. These results suggest that PV cells play important roles in persistence of the up state and in the balance between gamma and beta bands across cortical layers, whereas SOM and PV cells may make an asymmetric contribution to regulate up-state and delta oscillations.

The NMDA-type glutamate receptor is a heteromeric complex composed of the NR1 and at least one of the NR2 subunits. Switching from the NR2B to the NR2A subunit is thought to underlie functional alteration of the NMDA receptor during synaptic maturation, and it is generally believed that it results in preferential localization of NR2A subunits on the synaptic site and that of NR2B subunits on the extracellular site in the mature brain. It has also been proposed that activation of the NR2A and NR2B subunits results in long-term potentiation (LTP) and long-term depression (LTD), respectively. Furthermore, recent reports suggest that synaptic and extrasynaptic receptors may have distinct roles in synaptic plasticity as well as in gene expression associated with neuronal death. Here, we have investigated whether NR2B subunit-containing receptors are present and functional at mature synapses in the lateral nucleus of the amygdala (LA) and the CA1 region of the hippocampus, comparing their properties between the two brain regions. We have found, in contrast to the above hypotheses, that the NR2B subunit significantly contributes to synaptic transmission as well as LTP induction. Furthermore, its contribution is greater in the LA than in the CA1 region, and biophysical properties of NMDA receptors and the NR2B/NR2A ratio are different between the two brain regions. These results indicate that NR2B subunit-containing NMDA receptors accumulate on the synaptic site and are responsible for the unique properties of synaptic function and plasticity in the amygdala.

Ca 2+-dependent activator protein for secretion 2 (CAPS2 or CADPS2) potently promotes the release of brain-derived neurotrophic factor (BDNF). A rare splicing form of CAPS2 with deletion of exon3 (dex3) was identified to be overrepresented in some patients with autism. Here, we generated Caps2-dex3 mice and verified a severe impairment in axonal Caps2-dex3 localization, contributing to a reduction in BDNF release from axons. In addition, circuit connectivity, measured by spine and interneuron density, was diminished globally. The collective effect of reduced axonal BDNF release during development was a striking and selective repertoire of deficits in socialand anxiety-related behaviors. Together, these findings represent a unique mouse model of a molecular mechanism linking BDNFmediated coordination of brain development to autism-related behaviors and patient genotype.-dependent activator protein for secretion 2 (CAPS2 or CADPS2) is a member of the CAPS protein family that regulates the trafficking of dense-core vesicles by binding both phosphoinositides and dense-core vesicles (1-5). We initially identified mouse Caps2 as a potent factor promoting the release of brain-derived neurotrophic factor (BDNF) during cerebellar development (6, 7). Our subsequent knockout mouse study showed that Caps2 not only plays a role in neuronal development of the cerebrum and hippocampus as well as the cerebellum, but that it is also associated with social interaction, anxiety, and maternal and circadian behaviors in mice (7,8). We also showed that the expression of an exon 3-skipped (or -spliced out) form of CAPS2 (designated CAPS2-dex3) (8), which is now known to be a rare alternative splicing variant (9, 10), is increased in a subgroup of patients with autism and is not properly localized in axons (8). Thus, neurons overexpressing dex3 may fail to coordinate local BDNF release from axons properly (8, 9), resulting in improper brain development and function. The human CAPS2 gene locus (7q31.32) is intriguingly located within the autism susceptibility locus 1 (AUTS1) (11) on chromosome 7q31-q33, one of several susceptibility loci for autism (12). Moreover, an association of CAPS2 with autism has been suggested recently, not only by the presence of copy number variations in the CAPS2 gene in autistic patients (13-15), but also by decreased transcription of CAPS2 in the brains of people with autism (16). Thus, clarifying the biological significance of dex3 expression is an important step in elucidating the association of CAPS2 with brain circuit development and behaviors related to autism.The potential molecular risk factors for autism susceptibility have been increasingly reported (17-26) but are poorly characterized in animal models. In this report, we generated a mouse model expressing dex3 and analyzed the cellular and autistic-like behavioral phenotypes of dex3 mice. Our results support the involvement of the rare dex3 form of Caps2 in defective axonal BDNF secretion, affecting proper brain circuit development and/ or functio...

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a b s t r a c tThe neurogenic gene Drosophila big brain (bib) has a high sequence homology to aquaporin-4. However, its cellular functions in Drosophila neurogenesis have remained elusive. Here we investigated cell adhesion, and the ion and water permeability of Bib. The adhesive function was examined by a cell aggregation assay using L cells. Bib-transfected L cells formed aggregated clusters, while control-L cells remained as a single cell suspension. Ion permeation was not confirmed in L cells stably expressing Bib. When expressed in COS7 cells, Bib exhibited limited water permeability. This newly found cell adhesive function of Bib may be important for Drosophila neurogenesis.

Survival in CTEPH in the recent era has significantly improved, especially in non-PEA patients. BPA and selective pulmonary vasodilators could improve survival in the non-PEA group. In the present study, no difference in survival was found between PEA and non-PEA.

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