Impairment of sensorimotor gating in mice deficient in the cell adhesion molecule L1 or its close homologue, CHL1

doi:10.1016/j.brainres.2004.09.042

Brain Research

Volume 1029, Issue 1, 10 December 2004, Pages 131-134

https://doi.org/10.1016/j.brainres.2004.09.042 Get rights and content

Abstract

Mutations in the gene encoding the cell adhesion molecule L1 or its close homologue, CHL1 (close homologue of L1), cause brain dysfunction in both humans and mice. Here we report that prepulse inhibition (PPI) of the acoustic startle response is impaired in mice deficient in either L1 or CHL1. This newly identified feature may provide a basis for using these mice as models for sensorimotor gating impairment found in some neuropsychiatric disorders such as schizophrenia.

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Acknowledgements

The authors are grateful to Peggy Putthoff for genotyping. The studies were supported in part by grants from the NIH to P.M. (NS26620 and MH064056) and a NARSAD Young Investigator Award to L.K.N.

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Cited by (41)

Chronic mild stress impairs latent inhibition and induces region-specific neural activation in CHL1-deficient mice, a mouse model of schizophrenia
2017, Behavioural Brain Research
Citation Excerpt :
CHL1 and other cell adhesion molecules of the immunoglobulin superfamily are highly expressed during the development of the nervous system [13], have multiple functions in the formation of appropriate neuronal connections during development [14] and in synaptic function and plasticity in the adult [15], processes which are thought to be disrupted in intellectual disabilities and schizophrenia [16]. CHL1-deficient mice [17] exhibit behavioral alterations suggestive of those found in schizophrenic patients [18–23], such as impaired sensorimotor gating (prepulse inhibition) [24,25] and reduced exploratory behavior in novel environments [17,26]. Timekeeping is disrupted in schizophrenic patients and individuals at risk for schizophrenia [22,27–31], as well as CHL1-deficient mice [32].
Schizophrenia is a neurodevelopmental disorder characterized by abnormal processing of information and attentional deficits. Schizophrenia has a high genetic component but is precipitated by environmental factors, as proposed by the ‘two-hit’ theory of schizophrenia. Here we compared latent inhibition as a measure of learning and attention, in CHL1-deficient mice, an animal model of schizophrenia, and their wild-type littermates, under no-stress and chronic mild stress conditions. All unstressed mice as well as the stressed wild-type mice showed latent inhibition. In contrast, CHL1-deficient mice did not show latent inhibition after exposure to chronic stress. Differences in neuronal activation (c-Fos-positive cell counts) were noted in brain regions associated with latent inhibition: Neuronal activation in the prelimbic/infralimbic cortices and the nucleus accumbens shell was affected solely by stress. Neuronal activation in basolateral amygdala and ventral hippocampus was affected independently by stress and genotype. Most importantly, neural activation in nucleus accumbens core was affected by the interaction between stress and genotype. These results provide strong support for a ‘two-hit’ (genes x environment) effect on latent inhibition in CHL1-deficient mice, and identify CHL1-deficient mice as a model of schizophrenia-like learning and attention impairments.
Increased temporal discounting after chronic stress in CHL1-deficient mice is reversed by 5-HT2C agonist Ro 60-0175
2017, Neuroscience
Citation Excerpt :
Genetic associations between CHL1 gene polymorphisms and schizophrenia (Sakurai et al., 2002; Chen et al., 2005; Shaltout et al., 2013) were found in Asian populations and rare copy number variants of this gene were identified in a Scottish study (Tam et al., 2010). Prepulse inhibition of the acoustic startle response is impaired in CHL1-KO mice, which can thus model sensorimotor gating impairments found in schizophrenic patients (Irintchev et al., 2004). Our current results show that other SZ-like deficits, such as impulsivity, can be revealed in these mice by stress, supporting a ‘double hit’ hypothesis (Bayer et al., 1999).
Schizophrenia is a neurodevelopmental disorder in which impaired decision-making and goal-directed behaviors are core features. One of the genes associated with schizophrenia is the Close Homolog of L1 (CHL1); CHL1-deficient mice are considered a model of schizophrenia-like deficits, including sensorimotor gating, interval timing and spatial memory impairments. Here we investigated temporal discounting in CHL1-deficient (KO) mice and their wild-type littermates. Although no discounting differences were found under baseline conditions, CHL1-KO mice showed increased impulsive choice following chronic unpredictable stress (fewer % larger-later choices, and reduced area under the discounting curve). Stressed CHL1-KO mice also showed decreased neuronal activation (number of cFos positive neurons) in the discounting task in the prelimbic cortex and dorsal striatum, areas thought to be part of executive and temporal processing circuits. Impulsive choice alterations were reversed by the 5-HT2C agonist Ro 60-0175. Our results provide evidence for a gene x environment, double-hit model of stress-related decision-making impairments, and identify CHL1-deficient mice as a mouse model for these deficits in regard to schizophrenia-like phenotypes.
Heterozygous deletion of CHL1 gene: Detailed array-CGH and clinical characterization of a new case and review of the literature
2014, European Journal of Medical Genetics
Citation Excerpt :
The importance of CHL1 function is pointed out by studies in partially or completely Chl1deficient mice, showing defects in neurotransmission, behavior, motor coordination, fiber organization in both olfactory bulb and hippocampus, and migration of cortical neurons. Moreover, a gene dosage effect of CHL1 expression levels was demonstrated [Frints et al., 2003; Demyanenko et al., 2004; Irintchev et al., 2004; Pratte and Jamon, 2004]. In humans, heterozygous loss of CHL1 gene has been associated with cognitive impairment characterized by learning and language difficulties.
CHL1 gene maps at 3p26.3 and encodes a cell adhesion molecule of the immunoglobulin superfamily highly expressed in the brain. CHL1 regulates neuronal migration and neurite overgrowth in the developing brain, while in mature neurons it accumulates in the axonal membrane and regulates synapse function via the clathrin-dependent pathways. To our knowledge, to date only three familial cases presenting heterozygous deletion of chromosome 3 at band p26.3, including only the CHL1 gene, have been reported. All the patients presented cognitive impairment characterized by learning and language difficulties. Here, we describe a six-year-old boy in which array-CGH analysis disclosed a terminal 3p26.3 deletion. The deletion was transmitted from his normal mother and included only the CHL1 gene. Our patient presented microcephaly, short stature, mild mental retardation, learning and language delay, and strabismus.
In our study we compare the phenotypic and molecular cytogenetic features of CHL1 gene deletion cases. Verbal function developmental delay seems to be a common key finding. The concomitance of the genetic and phenotypic alterations could be a good evidence of a new emerging syndrome associated with the deletion of CHL1 gene alone, although the identification of new cases is required.
Loss of function studies in mice and genetic association link receptor protein tyrosine phosphatase α to schizophrenia
2011, Biological Psychiatry
Citation Excerpt :
Absence of the NCAM isoform NCAM180 leads to increased lateral ventricle size, one of the most reliable morphological features in brains of schizophrenics, and is often accompanied by cognitive impairments (70). Association studies implicate NCAM and CHL1 in human SZ risk, and LOF of the corresponding genes in mice engenders intriguing phenotypic overlaps with Ptpra LOF in terms of cortical radial migration (72), dendrite orientation (24), impaired long-term potentiation (69), and impaired sensorimotor gating/PPI (73). Thus, phenotypes observed in Ptpra−/− mice could be mediated by the effect of RPTPα on these molecules.
Solid evidence links schizophrenia (SZ) susceptibility to neurodevelopmental processes involving tyrosine phosphorylation-mediated signaling. Mouse studies implicate the Ptpra gene, encoding protein tyrosine phosphatase RPTPα, in the control of radial neuronal migration, cortical cytoarchitecture, and oligodendrocyte differentiation. The human gene encoding RPTPα, PTPRA, maps to a chromosomal region (20p13) associated with susceptibility to psychotic illness.
We characterized neurobehavioral parameters, as well as gene expression in the central nervous system, of mice with a null mutation in the Ptpra gene. We searched for genetic association between polymorphisms in PTPRA and schizophrenia risk (two independent cohorts, 1420 cases and 1377 controls), and we monitored PTPRA expression in prefrontal dorsolateral cortex of SZ patients (35 cases, 2 control groups of 35 cases).
We found that Ptpra^−/− mice reproduce neurobehavioral endophenotypes of human SZ: sensitization to methamphetamine-induced hyperactivity, defective sensorimotor gating, and defective habituation to a startle response. Ptpra loss of function also leads to reduced expression of multiple myelination genes, mimicking the hypomyelination-associated changes in gene expression observed in postmortem patient brains. We further report that a polymorphism at the PTPRA locus is genetically associated with SZ, and that PTPRA mRNA levels are reduced in postmortem dorsolateral prefrontal cortex of subjects with SZ.
The implication of this well-studied signaling protein in SZ risk and endophenotype manifestation provides novel entry points into the etiopathology of this disease.
Impairment of novelty detection in mice targeted for the Chl1 gene
2009, Physiology and Behavior
A deficit in cell adhesion molecules including the human Chl1 (close homologue of the L1 cell adhesion molecule) gene may cause impairment of cognitive processes. Aberrant connectivity in the CA3 region of the hippocampus has been reported in mice lacking the CHL1 protein after Chl1 gene targeting. Previous studies have observed a deficit in the processing of novel information by CHL1-deficient mice. We investigated deficits in spatial discrimination and object discrimination in three groups of mice — Chl1^+/+, Chl1^+/− and Chl1^−/− — performing spatial and object novelty tasks. The results indicated that wild-type mice easily recognized objects that were either “displaced” or “substituted”. Chl1^−/− mice showed severe impairment of the capacity to react to both spatial and non-spatial novelty. Chl1^+/− mice were severely restricted in their ability to detect spatial changes, but succeeded in novel object discrimination. A dose-dependent sensitivity of the organization of the CA3 layer to the CHL1 protein may explain this result. However, the observations suggest that a dysfunction of parts of the brain other than the hippocampus may be involved in the impairment.
Modulation of synaptic transmission and plasticity by cell adhesion and repulsion molecules
2008, Neuron Glia Biology

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Short communicationImpairment of sensorimotor gating in mice deficient in the cell adhesion molecule L1 or its close homologue, CHL1

Abstract

Section snippets

Acknowledgements

Mol. Cell. Neurosci.

Am. J. Hum. Genet.

Behav. Brain Res.

Mol. Cell. Neurosci.

Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies

Psychopharmacology (Berl)

Disruption of the mouse L1 gene leads to malformations of the nervous system

Nat. Genet.

Abnormalities in neuronal process extension, hippocampal development, and the ventricular system of L1 knockout mice

J. Neurosci.

Close homolog of L1 (CHL1) modulates area-specific neuronal migration and dendrite orientation in the cerebral cortex

Neuron

A new role for the cell adhesion molecule L1 in neural precursor cell proliferation, differentiation, and transmitter-specific subtype generation

J. Neurosci.

Short communication
Impairment of sensorimotor gating in mice deficient in the cell adhesion molecule L1 or its close homologue, CHL1