PubMed Health⌕ Search

Biomedical subjects

Susumu Tonegawa

Publications and source records attributed to Susumu Tonegawa.

At least 19 recordsLinked to original sources
PubMed2006

Transgenic brain-derived neurotrophic factor expression causes both anxiogenic and antidepressant effects.

Although neurotrophins have been postulated to have antidepressant properties, their effect on anxiety is not clear. We find that transgenic overexpression of the neurotrophin BDNF has an unexpected facilitatory effect on anxiety-like behavior, concomitant with increased spinogenesis in the basolateral amygdala. Moreover, anxiogenesis and amygdalar spinogenesis are also triggered by chronic stress in control mice but are occluded by BDNF overexpression, thereby suggesting a role for BDNF signaling in stress-induced plasticity in the amygdala. BDNF overexpression also causes antidepressant effects, because transgenic mice exhibit improved performance on the Porsolt forced-swim test and an absence of chronic stress-induced hippocampal atrophy. Thus, structural changes in the amygdala and hippocampus, caused by genetic manipulation of the same molecule BDNF, give rise to contrasting effects on anxiety and depressive symptoms, both of which are major behavioral correlates of stress disorders.

Amygdala↗
PubMed2006

In vivo two-photon imaging reveals a role of arc in enhancing orientation specificity in visual cortex.

Cortical representations of visual information are modified by an animal's visual experience. To investigate the mechanisms in mice, we replaced the coding part of the neural activity-regulated immediate early gene Arc with a GFP gene and repeatedly monitored visual experience-induced GFP expression in adult primary visual cortex by in vivo two-photon microscopy. In Arc-positive GFP heterozygous mice, the pattern of GFP-positive cells exhibited orientation specificity. Daily presentations of the same stimulus led to the reactivation of a progressively smaller population with greater reactivation reliability. This adaptation process was not affected by the lack of Arc in GFP homozygous mice. However, the number of GFP-positive cells with low orientation specificity was greater, and the average spike tuning curve was broader in the adult homozygous compared to heterozygous or wild-type mice. These results suggest a physiological function of Arc in enhancing the overall orientation specificity of visual cortical neurons during the post-eye-opening life of an animal.

Animals↗
PubMed2006

Impaired sequential egocentric and allocentric memories in forebrain-specific-NMDA receptor knock-out mice during a new task dissociating strategies of navigation.

The hippocampus is considered to play a role in allocentric but not in egocentric spatial learning. How does this view fit with the emerging evidence that the hippocampus and possibly related cortical areas are necessary for episodic-like memory, i.e., in all situations in which events need to be spatially or sequentially organized? Are NMDA receptor-dependent mechanisms crucial for the acquisition of spatiotemporal relationships? To address this issue, we used knock-out (KO) mice lacking hippocampal CA1 NMDA receptors and presenting a reduction of these receptors in the deep cortical layers (NR1-KO mice). A new task (the starmaze) was designed, allowing us to distinguish allocentric and sequential-egocentric memories. NR1-KO mice were impaired in acquiring both types of memory. Our findings suggest that memories composed of multiple spatiotemporal events require intact NMDA receptors-dependent mechanisms in CA1 and possibly in the deep cortical layers.

Animals↗
PubMed2006

Hippocampal CA3 NMDA receptors are crucial for adaptive timing of trace eyeblink conditioned response.

Classical conditioning of the eyeblink reflex is a simple form of associative learning for motor responses. To examine the involvement of hippocampal CA3 NMDA receptors (NRs) in nonspatial associative memory, mice lacking an NR1 subunit selectively in adult CA3 pyramidal cells [CA3-NR1 knock-out (KO) mice] were subjected to eyeblink conditioning paradigms. Mice received paired presentations of an auditory conditioned stimulus (CS) and a periorbital shock unconditioned stimulus (US). With repeated presentation of the CS followed by the US, wild-type mice learned to blink in anticipation of the US before its onset. We first confirmed that wild-type mice require an intact hippocampus in the trace version of eyeblink conditioning in which the CS and US do not overlap, creating a stimulus-free time gap of 500 ms. Under the same condition, CA3-NR1 KO mice successfully acquired conditioned responses (CRs) during the 10 d acquisition sessions, whereas the extinction of CRs was impaired on the first day of extinction sessions. Importantly, CA3-NR1 KO mice were impaired in the formation of an adaptively timed CR during the first five trials in the daily acquisition sessions. The aberrantly timed CR was also observed in the extinction sessions in accordance with the impaired extinction of CRs. These results indicate that CA3-NR1 KO mice are unable to rapidly retrieve adaptive CR timing, suggesting that CA3 NRs play a crucial role in the memory of adaptive CR timing in trace conditioning.

Adaptation, Physiological↗
PubMed2006

A clustered plasticity model of long-term memory engrams.

Long-term memory and its putative synaptic correlates the late phases of both long-term potentiation and long-term depression require enhanced protein synthesis. On the basis of recent data on translation-dependent synaptic plasticity and on the supralinear effect of activation of nearby synapses on action potential generation, we propose a model for the formation of long-term memory engrams at the single neuron level. In this model, which we call clustered plasticity, local translational enhancement, along with synaptic tagging and capture, facilitates the formation of long-term memory engrams through bidirectional synaptic weight changes among synapses within a dendritic branch.

Animals↗
PubMed2005

Hippocampal neurons express a calcineurin-activated adenylyl cyclase.

Ca2+-stimulated adenylyl cyclases are important for several forms of neuroplasticity because they couple activity-dependent Ca2+ increases to cAMP in neurons. For example, the calmodulin-stimulated adenylyl cyclases, AC1 and AC8, are required for hippocampus-dependent memory and long-lasting long-term potentiation. To identify other mechanisms for Ca2+ stimulation of adenylyl cyclases, cultured hippocampal neurons from transgenic mice lacking both AC1 and AC8 [double knock-out (DKO) mice] were analyzed for Ca2+ stimulation of intracellular cAMP. Surprisingly, neurons from DKO mice showed significant Ca2+-stimulated cAMP accumulation that was blocked by inhibitors of calcineurin [PP2B (protein phosphatase 2B)], a Ca2+-activated protein phosphatase. Analysis of cultured neurons from calcineurin(-/-) mice confirmed that hippocampal neurons exhibit a calcineurin-dependent cAMP increase, which may contribute to some forms of neuroplasticity.

Adenylyl Cyclases↗
PubMed2005

Thalamic Cav3.1 T-type Ca2+ channel plays a crucial role in stabilizing sleep.

It has long been suspected that sensory signal transmission is inhibited in the mammalian brain during sleep. We hypothesized that Cav3.1 T-type Ca2+ channel currents inhibit thalamic sensory transmission to promote sleep. We found that T-type Ca2+ channel activation caused prolonged inhibition (>9 s) of action-potential firing in thalamic projection neurons of WT but not Cav3.1 knockout mice. Inhibition occurred with synaptic transmission blocked and required an increase of intracellular Ca2+. Furthermore, focal deletion of the gene encoding Cav3.1 from the rostral-midline thalamus by using Cre/loxP recombination led to frequent and prolonged arousal, which fragmented and reduced sleep. Interestingly, sleep was not disturbed when Cav3.1 was deleted from cortical pyramidal neurons. These findings support the hypothesis that thalamic T-type Ca2+ channels are required to block transmission of arousal signals through the thalamus and to stabilize sleep.

Action Potentials↗
PubMed2004

Translational regulatory mechanisms in persistent forms of synaptic plasticity.

Memory and synaptic plasticity exhibit distinct temporal phases, with long-lasting forms distinguished by their dependence on macromolecular synthesis. Prevailing models for the molecular mechanisms underlying long-lasting synaptic plasticity have largely focused on transcriptional regulation. However, a growing body of evidence now supports a crucial role for neuronal activity-dependent mRNA translation, which may occur in dendrites for a subset of neuronal mRNAs. Recent work has begun to define the signaling mechanisms coupling synaptic activation to the protein synthesis machinery. The ERK and mTOR signaling pathways have been shown to regulate the activity of the general translational machinery, while the translation of particular classes of mRNAs is additionally controlled by gene-specific mechanisms. Rapid enhancement of the synthesis of a diverse array of neuronal proteins through such mechanisms provides the components necessary for persistent forms of LTP and LTD. These findings have important implications for the synapse specificity and associativity of protein synthesis-dependent changes in synaptic strength.

Animals↗
PubMed2004

Acceleration of visually cued conditioned fear through the auditory pathway.

Defensive responses elicited by sensory experiences are critical for survival. Mice acquire a conditioned fear response rapidly to an auditory cue but slowly to a visual cue, a difference in learned behavior that is likely to be mediated by direct projections to the lateral amygdala from the auditory thalamus but mainly indirect ones from the visual thalamus. Here, we show that acquisition of visually cued conditioned fear is accelerated in 'rewired' mice that have retinal projections routed to the auditory thalamus. Visual stimuli induce expression of the immediate early gene Fos (also known as c-fos) in the auditory thalamus and the lateral amygdala in rewired mice, similar to the way auditory stimuli do in control mice. Thus, the rewired auditory pathway conveys visual information and mediates rapid activity-dependent plasticity in central structures that influence learned behavior.

Amygdala↗
PubMed2004

Altered cortical synaptic morphology and impaired memory consolidation in forebrain- specific dominant-negative PAK transgenic mice.

Molecular and cellular mechanisms for memory consolidation in the cortex are poorly known. To study the relationships between synaptic structure and function in the cortex and consolidation of long-term memory, we have generated transgenic mice in which catalytic activity of PAK, a critical regulator of actin remodeling, is inhibited in the postnatal forebrain. Cortical neurons in these mice displayed fewer dendritic spines and an increased proportion of larger synapses compared to wild-type controls. These alterations in basal synaptic morphology correlated with enhanced mean synaptic strength and impaired bidirectional synaptic modifiability (enhanced LTP and reduced LTD) in the cortex. By contrast, spine morphology and synaptic plasticity were normal in the hippocampus of these mice. Importantly, these mice exhibited specific deficits in the consolidation phase of hippocampus-dependent memory. Thus, our results provide evidence for critical relationships between synaptic morphology and bidirectional modifiability of synaptic strength in the cortex and consolidation of long-term memory.

Analysis of Variance↗
PubMed2004

Translational control by MAPK signaling in long-term synaptic plasticity and memory.

Enduring forms of synaptic plasticity and memory require new protein synthesis, but little is known about the underlying regulatory mechanisms. Here, we investigate the role of MAPK signaling in these processes. Conditional expression of a dominant-negative form of MEK1 in the postnatal murine forebrain inhibited ERK activation and caused selective deficits in hippocampal memory retention and the translation-dependent, transcription-independent phase of hippocampal L-LTP. In hippocampal neurons, ERK inhibition blocked neuronal activity-induced translation as well as phosphorylation of the translation factors eIF4E, 4EBP1, and ribosomal protein S6. Correspondingly, protein synthesis and translation factor phosphorylation induced in control hippocampal slices by L-LTP-generating tetanization were significantly reduced in mutant slices. Translation factor phosphorylation induced in the control hippocampus by memory formation was similarly diminished in the mutant hippocampus. These results suggest a crucial role for translational control by MAPK signaling in long-lasting forms of synaptic plasticity and memory.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Visual cortex is rescued from the effects of dark rearing by overexpression of BDNF.

Visual deprivation such as dark rearing (DR) prolongs the critical period for ocular dominance plasticity and retards the maturation of gamma-aminobutyric acid (GABA)ergic inhibition in visual cortex. The molecular signals that mediate the effects of DR on the development of visual cortex are not well defined. To test the role of brain-derived neurotrophic factor (BDNF), we examined the effects of DR in transgenic mice in which BDNF expression in visual cortex was uncoupled from visual experience and remained elevated during DR. In dark-reared transgenic mice, visual acuity, receptive field size of visual cortical neurons, critical period for ocular dominance plasticity, and intracortical inhibition were indistinguishable from those observed in light-reared mice. Therefore, BDNF overexpression is sufficient for the development of aspects of visual cortex in the absence of visual experience. These results suggest that reduced BDNF expression contributes to retarded maturation of GABAergic inhibition and delayed development of visual cortex during visual deprivation.

Animals↗
PubMed2003

Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia.

Calcineurin (CN), a calcium- and calmodulin-dependent protein phosphatase, plays a significant role in the central nervous system. Previously, we reported that forebrain-specific CN knockout mice (CN mutant mice) have impaired working memory. To further analyze the behavioral effects of CN deficiency, we subjected CN mutant mice to a comprehensive behavioral test battery. Mutant mice showed increased locomotor activity, decreased social interaction, and impairments in prepulse inhibition and latent inhibition. In addition, CN mutant mice displayed an increased response to the locomotor stimulating effects of MK-801. Collectively, the abnormalities of CN mutant mice are strikingly similar to those described for schizophrenia. We propose that alterations affecting CN signaling could comprise a contributing factor in schizophrenia pathogenesis.

Amphetamine↗
PubMed2003

Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC, encoding the calcineurin gamma subunit.

Schizophrenia is a severe psychiatric disorder characterized by a complex mode of inheritance. Forebrain-specific CNB knockout mice display a spectrum of behavioral abnormalities related to altered behaviors observed in schizophrenia patients. To examine whether calcineurin dysfunction is involved in schizophrenia etiology, we undertook studies of an initial subset of calcineurin-related genes, prioritizing ones that map to loci previously implicated in schizophrenia by linkage studies. Transmission disequilibrium studies in a large sample of affected families detected association of the PPP3CC gene, which encodes the calcineurin gamma catalytic subunit, with disease. Our results identify PPP3CC, located at 8p21.3, as a potential schizophrenia susceptibility gene and support the proposal that alterations in calcineurin signaling contribute to schizophrenia pathogenesis.

Adult↗
PubMed2003

NMDA receptor-dependent ocular dominance plasticity in adult visual cortex.

The binocular region of mouse visual cortex is strongly dominated by inputs from the contralateral eye. Here we show in adult mice that depriving the dominant contralateral eye of vision leads to a persistent, NMDA receptor-dependent enhancement of the weak ipsilateral-eye inputs. These data provide in vivo evidence for metaplasticity as a mechanism for binocular competition and demonstrate that an ocular dominance shift can occur solely by the mechanisms of response enhancement. They also show that adult mouse visual cortex has a far greater potential for experience-dependent plasticity than previously appreciated. These insights may force a revision in how data on ocular dominance plasticity in mutant mice have been interpreted.

Aging↗