Adaptation of ocular reflexes is a prototype of motor learning. While the cerebellum is acknowledged as the critical site for motor learning, the functional differences between the cerebellar cortex ...and nuclei in motor memory formation are not precisely known. Two different views are proposed: one that the memory is formed within the cerebellar flocculus, and the other that the memory is formed within vestibular nuclei. Here we developed a new paradigm of long-term adaptation of mouse horizontal optokinetic response eye movements and examined the location of its memory trace. We also tested the role of flocculus and inferior olive in long-term adaptation by chronic lesion experiments. Reversible bilateral flocculus shutdown with local application of 0.5 μl–5% lidocaine extinguished the memory trace of day-long adaptation, while it very little affected the memory trace of week-long adaptation. The responsiveness of vestibular nuclei after week-long adaptation was examined by measuring the extracellular field responses to the electrical stimulation of vestibular nerve under trichloroacetaldehyde anesthesia. The amplitudes and slopes of evoked monosynaptic field response (N
1) of week-long adapted mice were enhanced around the medial vestibular nucleus compared with those of control mice. Chronic flocculus or inferior olive lesions abolished both day and week-long adaptations. These results suggest that the functional memory trace of short-term adaptation is formed initially within the cerebellar cortex, and later transferred to vestibular nuclei to be consolidated to a long-term memory. Both day and week-long adaptations were markedly depressed when neural nitric oxide was pharmacologically blocked locally and when neuronal nitric oxide synthase was ablated by gene knockout, suggesting that cerebellar long-term depression underlies both acquisition and consolidation of motor memory.
Abstract Dendritic spines are postsynaptic structures at excitatory synapses that play important roles in synaptic transmission and plasticity. Dendritic spine morphology and function are regulated ...by an actin-based cytoskeletal network. Drebrin A, an adult form of drebrin, is an actin-binding protein in dendritic spines, and its decrease is purportedly concerned with synaptic dysfunction in Alzheimer's disease. Rapid conversion of drebrin E, an embryonic form of drebrin, to drebrin A occurs in parallel with synaptic maturation. To understand the physiological role of drebrin isoform conversion in vivo , we generated knockout mice in which a drebrin A-specific exon was deleted from the drebrin gene. Drebrin A-specific knockout (DAKO) mice expressed drebrin E, which substituted for drebrin A. Subcellular fractionation experiment indicated that cytosolic form of drebrin was increased in the brains of DAKO mice. Furthermore, drebrin accumulation in synaptosomes of DAKO mice was much higher than that of wild-type (WT) mice. DAKO mice were viable and showed no apparent abnormalities in their gross brain morphology and general behaviors. However, DAKO mice were impaired in a context-dependent freezing after fear conditioning. These data indicate that drebrin A plays an indispensable role in some processes of generating fear learning and memory.
Matrix metalloproteinases (MMPs) are essential for proper extracellular matrix remodeling. We previously found that a membrane-anchored glycoprotein, RECK, negatively regulates MMP-9 and inhibits ...tumor invasion and metastasis. Here we show that RECK regulates two other MMPs, MMP-2 and MT1-MMP, known to be involved in cancer progression, that mice lacking a functional
RECK gene die around E10.5 with defects in collagen fibrils, the basal lamina, and vascular development, and that this phenotype is partially suppressed by MMP-2 null mutation. Also, vascular sprouting is dramatically suppressed in tumors derived from RECK-expressing fibrosarcoma cells grown in nude mice. These results support a role for RECK in the regulation of MMP-2 in vivo and implicate RECK downregulation in tumor angiogenesis.
Highlights • Mice devoid of thalamic adenylyl cyclase 1 (AC1) are generated. • Thalamic AC1 is required for cortical barrel formation. • Thalamic AC1 is required for refinement of thalamocortical ...axons. • Cortical calcium-stimulated adenylyl cyclases are dispensable for barrel formation.
ABSTRACT
The matrix metalloproteinases (MMPs) play a key role in normal and pathological angiogenesis by mediating extracellular matrix degradation and/or controlling the biological activity of ...growth factors, chemokines, and/or cytokines. Specific functions of individual MMPs as anti‐ or proangiogenic mediators remain to be elucidated. In the present study, we assessed the impact of single or combined MMP deficiencies in in vivo and in vitro models of angiogenesis (malignant keratinocyte transplantation and the aortic ring assay, respectively). MMP‐9 was predominantly expressed by neutrophils in tumor transplants, whereas MMP‐2 and MMP‐3 were stromal. Neither the single deficiency of MMP‐2, MMP‐3, or MMP‐9, nor the combined absence of MMP‐9 and MMP‐3 did impair tumor invasion and vascularization in vivo. However, there was a striking cooperative effect in double MMP‐2:MMP‐9‐deficient mice as demonstrated by the absence of tumor vascularization and invasion. In contrast, the combined lack of MMP‐2 and MMP‐9 did not impair the in vitro capillary outgrowth from aortic rings. These results point to the importance of a cross talk between several host cells for the in vivo tumor promoting and angiogenic effects of MMP‐2 and MMP‐9. Our data demonstrate for the first time in an experimental model that MMP‐2 and MMP‐9 cooperate in promoting the in vivo invasive and angiogenic phenotype of malignant keratinocytes.
In understanding the mechanism of schizophrenia pathogenesis, a significant finding is that drug abuse of phencyclidine or its analog ketamine causes symptoms similar to schizophrenia. Such drug ...effects are triggered even by administration at post-adolescent stages. Both drugs are N-methyl-d-aspartate receptor (NMDAR) antagonists, leading to a major hypothesis that glutamate hypofunction underlies schizophrenia pathogenesis. The precise region that depends on NMDAR function, however, is unclear. Here, we developed a mouse strain in which NMDARs in the intralaminar thalamic nuclei (ILN) were selectively disrupted. The mutant mice exhibited various schizophrenia-like phenotypes, including deficits in working memory, long-term spatial memory, and attention, as well as impulsivity, impaired prepulse inhibition, hyperlocomotion and hyperarousal. The electroencephalography analysis revealed that the mutant mice had a significantly reduced power in a wide range of frequencies including the alpha, beta and gamma bands, both during wake and rapid eye movement (REM) sleep, and a modest decrease of gamma power during non-REM sleep. Notably, restoring NMDARs in the adult ILN rescued some of the behavioral abnormalities. These findings suggest that NMDAR dysfunction in the ILN contributes to the pathophysiology of schizophrenia-related disorders. Furthermore, the reversal of inherent schizophrenia-like phenotypes in the adult mutant mice supports that ILN is a potential target site for a therapeutic strategy.
Transcranical direct current stimulation (tDCS) is a treatment known to ameliorate various neurological conditions and enhance memory and cognition in humans. tDCS has gained traction for its ...potential therapeutic value; however, little is known about its mechanism of action. Using a transgenic mouse expressing G-CaMP7 in astrocytes and a subpopulation of excitatory neurons, we find that tDCS induces large-amplitude astrocytic Ca2+ surges across the entire cortex with no obvious changes in the local field potential. Moreover, sensory evoked cortical responses are enhanced after tDCS. These enhancements are dependent on the alpha-1 adrenergic receptor (A1AR) and are not observed in IP3 R2 (inositol trisphosphate receptor type 2) knockout mice, in which astrocytic Ca2+ surges are absent. Together, we propose that tDCS changes the metaplasticity of the cortex through astrocytic Ca2+ /IP3 signalling. Moreover, the stimulation parameters were found to be sufficient to alleviate a mouse model of depression by chronic restraint stress.
Prions prevent neuronal cell-line death Kuwahara, Chieko; Takeuchi, Alice M; Nishimura, Takuya ...
Nature (London),
07/1999, Letnik:
400, Številka:
6741
Journal Article
Recenzirano
Prion diseases, such as scrapie and bovine spongiform encephalopathy (BSE) in animals and Creutzfeldt-Jakob disease (CJD) in humans, are neurodegenerative conditions characterized by the accumulation ...of a post-transcriptionally modified, pathological form of a host-encoded glycoprotein, designated PrPSc. The physiological function of the normal cellular isoform, PrPC, is unknown, although studies of mice devoid of PrPC have indicated that it may be involved in normal synaptic function and survival of Purkinje cells, but findings have been inconsistent. We find that serum removal from the cell culture causes apoptosis in Prnp −/− cells (in which a disrupted form of the prion protein is produced) but not in Prnp +/+ (wild-type) cells. Transduction of PrP or the Bcl-2 gene suppressed apoptosis of Prnp −/− cells under serum-free conditions. We also found that Prnp −/− cells extended shorter neurites than Prnp +/+ cells, but expression of PrPC increased their length. These findings support the idea that the loss of function of PrPC may partly underlie the pathogenesis of prion diseases.
Long-lasting neuronal plasticity as well as long-term memory (LTM) requires de novo synthesis of proteins through dynamic regulation of gene expression. cAMP-responsive element (CRE)-mediated gene ...transcription occurs in an activity-dependent manner and plays a pivotal role in neuronal plasticity and LTM in a variety of species. To study the physiological role of inducible cAMP early repressor (ICER), a CRE-mediated gene transcription repressor, in neuronal plasticity and LTM, we generated two types of ICER mutant mice: ICER-overexpressing (OE) mice and ICER-specific knock-out (KO) mice. Both ICER-OE and ICER-KO mice show no apparent abnormalities in their development and reproduction. A comprehensive battery of behavioral tests revealed no robust changes in locomotor activity, sensory and motor functions, and emotional responses in the mutant mice. However, long-term conditioned fear memory was attenuated in ICER-OE mice and enhanced in ICER-KO mice without concurrent changes in short-term fear memory. Furthermore, ICER-OE mice exhibited retardation of kindling development, whereas ICER-KO mice exhibited acceleration of kindling. These results strongly suggest that ICER negatively regulates the neuronal processes required for long-term fear memory and neuronal plasticity underlying kindling epileptogenesis, possibly through suppression of CRE-mediated gene transcription.
The neuronal circuits mediating the sedative action of diazepam are unknown. Although the motor-depressant action of diazepam is suppressed in alpha1(H101R) homozygous knockin mice expressing ...diazepam-insensitive alpha1-GABA(A) receptors, global alpha1-knockout mice show greater motor sedation with diazepam. To clarify this paradox, attributed to compensatory up-regulation of the alpha2 and alpha3 subunits, and to further identify the neuronal circuits supporting diazepam-induced sedation, we generated Emx1-cre-recombinase-mediated conditional mutant mice, selectively lacking the alpha1 subunit (forebrain-specific alpha1(-/-)) or expressing either a single wild-type (H) or a single point-mutated (R) alpha1 allele (forebrain-specific alpha1(-/H) and alpha1(-/R) mice, respectively) in forebrain glutamatergic neurons. In the rest of the brain, alpha1(-/R) mutants are heterozygous alpha1(H101R) mice. Forebrain-specific alpha1(-/-) mice showed enhanced diazepam-induced motor depression and increased expression of the alpha2 and alpha3 subunits in the neocortex and hippocampus, in comparison with their pseudo-wild-type littermates. Forebrain-specific alpha1(-/R) mice were less sensitive than alpha1(-/H) mice to the motor-depressing action of diazepam, but each of these conditional mutants had a similar behavioral response as their corresponding control littermates. Unexpectedly, expression of the alpha1 subunit was reduced in forebrain, notably in alpha1(-/R) mice, and the alpha3 subunit was up-regulated in neocortex, indicating that proper alpha1 subunit expression requires both alleles. In conclusion, conditional manipulation of GABA(A) receptor alpha1 subunit expression can induce compensatory changes in the affected areas. Specifically, alterations in GABA(A) receptor expression restricted to forebrain glutamatergic neurons reproduce the behavioral effects seen after a global alteration, thereby implicating these neurons in the motor-sedative effect of diazepam.
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