Disrupted in schizophrenia 1 (DISC1) L100P mutants have impaired activity-dependent plasticity in vivo and in vitro

Major neuropsychiatric disorders are genetically complex but share overlapping etiology. Mice mutant for rare, highly penetrant risk variants can be useful in dissecting the molecular mechanisms involved. The gene disrupted in schizophrenia 1 (DISC1) has been associated with increased risk for neuropsychiatric conditions. Mice mutant for Disc1 display morphological, functional and behavioral deficits that are consistent with impairments observed across these disorders. Here we report that Disc1 L100P mutants are less able to reorganize cortical circuitry in response to stimulation in vivo. Molecular analysis reveals that the mutants have a reduced expression of PSD95 and pCREB in visual cortex and fail to adjust expression of such markers in response to altered stimulation. In vitro analysis shows that mutants have impaired functional reorganization of cortical neurons in response to selected forms of neuronal stimulation, but there is no altered basal expression of synaptic markers. These findings suggest that DISC1 has a critical role in the reorganization of cortical plasticity and that this phenotype becomes evident only under challenge, even at early postnatal stages. This result may represent an important etiological mechanism in the emergence of neuropsychiatric disorders

Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1

Summary Maternally inherited 15q11-13 chromosomal triplications cause a frequent and highly penetrant autism linked to increased gene dosages of UBE3A, which both possesses ubiquitin-ligase and transcriptional co-regulatory functions. Here, using in vivo mouse genetics, we show that increasing UBE3A in the nucleus down-regulates glutamatergic synapse organizer cerebellin-1 (Cbln1) that is needed for sociability in mice. Epileptic seizures also repress Cbln1 and are found to expose sociability impairments in mice with asymptomatic increases of UBE3A. This Ube3a-seizure synergy maps to glutamate neurons of the midbrain ventral tegmental area (VTA) where Cbln1 deletions impair sociability and weaken glutamatergic transmission. We provide preclinical evidence that viral-vector-based chemogenetic activations of, or Cbln1 restorations in VTA glutamatergic neurons rescues sociability deficits induced by Ube3a and/or seizures. Our results suggest a gene × seizure interaction in VTA glutamatergic neurons that impairs sociability by downregulating Cbln1, a key node in the expanding protein interaction network of autism genes

Regulation of an «Aplysia» Trk-like receptor by serotonin and identification of serotonin G protein- coupled receptors that can activate protein kinase C Apl II

ApTrkl, an Aplysia Trk-like receptor, is required for serotonin (5-HT)-induced activation of ERK and LTF, which underlies behavioral sensitization. We observed constitutive activation of ApTrkl by overexpression, which is dependent on kinase activity. Two modes of internalization were revealed; kinase activity-dependent constitutive internalization and kinase activity-independent internalization induced by 5-HT. Both modes of internalization were independent of a ligand, and the action of 5-HT was mediated through G protein-coupled receptors (GPCRs). Surprisingly, methiothepin, an antagonist to 5-HT GPCRs, increased activation of endogenous ApTrkl to the same level as 5-HT, suggesting a transactivation mechanism due to a novel coupling of GPCRs to receptor tyrosine kinase activation. The neuropeptide sensorin could transiently activate ApTrkl but was not required for 5-HT-induced ApTrkl activation.Protein kinase C (PKC) Apl II, a novel calcium-independent PKC in Aplysia, is required for reversal of synaptic depression, which is thought to underlie behavioral dishabituation. PKC Apl II is translocated to the plasma membrane by 5-HT in sensory neurons. We isolated three 5-HT GPCRs from Aplysia Californica; 5-HT2Ap, 5-HT4Ap and 5-HT7Ap, and demonstrated that 5-HT2Ap and 5-HT7Ap were both able to translocate PKC Apl II in a heterologous system, SF9 cells. Translocation by 5-HT2Ap required PLC activation, while that by 5-HT7Ap required both PLC and PLD activation. However, blocking 5-HT2Ap with the effective antagonist pirenperone did not block the translocation of PKC Apl II nor reversal of synaptic depression in neurons. On the other hand, genistein, a general tyrosine kinase inhibitor, decreased both the translocation and reversal of synaptic depression. These results suggest that there are multiple pathways leading to the activation of PKC Apl II through PLC and PLD as well as tyrosine kianses, which might give a flexibility to the system.Le récepteur ApTrkl, qui est un récepteur de type Trk-like chez l'Aplysie, est essentiel pour l'induction de 5-HT et l'activation subséquente de ERK ainsi que pour LTF, deux processus responsables de la sensibilisation behaviorale. Nous avons observé que la surexpression de ApTrkl engendre son activation et que cette activation constitutive est tributaire de l'activité kinase. Deux modes d'internalisation furent démontrés; l'internalisation constitutive tributaire de l'activité kinase et l'internalisation non-tributaire de l'activité kinase induite par 5-HT. Les deux modes d'internalisation peuvent survenir en l'absence d'un ligand et l'action de 5-HT dépend des récepteurs couplés à la protéine G (GPCRs). Fait intéressant, la méthiothépine, un antagoniste de 5-HT GPCRs, augmente l'activation des récepteurs ApTrkl endogènes au même niveau que le fait 5-HT, suggérant ainsi la présence d'un nouveau mécanisme de transactivation qui couplerait les GPCRs à l'activation du récepteur tyrosine kinase (RTK). Le neuropeptide sensorine, pourrait activer transitoirement ApTrkl mais ne serait pas essentiel pour l'activation de ApTrkl tributaire de 5-HT.Protéine kinase C (PKC) Apl II, une nouvelle PKC non-tributaire du calcium chez l'Aplysie, est requise pour contrecarrer la dépression synaptique qui croit-on, est le mécanisme responsable de la désensibilisation behaviorale. PKC Apl II est relocalisée à la membrane plasmique par 5-HT dans les neurones sensoriels. Nous avons isolé trois 5-HT GPCRs à partir de l'Aplysie Californica; 5-HT2Ap, 5-HT4Ap et 5-HT7Ap. Nous avons par la suite démontré que 5-HT2Ap et 5-HT7Ap étaient capable de relocaliser PKC Apl II dans les cellules SF9. La relocalisation de 5-HT2Ap requiert l'activation de PLC tandis que la relocalisation de 5-HT7Ap requiert l'activation de PLC et de PLD. Toutefois, l'inhibition de 5-HT2Ap par l'antagoniste pirenperone n'a pas réussi à bloquer la relocalisation de PKC Apl II ni n'a réussi à contrecarrer la dépression synaptique dans les neurones. Cependant, l'utilisation de la génistéine, un inhibiteur des tyrosine kinases, cause une diminution de la relocalisation et la dépression synaptique. Ces résultats suggèrent que plusieurs mécanismes cellulaires conduisent à l'activation de PKC Apl II par PLC et PLD et des tyrosine kinases qui pourrait contribuer à la flexibilité de ce processus cellulaire

Physiological Role for Phosphatidic Acid in the Translocation of the Novel Protein Kinase C Apl II in Aplysia Neurons▿

In Aplysia californica, the serotonin-mediated translocation of protein kinase C (PKC) Apl II to neuronal membranes is important for synaptic plasticity. The orthologue of PKC Apl II, PKCɛ, has been reported to require phosphatidic acid (PA) in conjunction with diacylglycerol (DAG) for translocation. We find that PKC Apl II can be synergistically translocated to membranes by the combination of DAG and PA. We identify a mutation in the C1b domain (arginine 273 to histidine; PKC Apl II-R273H) that removes the effects of exogenous PA. In Aplysia neurons, the inhibition of endogenous PA production by 1-butanol inhibited the physiological translocation of PKC Apl II by serotonin in the cell body and at the synapse but not the translocation of PKC Apl II-R273H. The translocation of PKC Apl II-R273H in the absence of PA was explained by two additional effects of this mutation: (i) the mutation removed C2 domain-mediated inhibition, and (ii) the mutation decreased the concentration of DAG required for PKC Apl II translocation. We present a model in which, under physiological conditions, PA is important to activate the novel PKC Apl II both by synergizing with DAG and removing C2 domain-mediated inhibition

Major Vault Protein, a Candidate Gene in 16p11.2 Microdeletion Syndrome, Is Required for the Homeostatic Regulation of Visual Cortical Plasticity

Microdeletion of a region in chromosome 16p11.2 increases susceptibility to autism. Although this region contains exons of 29 genes, disrupting only a small segment of the region, which spans five genes, is sufficient to cause autistic traits. One candidate gene in this critical segment is MVP, which encodes for the major vault protein (MVP) that has been implicated in regulation of cellular transport mechanisms. MVP expression levels in MVP+/- mice closely phenocopy those of 16p11.2 mutant mice, suggesting that MVP+/- mice may serve as a model of MVP function in 16p11.2 microdeletion. Here we show that MV Pregulates the homeostatic component of ocular dominance (OD) plasticity in primary visual cortex. MVP+/- mice of both sexes show impairment in strengthening of open-eye responses after several days of monocular deprivation (MD), whereas closed-eye responses are weakened as normal, resulting in reduced overall OD plasticity. The frequency of miniature EPSCs (mEPSCs) in pyramidal neurons is decreased in MVP+/- mice after extended MD, suggesting a reduction of functional synapses. Correspondingly, upregulation of surface GluA1 AMPA receptors is reduced in MVP+/- mice after extended MD, and is accompanied by altered expression of STAT1 and phosphorylated ERK, which have been previously implicated in OD plasticity. Normalization of STAT1 levels by introducing STAT1 shRNA rescues surface GluA1 and open-eye responses, implicating STAT1 as a downstream effector of MVP. These findings demonstrate a specific role for MVP as a key molecule influencing the homeostatic component of activity-dependent synaptic plasticity, and potentially the corresponding phenotypes of 16p11.2 microdeletion syndrome. Keywords: autism spectrum disorder; glutamate receptors; ocular dominance plasticity; signaling; molecules; synapse development; visual cortexNational Institutes of Health (U.S.) (Grant MH085802)National Institutes of Health (U.S.) (Grant EY007023

STAT1 Regulates the Homeostatic Component of Visual Cortical Plasticity via an AMPA Receptor-Mediated Mechanism

Accumulating evidence points to a role for Janus kinase/signal transducers and activators of transcription (STAT) immune signaling in neuronal function; however, its role in experience-dependent plasticity is unknown. Here we show that one of its components, STAT1, negatively regulates the homeostatic component of ocular dominance plasticity in visual cortex. After brief monocular deprivation (MD), STAT1 knock-out (KO) mice show an accelerated increase of open-eye responses, to a level comparable with open-eye responses after a longer duration of MD in wild-type (WT) mice. Therefore, this component of plasticity is abnormally enhanced in KO mice. Conversely, increasing STAT1 signaling by IFNγ treatment in WT mice reduces the homeostatic component of plasticity by impairing open-eye responses. Enhanced plasticity in KO mice is accompanied by sustained surface levels of GluA1 AMPA receptors and increased amplitude and frequency of AMPA receptor-mediated mEPSCs, which resemble changes in WT mice after a longer duration of MD. These results demonstrate a unique role for STAT1 during visual cortical plasticity in vivo through a mechanism that includes AMPA receptorsNational Institutes of Health (U.S.)Simons Foundation (Fellowship)National Institutes of Health (U.S.) (National Research and Service Award