Impairment of Suckling Response, Trigeminal Neuronal Pattern Formation, and Hippocampal LTD in NMDA Receptor ε2 Subunit Mutant Mice

Kutsuwada, Tatsuya; Sakimura, Kenji; Manabe, Toshiya; Takayama, Chitoshi; Katakura, Nobuo; Kushiya, Etsuko; Natsume, Rie; Watanabe, Masahiko; Inoue, Yoshiro; Yagi, Takeshi; Aizawa, Shinichi; Arakawa, Masaaki; Takahashi, Tomoyuki; Nakamura, Yoshio; Mori, Hisashi; Mishina, Masayoshi

doi:10.1016/s0896-6273(00)80051-3

Cited by 458 publications

(385 citation statements)

References 58 publications

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“…Because the NR2D is expressed at very low levels in the hippocampus (Wenzel et al, 1996), it appears that a single type of NMDA receptor, containing the NR1 and NR2B subunit, is present in this area from P0 to PlO (Table 1). This is supported by studies on NR2B subunit-deficient mice, in which no functional NMDA receptors were detected in hippocampal slice preparations prepared from P2-PS mice (Kutsuwada et al, 1996).…”

Section: Expression Of Nr Mrna and Proteinmentioning

confidence: 73%

NMDA Receptor Heterogeneity During Postnatal Development of the Rat Brain: Differential Expression of the NR2A, NR2B, and NR2C Subunit Proteins

Wenzel

Fritschy

Möhler

et al. 1997

Journal of Neurochemistry

406

254

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Abstract:Changes in the expression of the NMDA receptor subunits (NRs) NR2A, 2B, and 2C were investigated in histo blots of the developing rat brain with subunitspecific antisera. At birth, the NR2B subunit was detected almost ubiquitously, the NR2A subunit staining was faint and restricted to the hippocampus, cerebral cortex, and striatum, and no NR2C subunit immunoreactivity was detected. During the first 3 postnatal weeks, the NR2B subunit became confined to forebrain structures, whereas the NR2A immunoreactivity became abundantly expressed throughout the brain. The NR2C immunoreactivity emerged 5 days after birth in the olfactory bulb, thalamus, and vestibular nuclei and became very intense after 10 days in cerebellar granule cells, its primary site of expression in adulthood. After 3 weeks, NR2A and NR2B immunoreactivity decreased to adult levels, whereas NR2C immunoreactivity remained unchanged. The patterns of distribution of the subunit proteins were in agreement with those of their corresponding mRNAs, as monitored by in situ hybridization histochemistry, although the mRNA translation appeared to be delayed by several days in certain areas. Our results reveal a progressive increase in the heterogeneity of NMDA receptors due to the comparably late onset of NR2A and NR2C subunit expression and by the area-specific rearrangement of NR2B subunit expression following birth. Key Words: NMDA receptor -Subunit -specific antisera -DevelopjiientHisto blots-Rat. J. Neurochem. 68, 469-478 (1997).N-Methyl-D-aspartate (NMDA) receptors are glutamate-activated cation channels, characterized by a high Ca 2~INa~permeability ratio, a voltage-dependent Mg 2+ block, a requirement for glycine as coagonist, and slow activation and deactivation kinetics (Nowak et al

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Section: Expression Of Nr Mrna and Proteinmentioning

confidence: 73%

NMDA Receptor Heterogeneity During Postnatal Development of the Rat Brain: Differential Expression of the NR2A, NR2B, and NR2C Subunit Proteins

Wenzel

Fritschy

Möhler

et al. 1997

Journal of Neurochemistry

406

254

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“…In contrast, genetic manipulations of NMDARs showed an absence of periphery-related patterns in the somatosensory cortex 6 . This result could not be ascribed to direct effects on the neocortex, however, as it could have been a consequence of impaired patterns at the brainstem level 6,12,13 . To delineate the specific role(s) of cortical NMDARs in patterning, here we disrupted the function of NR1-the essential subunit of the NMDAR-specifically in the cortex, using the Cre/loxP system 14 .…”

mentioning

confidence: 85%

“…When NMDAR function is insufficient or absent in the entire brain, neuronal patterns do not form in the brainstem trigeminal nuclei 6,12,13 . In these cases, trigeminal afferent terminals convey a topographic projection to the brainstem but fail to develop patterns, showing that NMDAR function in the brainstem is required for presynaptic patterning (a presynaptic effect).…”

Section: Introductionmentioning

confidence: 99%

“…The morphological abnormalities observed in our CxNRIKO mice cannot be attributed to a general deficit in cortical development, because layers form normally, thalamocortical axons terminate in their proper cortical layers and somatotopy is established in the CxNR1KOmice. Furthermore, cortical cell migration is not impaired in mice with complete deletion of the NR1 gene 26 .When NMDAR function is insufficient or absent in the entire brain, neuronal patterns do not form in the brainstem trigeminal nuclei 6,12,13 . In these cases, trigeminal afferent terminals convey a topographic projection to the brainstem but fail to develop patterns, showing that NMDAR function in the brainstem is required for presynaptic patterning (a presynaptic effect).…”

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confidence: 99%

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Cortex-restricted disruption of NMDAR1 impairs neuronal patterns in the barrel cortex

Iwasato

Datwani

Wolf

et al. 2000

Nature

463

509

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In the rodent primary somatosensory cortex, the configuration of whiskers and sinus hairs on the snout and of receptor-dense zones on the paws is topographically represented as discrete modules of layer IV granule cells (barrels) and thalamocortical afferent terminals 1,2 . The role of neural activity, particularly activity mediated by NMDARs (N-methyl-D-aspartate receptors), in patterning of the somatosensory cortex has been a subject of debate [3][4][5][6] . We have generated mice in which deletion of the NMDAR1 (NR1) gene is restricted to excitatory cortical neurons, and here we show that sensory periphery-related patterns develop normally in the brainstem and thalamic somatosensory relay stations of these mice. In the somatosensory cortex, thalamocortical afferents corresponding to large whiskers form patterns and display critical period plasticity, but their patterning is not as distinct as that seen in the cortex of normal mice. Other thalamocortical patterns corresponding to sinus hairs and digits are mostly absent. The cellular aggregates known as barrels and barrel boundaries do not develop even at sites where thalamocortical afferents cluster. Our findings indicate that cortical NMDARs are essential for the aggregation of layer IV cells into barrels and for development of the full complement of thalamocortical patterns.The rodent somatosensory system is an excellent model to study molecular mechanisms underlying the establishment of patterned topographic connections between the sensory periphery and the brain. Trigeminal and dorsal column pathways convey a somatosensory map from the periphery to the neocortex by relay stations in the brainstem and the ventrobasal thalamus. At each level, pre-synaptic afferents and their target cells establish a patterned array of modules corresponding to the arrangement of whiskers and sinus hairs on the snout (trigeminal pathway), and receptor-dense zones of the paws (dorsal column pathway) 2,7,8 . These patterns are consolidated during the first postnatal week, and are subject to alterations if the sensory periphery is perturbed by nerve or whisker lesions during a critical period 2,7,8 . Thus, early neural activity might be essential in the development and plasticity of central patterns much like that of the vertebrate visual system 9,10 . Within this context, NMDAR activity has attracted much attention 9,11 . Initial studies using pharmacological blockade of NMDARs in postnatal rat somatosensory cortex did not detect effects on thalamocortical patterning, but revealed functional impairment of thalamocortical connectivity and whisker-specific responsiveness of barrel neurons 4,5 . In contrast, genetic manipulations of NMDARs showed an absence of periphery-related patterns in the somatosensory cortex 6 . This result could not be ascribed to direct effects on the neocortex, however, as it could have been a consequence of impaired patterns at the brainstem level 6,12,13 . To delineate the specific role(s) of cortical NMDARs in patterning, here we disrupted the ...

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“…Physiol. 85.6 death (Kutsuwada et al 1996). Although no gross brain malformation could be detected in either NR1-or NR2B-deficient animals, failures in the formation of neuronal pattern in the brainstem trigeminal complex, in the refinement of synapses and the formation of barrelette structure were detected (Li et al 1994;Kutsuwada et al 1996).…”

Section: Gene Targeting For the Study Of Brain Receptor Functionsmentioning

confidence: 97%

Mouse genetics in cell biology

Mansuy¹,

Suter²

2000

Exp. Physiol.

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One of the most fascinating challenges in modern cell biology is the unravelling of the molecular mechanisms underlying the development and formation of functional organs, and the maintenance and regeneration of vertebrate tissues. In such processes, cell-cell interactions, mediated by direct contacts or secreted factors, and cell-extracellular matrix interactions are essential for the control of cell proliferation, migration, differentiation and death. These events are mediated by numerous molecular signals that have to be integrated within the cell to activate specific sets of regulatory factors responsible for correct spatial and temporal gene regulation. We are still far away from a complete understanding of these complex events at a molecular level but molecular genetic and genomic approaches have provided valuable tools and methodologies for the study of complex cellular functions in vivo. In particular, the development of reverse genetic methods such as transgene expression and gene targeting has allowed substantial progress in the understanding of the molecular mechanisms of cell-cell and cell-extracellular interactions. Although initially limited by a lack of spatial and temporal specificity, these approaches have recently undergone major developments partly overcoming these limitations, and have brought novel perspective into the application of genetic tools for the study of highly complex biological functions. To illustrate the power of genetic approaches in cell biology, we will describe in the first part of this review, several examples of mutant mice models that have allowed studies of developmental processes and neuron-glia interactions in the peripheral nervous system (PNS). The second part of the review will focus on recent advances of genetic approaches by describing the major methodologies, their latest developments and a few remarkable examples of their application in neurobiology and cancer research. Cell-cell and cell-extracellular matrix interactionsNeuronal and glial cell interactions in the nervous system Peripheral nerves are well suited to the study of the mechanisms of cell-cell interactions in organogenesis, a process in which cells determine the fate of their neighbours (Taylor & Suter, 1997;Jessen & Mirsky, 1999). This is exemplified in the process of myelination where two cell types, neurons and Schwann cells, exhibit a profound influence on each other. While axons regulate the proliferation and differentiation of Schwann cells, the latter are the main determinants of axon calibre and ion channel distribution. It has recently become clear that this cellular interdependence is not restricted to postnatal events, but that embryonic Schwann cell precursors and neurons also support each other for survival during critical periods of development. Furthermore, disturbance of the delicate balance between neuron and glia interactions by genetic manipulation has been revealed to be Genetic methodologies have provided powerful means for investigating the cellular and molecular mechanisms of ...

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Impairment of Suckling Response, Trigeminal Neuronal Pattern Formation, and Hippocampal LTD in NMDA Receptor ε2 Subunit Mutant Mice

Cited by 458 publications

References 58 publications

NMDA Receptor Heterogeneity During Postnatal Development of the Rat Brain: Differential Expression of the NR2A, NR2B, and NR2C Subunit Proteins

NMDA Receptor Heterogeneity During Postnatal Development of the Rat Brain: Differential Expression of the NR2A, NR2B, and NR2C Subunit Proteins

Cortex-restricted disruption of NMDAR1 impairs neuronal patterns in the barrel cortex

Mouse genetics in cell biology

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