Neural cell adhesion molecule ablation in mice causes hippocampal dysplasia and loss of septal cholinergic neurons

Tereshchenko, Yuliya; Morellini, Fabio; Dityatev, Alexander; Schachner, Melitta; Irintchev, Andrey

doi:10.1002/cne.22636

Cited by 13 publications

(11 citation statements)

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“…Furthermore, a progressive decline in PSA-NCAM with age is observed in schizophrenia (Barbeau et al, 1995;Seki and Arai, 1999;Cox et al, 2009) and accompanies structural changes in the brain. Similarly to schizophrenic and elderly patients (Convit et al, 2001), brain size and weight are decreased in NCAM Ϫ/Ϫ mice (Wood et al, 1998;Tereshchenko et al, 2011). Overall, DCS ameliorates impairments related to schizophrenia (Javitt, 2006), other age-related brain pathologies (Mohr et al, 1995;Tsai et al, 1999), and deficits found in adult and aged NCAM Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 93%

Restoration of Synaptic Plasticity and Learning in Young and Aged NCAM-Deficient Mice by Enhancing Neurotransmission Mediated by GluN2A-Containing NMDA Receptors

Kochlamazashvili¹,

Bukalo²,

Senkov³

et al. 2012

J. Neurosci.

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Neural cell adhesion molecule (NCAM) is the predominant carrier of the unusual glycan polysialic acid (PSA)., but not NCAM ϩ/ϩ mice, there was a decline in LTP compared with 3-month-old mice that could be rescued by DCS. In 24-month-old mice of both genotypes, there was a reduction in LTP that could be fully restored by DCS in NCAM ϩ/ϩ mice but only partially restored in NCAM Ϫ/Ϫ mice. Thus, several deficiencies of NCAM Ϫ/Ϫ mice can be ameliorated by enhancing GluN2A-mediated neurotransmission with DCS.

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Section: Discussionmentioning

confidence: 93%

Restoration of Synaptic Plasticity and Learning in Young and Aged NCAM-Deficient Mice by Enhancing Neurotransmission Mediated by GluN2A-Containing NMDA Receptors

Kochlamazashvili¹,

Bukalo²,

Senkov³

et al. 2012

J. Neurosci.

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“…Whereas constitutive NCAM knockout mice have been much characterized (Theodosis et al 2004;Tereshchenko et al 2011;Kochlamazashvili et al 2012), information regarding the (neuro)-physiological impact of the mutation in NCAMffcre mice is scarce. However, available information indicates an existing vulnerability in these mice.…”

Section: Discussionmentioning

confidence: 99%

Age-related cognitive impairments in mice with a conditional ablation of the neural cell adhesion molecule

et al. 2013

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Most of the mechanisms involved in neural plasticity support cognition, and aging has a considerable effect on some of these processes. The neural cell adhesion molecule (NCAM) of the immunoglobulin superfamily plays a pivotal role in structural and functional plasticity and is required to modulate cognitive and emotional behaviors. However, whether aging is associated with NCAM alterations that might contribute to age-related cognitive decline is not currently known. In this study, we determined whether conditional NCAM-deficient mice display increased vulnerability to age-related cognitive and emotional alterations. We assessed the NCAM expression levels in the hippocampus and medial prefrontal cortex (mPFC) and characterized the performance of adult and aged conditional NCAM-deficient mice and their age-matched wild-type littermates in a delayed matching-to-place test in the Morris water maze and a delayed reinforced alternation test in the T-maze. Although aging in wild-type mice is associated with an isoform-specific reduction of NCAM expression levels in the hippocampus and mPFC, these mice exhibited only mild impairments in working/episodic-like memory performance. However, aged conditional NCAM-deficient mice displayed pronounced impairments in both the delayed matching-to-place and the delayed reinforced alternation tests. Importantly, the deficits of aged NCAM-deficient mice in these working/episodic-like memory tasks could not be attributed to increased anxiety-like behaviors or to differences in locomotor activity. Taken together, these data indicate that reduced NCAM expression in the forebrain might be a critical factor for the occurrence of cognitive impairments during aging.[Supplemental material is available for this article.]One of the hallmarks of normal aging is a gradual decline in cognitive function associated with the progressive reduction of structural and functional plasticity in brain regions that play a key role in cognitive functions, such as the hippocampus and the prefrontal cortex (Seki and

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“…We could exclude glial cells from these counts as their nuclei were easily recognizable by their small size compared with neuronal nuclei, but we were unable to distinguish nuclei of principal cells from interneurons, a fact that appears negligible in the context of our study, since interneurons, both PV‐positive and negative, are very rare (< 1%) in the principal cell layers compared with the overwhelming numbers of densely packed pyramidal or granule cells (Tereshchenko et al . ).…”

Section: Methodsmentioning

confidence: 97%

“…The cingulate cortical area Cg1‐Cg2 (Franklin and Paxinos ) and the subdivisions of the hippocampus (Tereshchenko et al . ) were identified and delineated on the basis of the nuclear staining pattern seen at low‐power magnification (10× objective). The border between the dorsal and ventral hippocampus in the coronal plane was defined to be at bregma −2.3 mm (Franklin and Paxinos ).…”

Section: Methodsmentioning

confidence: 99%

Age‐dependent loss of parvalbumin‐expressing hippocampal interneurons in mice deficient in CHL1, a mental retardation and schizophrenia susceptibility gene

Schmalbach

Lepsveridze

Djogo

et al. 2015

Journal of Neurochemistry

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In humans, deletions/mutations in the CHL1/CALL gene are associated with mental retardation and schizophrenia. Juvenile CHL1-deficient (CHL1 À/À ) mice have been shown to display abnormally high numbers of parvalbumin-expressing (PV + ) hippocampal interneurons and, as adults, display behavioral traits observed in neuropsychiatric disorders. Here, we addressed the question whether inhibitory interneurons and synaptic plasticity in the CHL1 À/À mouse are affected during brain maturation and in adulthood. We found that hippocampal, but not neocortical, PV + interneurons were reduced with age in CHL1 À/À mice, from a surplus of +27% at 1 month to a deficit of -20% in adulthood compared with wild-type littermates. This loss occurred during brain maturation, correlating with microgliosis and enhanced interleukin-6 expression. In parallel with the loss of PV + interneurons, the inhibitory input to adult CA1 pyramidal cells was reduced and a deficit in short-and long-term potentiation developed at CA3-CA1 excitatory synapses between 2 and 9 months of age in CHL1 À/À mice.This deficit could be abrogated by a GABA A receptor agonist. We propose that region-specific aberrant GABAergic synaptic connectivity resulting from the mutation and a subsequently enhanced synaptic elimination during brain maturation lead to microgliosis, increase in pro-inflammatory cytokine levels, loss of interneurons, and impaired synaptic plasticity.

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Neural cell adhesion molecule ablation in mice causes hippocampal dysplasia and loss of septal cholinergic neurons

Cited by 13 publications

References 100 publications

Restoration of Synaptic Plasticity and Learning in Young and Aged NCAM-Deficient Mice by Enhancing Neurotransmission Mediated by GluN2A-Containing NMDA Receptors

Restoration of Synaptic Plasticity and Learning in Young and Aged NCAM-Deficient Mice by Enhancing Neurotransmission Mediated by GluN2A-Containing NMDA Receptors

Age-related cognitive impairments in mice with a conditional ablation of the neural cell adhesion molecule

Age‐dependent loss of parvalbumin‐expressing hippocampal interneurons in mice deficient in CHL1, a mental retardation and schizophrenia susceptibility gene

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