Maternal Immune Activation Causes Behavioral Impairments and Altered Cerebellar Cytokine and Synaptic Protein Expression

Emerging epidemiology studies indicate that maternal immune activation (MIA) resulting from inflammatory stimuli such as viral or bacterial infections during pregnancy serves as a risk factor for multiple neurodevelopmental disorders including autism spectrum disorders and schizophrenia. Although alterations in the cortex and hippocampus of MIA offspring have been described, less evidence exists on the impact on the cerebellum. Here, we report altered expression of cytokines and chemokines in the cerebellum of MIA offspring, including increase in the neuroinflammatory cytokine TNFα and its receptor TNFR1. We also report reduced expression of the synaptic organizing proteins cerebellin-1 and GluRδ2. These synaptic protein alterations are associated with a deficit in the ability of cerebellar neurons to form synapses and an increased number of dendritic spines that are not in contact with a presynaptic terminal. These impairments are likely contributing to the behavioral deficits in the MIA exposed offspring

Maternal Immune Activation Causes Behavioral Impairments and Altered Cerebellar Cytokine and Synaptic Protein Expression

Emerging epidemiology studies indicate that maternal immune activation (MIA) resulting from inflammatory stimuli such as viral or bacterial infections during pregnancy serves as a risk factor for multiple neurodevelopmental disorders including autism spectrum disorders and schizophrenia. Although alterations in the cortex and hippocampus of MIA offspring have been described, less evidence exists on the impact on the cerebellum. Here, we report altered expression of cytokines and chemokines in the cerebellum of MIA offspring, including increase in the neuroinflammatory cytokine TNFα and its receptor TNFR1. We also report reduced expression of the synaptic organizing proteins cerebellin-1 and GluRδ2. These synaptic protein alterations are associated with a deficit in the ability of cerebellar neurons to form synapses and an increased number of dendritic spines that are not in contact with a presynaptic terminal. These impairments are likely contributing to the behavioral deficits in the MIA exposed offspring

RG-5 induziert Spine-Bildung in unreifen primären Neuronen

Die PRG-Familie, eine Gruppe von fünf Membranproteinen, wurde als wirbeltierspezifisch definiert und ist hauptsächlich im Gehirngewebe exprimiert. Ihre biologische Funktion beinhaltet die Erweiterung der Neuriten, die axonale Wegfindung und die Reorganisation nach einer Läsion. Insbesondere die Deletion von PRG-1 führt zu einer starken Übererregbarkeit des Hippocampus, während die Überexpression von PRG-3 in HeLa-und COS7-Zellen die Anzahl der physiologischen Filopodien erhöht. Im zentralen Nervensystem ist die PRG-1-Expression auf die postsynaptischen Dendriten von glutamatergen Neuronen beschränkt. In dieser Studie möchte ich zunächst meine Aufmerksamkeit auf den vorgelagerten Bereich von Maus und Human PRG-1 fokussieren. Die PRG-1-Expression steht unter der Kontrolle eines TATA-less Promoters mit mehreren Stellen für den Transkriptionsstart. Der Promoter von PRG-1 wurde innerhalb von 450 bp identifiziert, da eine ca. 40 fache Steigerung der Transkription in kultivierten primären Ratten-Neuronen im Vergleich zu den Kontrollen festzustellen ist. Danach habe ich das letzte Mitglied der PRG- Familie, plasticity-related gene-5 (PRG-5) charakterisiert, das in der Lage ist, verschiedene spine-Strukturen in jungen primären Neuronen zu induzieren. Die Form des dendritischen Dornfortsatzes des Neurons bestimmt die Menge von Axonen, mit denen er synaptische Kontakte bilden kann, auf diese Weise Konnektivität innerhalb der neuronalen Schaltkreise herstellend. Die dynamische Zytoskelett-Umgestaltung ist ein wesentlicher Schritt in diesem Prozess. Mögliche extrazelluläre Signale können durch Membranproteine wirken, die Signale zu einem Netzwerk von intrazellulären Signalwegen weitergeben, die letztlich auf das Zytoskelett konvergieren. Allerdings wurden die molekularen Mechanismen, die an diesen Schritten beteiligt sind, noch nicht gut erforscht. PRG-5, das neue Multi-Spanning Membranprotein, lokalisiert und fördert die spine-Induktion in jungen primären Neuronen. Die Aminosäuren innerhalb der C1-C3 Domains sind für die spine-Induktion von Mäusen bei DIV2 und DIV4 verantwortlich. In der Tat zeigen Mutagenese-Experimente in PRG-5 Rückstände von Aminosäuren, die wichtig für die spine-Induktion sind. Unsere Daten zeigen, dass PRG-5 an der spine-Induktion in primären Neuronen beteiligt ist und damit den Umbau der Plasmamembran moduliert.The PRG family, a set of five trans-membrane proteins, were shown to be vertebrate specific and mainly expressed in brain tissue. Their actions include neurite extension, axonal path finding and reorganization after lesion. In particular, deletion of PRG-1 results in severe hippocampal overexcitability, while overexpression of PRG-3 in HeLa and COS7 cells increases the physiological number of filopodia. In the central nervous system, PRG-1 expression is restricted to postsynaptic dendrites on glutamatergic neurons. In this study, first of all I shortly focus my attention in the upstream region of mouse and human PRG-1; PRG-1 expression is under the control of a TATA-less promoter with multiple transcription start sites. The promoter architecture of PRG-1 resulted in the identification of 450 bp, mediating approximately 40 fold enhancement of transcription in cultured primary rat neurons, compared to controls. Afterwards, I characterized the last member of PRG family, plasticity-related gene-5 (PRG-5) which is able to induce spine-like structure in young primary neurons. The shape of a neuron’s dendritic arbour determines the set of axons with which it may form synaptic contacts, thus establishing connectivity within neural circuits. Dynamic cytoskeleton remodelling is an essential step during this process. Putative extracellular cues may act through membrane proteins that relay signals to a network of intracellular signalling pathways, which ultimately converge on the cytoskeleton. However, the molecular mechanisms involved in these steps are not well understood. The novel member of the vertebrate- and brain-specific PRG family, plasticity-related gene 5 (PRG-5), a multi-spanning membrane protein, localizes to and promotes the induction of spines in young primary neurons. A set of amino acid within the C1 – C3 domains are responsible for spine formation in primary neurons at DIV 2 and DIV 4. In fact, mutagenesis experiments in PRG-5 show residual amino acid that are important for the induction of spines. Our data show that PRG-5 may be involved in spine induction in primary neurons and thereby modulate plasma membrane rearrangement

Impaired synaptic development in a maternal immune activation mouse model of neurodevelopmental disorders

Both genetic and environmental factors are thought to contribute to neurodevelopmental and neuropsychiatric disorders with maternal immune activation (MIA) being a risk factor for both autism spectrum disorders and schizophrenia. Although MIA mouse offspring exhibit behavioral impairments, the synaptic alterations in vivo that mediate these behaviors are not known. Here we employed in vivo multiphoton imaging to determine that in the cortex of young MIA offspring there is a reduction in number and turnover rates of dendritic spines, sites of majority of excitatory synaptic inputs. Significantly, spine impairments persisted into adulthood and correlated with increased repetitive behavior, an ASD relevant behavioral phenotype. Structural analysis of synaptic inputs revealed a reorganization of presynaptic inputs with a larger proportion of spines being contacted by both excitatory and inhibitory presynaptic terminals. These structural impairments were accompanied by altered excitatory and inhibitory synaptic transmission. Finally, we report that a postnatal treatment of MIA offspring with the anti-inflammatory drug ibudilast, prevented both synaptic and behavioral impairments. Our results suggest that a possible altered inflammatory state associated with maternal immune activation results in impaired synaptic development that persists into adulthood but which can be prevented with early anti-inflammatory treatment. Includes supplementary materials

The Neurospora crassa White Collar-1 dependent Blue Light Response Requires Acetylation of Histone H3 Lysine 14 by NGF-1

Blue light-induced transcription in Neurospora crassa is regulated by the White Collar-1 (WC-1) photoreceptor. We report that residue K14 of histone H3 associated with the light-inducible albino-3 (al-3) promoter becomes transiently acetylated after photoinduction. This acetylation depends on WC-1. The relevance of this chromatin modification was directly evaluated in vivo by construction of a Neurospora strain with a mutated histone H3 gene (hH3(K14Q)). This strain phenocopies a wc-1 blind mutant and shows a strong reduction of light-induced transcriptional activation of both al-3 and vivid (vvd), another light-inducible gene. We mutated Neurospora GCN Five (ngf-1), which encodes a homologue of the yeast HAT Gcn5p, to generate a strain impaired in H3 K14 acetylation and found that it was defective in photoinduction. Together, our findings reveal a direct link between histone modification and light signaling in Neurospora and contribute to the developing understanding of the molecular mechanisms operating in light-inducible gene activation