Dysbindin-1 mutant mice implicate reduced fast-phasic inhibition as a final common disease mechanism in schizophrenia.

DTNBP1 (dystrobrevin binding protein 1) is a leading candidate susceptibility gene in schizophrenia and is associated with working memory capacity in normal subjects. In schizophrenia, the encoded protein dystrobrevin-binding protein 1 (dysbindin-1) is often reduced in excitatory cortical limbic synapses. We found that reduced dysbindin-1 in mice yielded deficits in auditory-evoked response adaptation, prepulse inhibition of startle, and evoked γ-activity, similar to patterns in schizophrenia. In contrast to the role of dysbindin-1 in glutamatergic transmission, γ-band abnormalities in schizophrenia are most often attributed to disrupted inhibition and reductions in parvalbumin-positive interneuron (PV cell) activity. To determine the mechanism underlying electrophysiological deficits related to reduced dysbindin-1 and the potential role of PV cells, we examined PV cell immunoreactivity and measured changes in net circuit activity using voltage-sensitive dye imaging. The dominant circuit impact of reduced dysbindin-1 was impaired inhibition, and PV cell immunoreactivity was reduced. Thus, this model provides a link between a validated candidate gene and an auditory endophenotypes. Furthermore, these data implicate reduced fast-phasic inhibition as a common underlying mechanism of schizophrenia-associated intermediate phenotypes.

Nicotine withdrawal exacerbates fear reactivity to CO2-induced bodily sensations among smokers.

INTRODUCTION: Independent lines of research suggest that smoking increases the prospective risk of panic disorder. Studies that have examined the hypothesized link between nicotine withdrawal and panic have typically employed light smokers or lacked optimal control groups. Our laboratory team previously found, for example, that smokers who abstained from cigarettes for 12 hr demonstrated greater fear reactivity to a CO(2) rebreathing challenge than nonsmokers. However, the absence of a smoking-as-usual group limited our ability to draw conclusions about the potential role of nicotine withdrawal. METHODS: We exposed 27 heavy smokers who abstained from smoking for 12 hr and 27 heavy smokers who smoked as usual to a 5-min CO(2) rebreathing challenge. RESULTS: More intense prechallenge nicotine withdrawal symptoms (regardless of group status) were associated with more severe panicky symptoms and a stronger urge to escape during the challenge, even after we controlled for prechallenge anxiety and daily cigarette use. Unexpectedly, group status did not predict challenge reactivity. CONCLUSION: Smokers who regularly experience intense withdrawal symptoms, regardless of length of smoking abstinence, may be at heightened risk for experiencing panic attacks.

A Strategy Toward Bridging a Complete Spinal Cord Lesion Using Stretch-Grown Axons.

In this study, we evaluated the ability of stretch-grown tissue-engineered nerve grafts (TENGs) to perform as a living scaffold for axonal regeneration across a severed spinal cord lesion. TENGs, consisting of stretch-grown axons spanning two populations of dorsal root ganglia neurons, have proven to be effective in bridging gaps in peripheral nerve injury. A complete transection was performed at the thoracic level in a rodent model and 5 mm of cord was completely removed. TENGs encapsulated in a collagen hydrogel were placed within the cavity and compared against a collagen only transplant. Through hematoxylin and eosin (H&E) staining and immunohistochemistry, we found that TENGs survived up to 6 weeks post-transplant, extending neuronal processes into and through host tissue early on in both the rostral and caudal direction. In several cases, TENG axons penetrated into and through glial scar tissue, appearing to overcome a common obstacle for axonal regeneration in spinal cord injuries (SCIs). H&E staining also provided evidence that animals treated with TENGs resulted in lesion sites with greater tissue infiltration and less compression than animals treated with a collagen hydrogel only, an encouraging finding given the severity of the injury model. We also observed effects the TENGs had on glial scar formation, cyst formation, and immune response at multiple time points as these are common difficulties faced in tissue engineering methods to treat or repair SCI. If able to address these universal challenges associated with SCI, TENGs may offer an alternative option in neural transplantation and may represent a viable tool in the multifaceted treatment of SCI. Impact statement In complete spinal cord injury (SCI), a significant gap forms in the injury sites replacing the neural connections and limiting the link between healthy spinal cord distal to the injury and cerebral cortex. This study aims to demonstrate the potential benefit of hydrogel collagen constructs bearing stretch-grown dorsal root ganglion axons to bridge a complete injury gap, to restore the lost connections and forming a basic infrastructure to support the regrowth of new connection. This application of stretch-grown axons in neural implants offers hope to achieve a highly modifiable and resilient bridging strategy to treat SCI.

Activity-dependent switch of GABAergic inhibition into glutamatergic excitation in astrocyte-neuron networks.

Interneurons are critical for proper neural network function and can activate Ca2+ signaling in astrocytes. However, the impact of the interneuron-astrocyte signaling into neuronal network operation remains unknown. Using the simplest hippocampal Astrocyte-Neuron network, i.e., GABAergic interneuron, pyramidal neuron, single CA3-CA1 glutamatergic synapse, and astrocytes, we found that interneuron-astrocyte signaling dynamically affected excitatory neurotransmission in an activity- and time-dependent manner, and determined the sign (inhibition vs potentiation) of the GABA-mediated effects. While synaptic inhibition was mediated by GABAA receptors, potentiation involved astrocyte GABAB receptors, astrocytic glutamate release, and presynaptic metabotropic glutamate receptors. Using conditional astrocyte-specific GABAB receptor (Gabbr1) knockout mice, we confirmed the glial source of the interneuron-induced potentiation, and demonstrated the involvement of astrocytes in hippocampal theta and gamma oscillations in vivo. Therefore, astrocytes decode interneuron activity and transform inhibitory into excitatory signals, contributing to the emergence of novel network properties resulting from the interneuron-astrocyte interplay.

Caudalized human iPSC-derived neural progenitor cells produce neurons and glia but fail to restore function in an early chronic spinal cord injury model.

Neural progenitor cells (NPCs) have shown modest potential and some side effects (e.g. allodynia) for treatment of spinal cord injury (SCI). In only a few cases, however, have NPCs shown promise at the chronic stage. Given the 1.275 million people living with chronic paralysis, there is a significant need to rigorously evaluate the cell types and methods for safe and efficacious treatment of this devastating condition. For the first time, we examined the pre-clinical potential of NPCs derived from human induced pluripotent stem cells (hiPSCs) to repair chronic SCI. hiPSCs were differentiated into region-specific (i.e. caudal) NPCs, then transplanted into a new, clinically relevant model of early chronic cervical SCI. We established the conditions for successful transplantation of caudalized hiPSC-NPCs and demonstrate their remarkable ability to integrate and produce multiple neural lineages in the early chronic injury environment. In contrast to prior reports in acute and sub-acute injury models, survival and integration of hiPSC-derived neural cells in the early chronic cervical model did not lead to significant improvement in forelimb function or induce allodynia. These data indicate that while hiPSCs show promise, future work needs to focus on the specific hiPSC-derivatives or co-therapies that will restore function in the early chronic injury setting.

Multiple horizontal gene transfer events and domain fusions have created novel regulatory and metabolic networks in the oomycete genome.

Complex enzymes with multiple catalytic activities are hypothesized to have evolved from more primitive precursors. Global analysis of the Phytophthora sojae genome using conservative criteria for evaluation of complex proteins identified 273 novel multifunctional proteins that were also conserved in P. ramorum. Each of these proteins contains combinations of protein motifs that are not present in bacterial, plant, animal, or fungal genomes. A subset of these proteins were also identified in the two diatom genomes, but the majority of these proteins have formed after the split between diatoms and oomycetes. Documentation of multiple cases of domain fusions that are common to both oomycetes and diatom genomes lends additional support for the hypothesis that oomycetes and diatoms are monophyletic. Bifunctional proteins that catalyze two steps in a metabolic pathway can be used to infer the interaction of orthologous proteins that exist as separate entities in other genomes. We postulated that the novel multifunctional proteins of oomycetes could function as potential Rosetta Stones to identify interacting proteins of conserved metabolic and regulatory networks in other eukaryotic genomes. However ortholog analysis of each domain within our set of 273 multifunctional proteins against 39 sequenced bacterial and eukaryotic genomes, identified only 18 candidate Rosetta Stone proteins. Thus the majority of multifunctional proteins are not Rosetta Stones, but they may nonetheless be useful in identifying novel metabolic and regulatory networks in oomycetes. Phylogenetic analysis of all the enzymes in three pathways with one or more novel multifunctional proteins was conducted to determine the probable origins of individual enzymes. These analyses revealed multiple examples of horizontal transfer from both bacterial genomes and the photosynthetic endosymbiont in the ancestral genome of Stramenopiles. The complexity of the phylogenetic origins of these metabolic pathways and the paucity of Rosetta Stones relative to the total number of multifunctional proteins suggests that the proteome of oomycetes has few features in common with other Kingdoms.