Mutations in autophagy genes can cause familial and sporadic amyotrophic lateral sclerosis (ALS). However, the role of autophagy in ALS pathogenesis is poorly understood, in part due to the lack of cell type-specific manipulations of this pathway in animal models. Using a mouse model of ALS expressing mutant superoxide dismutase 1 (SOD1), we show that motor neurons form large autophagosomes containing ubiquitinated aggregates early in disease progression. To investigate whether this response is protective or detrimental, we generated mice in which the critical autophagy gene was specifically disrupted in motor neurons (Atg7 cKO). Atg7 cKO mice were viable but exhibited structural and functional defects at a subset of vulnerable neuromuscular junctions. By crossing Atg7 cKO mice to the SOD1 mouse model, we found that autophagy inhibition accelerated early neuromuscular denervation of the tibialis anterior muscle and the onset of hindlimb tremor. Surprisingly, however, lifespan was extended in Atg7 cKO; SOD1 double-mutant mice. Autophagy inhibition did not prevent motor neuron cell death, but it reduced glial inflammation and blocked activation of the stress-related transcription factor c-Jun in spinal interneurons. We conclude that motor neuron autophagy is required to maintain neuromuscular innervation early in disease but eventually acts in a non-cell-autonomous manner to promote disease progression.

SAM-II riboswitches and other RNA motifs in bacteria

Comparative sequence analysis and structural probing identified five RNA elements in the intergenic region of Agrobacterium tumefaciens and other α-proteobacteria. One of these RNA elements is probably a SAM-II, the only riboswitch class identified so far that is not found in Gram-positive bacteria.

Extraordinary single-cell diversity is generated in the vertebrate nervous system by the combinatorial expression of the clustered protocadherin genes (Pcdhα, -β, and -γ). This diversity is generated by a combination of stochastic promoter choice and alternative premRNA splicing. Here we show that both the insulator-binding protein CTCF and the cohesin complex subunit Rad21 bind to two highly conserved DNA sequences, the first within and the second downstream of transcriptionally active Pcdhα promoters. Both CTCF and Rad21 bind to these sites in vitro and in vivo, this binding directly correlates with alternative isoform expression, and knocking down CTCF expression reduces alternative isoform expression. Remarkably, a similarly spaced pair of CTCF/Rad21 binding sites was identified within a distant enhancer element (HS5-1), which is required for normal levels of alternative isoform expression. We also identify an additional, unique regulatory role for cohesin, as Rad21 binds to another enhancer (HS7) independently of CTCF, and knockdown of Rad21 reduces expression of the constitutive, biallelically expressed Pcdhα isoforms αc1 and αc2. We propose that CTCF and the cohesin complex initiate and maintain Pcdhα promoter choice by mediating interactions between Pcdhα promoters and enhancers.

Introduction-Neuregulin-1 (NRG1) is one of susceptibility genes for schizophrenia and plays critical roles in glutamatergic, dopaminergic and GABAergic signaling. Using mutant mice heterozygous for Nrg1 (Nrg1 +/− ) we studied the effects of Nrg1 signaling on behavioral and electrophysiological measures relevant to schizophrenia.Experimental Procedure-Behavior of Nrg1 +/− mice and their wild type littermates was evaluated using pre-pulse inhibition, contextual fear conditioning, novel object recognition, locomotor, and social choice paradigms. Event-related potentials (ERPs) were recorded to assess auditory gating and novel stimulus detection.Results-Gating of ERPs was unaffected in Nrg1 +/− mice, but mismatch negativity in response to novel stimuli was attenuated. The Nrg1 +/− mice exhibited behavioral deficits in contextual fear conditioning and social interactions, while locomotor activity, pre-pulse inhibition and novel object recognition were not impaired.Summary-Nrg1 +/− mice had impairments in a subset of behavioral and electrophysiological tasks relevant to the negative/cognitive symptom domains of schizophrenia that are thought to be influenced by glutamatergic and dopaminergic neurotransmission. These mice are a valuable tool for studying endophenotypes of schizophrenia, but highlight that single genes can not account for the complex pathophysiology of the disorder.

Highlights d TBK1 kinase activity regulates disease progression in an ALS SOD1 mouse model d Loss of TBK1 in motor neurons increases SOD1 aggregation and accelerates disease onset d Loss of TBK1 activity in all cell types accelerates disease onset but extends survival d Loss of TBK1 activity in all cell types reduces the IFN response in microglia

Purpose-Chemotherapeutic agents are known to produce persistent cognitive deficits in cancer patients. However, little progress has been made in developing animal models to explore underlying mechanisms and potential therapeutic interventions. We report an electrophysiological model of chemotherapy-induced cognitive deficits using a sensory gating paradigm, to correspond with performance in two behavioral tasks.Experimental Design-Mice received four weekly injections of methotrexate and 5-fluorouracil. Whole-brain event-related potentials (ERPs) were recorded throughout using a paired-click paradigm. Mice underwent contextual fear conditioning (CFC) and novel-object recognition testing (NOR).Results-Chemotherapy treated animals showed significantly impaired gating five weeks after drug treatments began, as measured by the ratio of P1-N1 between first and second auditory stimuli. There was no effect of drug on the amplitude of P1-N1 or latency of P1. The drug treated animals also showed significantly increased freezing during fear conditioning and increased exploration without memory impairment during novel object recognition.Conclusions-Chemotherapy causes decreased ability to gate incoming auditory stimuli, which may underlie associated cognitive impairments. These gating deficits were associated with a hyperactive response to fear conditioning and reduced adaptation to novel objects, suggesting an additional component of emotional dysregulation. However, amplitudes and latencies of ERP components were unaffected, as was NOR performance, highlighting the subtle nature of these deficits.

Data suggest that smoking improves sensory processing. Varenicline mimics amplitude changes associated with nicotine and smoking but fails to alter habituation. The effect of medication order suggests a possible carryover effect from the previous arm. This study supports the predictive validity of ERPs in mice as a marker of drug effects in human studies.

Calcium ions (Ca 2+ ) released from inositol trisphosphate (IP 3 )-sensitive intracellular stores may participate in both the transient and extended regulation of neuronal excitability in neocortical and hippocampal pyramidal neurons. IP 3 receptor (IP 3 R) antagonists represent an important tool for dissociating these consequences of IP 3 generation and IP 3 R-dependent internal Ca 2+ release from the effects of other, concurrently stimulated second messenger signaling cascades and Ca 2+ sources. In this study, we have described the actions of the IP 3 R and store-operated Ca 2+ channel antagonist, 2-aminoethoxydiphenyl-borate (2-APB), on internal Ca 2+ release and plasma membrane excitability in neocortical and hippocampal pyramidal neurons. Specifically, we found that a dose of 2-APB (100 µM) sufficient for attenuating or blocking IP 3 -mediated internal Ca 2+ release also raised pyramidal neuron excitability. The 2-APB-dependent increase in excitability reversed upon washout and was characterized by an increase in input resistance, a decrease in the delay to action potential onset, an increase in the width of action potentials, a decrease in the magnitude of afterhyperpolarizations (AHPs), and an increase in the magnitude of post-spike afterdepolarizations (ADPs). From these observations, we conclude that 2-APB potently and reversibly increases neuronal excitability, likely via the inhibition of voltage-and Ca 2+ -dependent potassium (K + ) conductances.