Highlighted Papers from the Maness Lab
Maness, PF and Schachner, M. Neural recognition molecules of the
immunoglobulin superfamily: signaling transducers of axon guidance and neuronal
migration. Nature Neuroscience 10 (2007) 19-26.
Please read
our new review on neural cell adhesion molecules and their signaling pathways,
which was written with our long term colleague and collaborator Professor
Melitta Schachner (University of Hamburg).
Sullivan, PF, Keefe RSE, Lange LA, Lange EM,
Stroup TS, Lieberman J, and Maness PF. NCAM1 and Neurocognition in Schizophrenia.
Biological Psychiatry, 61 (2007) 902-910.
Background.
Alterations in neurocognition may be fundamental to schizophrenia and may be
endophenotypes. Neural cell adhesion molecule 1 (NCAM1,aliases NCAM and CD56)
may be a candidate gene for schizophrenia or for neurocognition in
schizophrenia is supported by linkage and functional findings. Methods.
Subjects were 641 patients with schizophrenia who participated in the CATIE
clinical trial. Neurocognition was assessed at study baseline. Nine NCAM1 SNPs
were blindly genotyped. Analysis of covariance was used to test for single SNP
associations and haplotype regression for multilocus associations. Results.
As there were suggestions of population stratification, all analyses were
conducted stratified by inferred ancestry. In the “Europe only”
stratum, there were nominally significant associations with five contiguous
SNPs (rs1943620, rs1836796, rs1821693, rs686050, rs584427) with the strongest
association at rs1836796 (p=0.007). Via permutation testing, the probability of
obtaining five consecutive statistically significant SNPs with p-values
≤0.05 was p=0.0044. These results were robust to examination of model
assumptions. Haplotype analyses did not identify significant haplotype
associations. Conclusions. Although it is essential to see if these
findings replicate in additional samples, we suggest that NCAM1 deserves
further scrutiny for its relevance to clinical and etiological aspects of
schizophrenia.
Hinkle, C.L., Diestel, S., Lieberman, J.,
and Maness, P.F.
Metalloprotease-induced ectodomain shedding of neural cell adhesion
molecule (NCAM). Journal of
Neurobiology 66 (2006) 1378-1395.
The
extracellular region of the transmembrane neural cell adhesion molecule NCAM
(NCAM-EC) is shed as a soluble fragment at elevated levels in schizophrenic
brain. A novel transgenic mouse
line was generated to identify consequences on cortical development and
function of expressing soluble NCAM-EC from the neuron-specific enolase
promoter in developing and mature neocortex and hippocampus. NCAM-EC transgenic mice exhibited a
striking reduction in synaptic puncta of GABAergic interneurons in the
cingulate, frontal association cortex, and amygdala, but not hippocampus, as
shown by decreased immunolabeling of glutamic acid decarboxylase-65 (GAD65),
GAD67, and the GABA transporter GAT-1.
Interneuron cell density was unaltered in the transgenic mice. Affected subpopulations of interneurons
included basket interneurons evident in NCAM-EC transgenic mice intercrossed
with a reporter line expressing green fluorescent protein and by parvalbumin
staining. Behavioral analyses demonstrated higher basal locomoter activity of
NCAM-EC mice and enhanced responses to amphetamine and MK-801 compared to wild
type controls. Transgenic mice were deficient in prepulse inhibition, which was
restored by clozapine but not haloperidol. Additionally, NCAM-EC mice were
impaired in contextual and cued fear conditioning. These results suggested that
elevated shedding of NCAM perturbs synaptic connectivity of GABAergic
interneurons, and produces abnormal behaviors that may be relevant to
schizophrenia and other neuropsychiatric disorders.
Pillai-Nair N, Panicker AK, Rodriguiz RM, Miller K, Demyanenko GP, Huang
JZ, Wetsel WC, and Maness PF: NCAM-secreting Transgenic Mice Display
Abnormalities in GABAergic Interneurons and Alterations in Behavior. Journal of Neuroscience 25, 4659-4671, 2005.
The
extracellular region of the transmembrane neural cell adhesion molecule NCAM
(NCAM-EC) is shed as a soluble fragment at elevated levels in schizophrenic
brain. A novel transgenic mouse line was generated to identify consequences on
cortical development and function of expressing soluble NCAM-EC from the
neuron-specific enolase promoter in developing and mature neocortex and
hippocampus. NCAM-EC transgenic mice exhibited a striking reduction in synaptic
puncta of GABAergic interneurons in the cingulate, frontal association cortex,
and amygdala, but not hippocampus, as shown by decreased immunolabeling of
glutamic acid decarboxylase-65 (GAD65), GAD67, and the GABA transporter GAT-1.
Interneuron cell density was unaltered in the transgenic mice. Affected subpopulations
of interneurons included basket interneurons evident in NCAM-EC transgenic mice
intercrossed with a reporter line expressing green fluorescent protein and by
parvalbumin staining. Behavioral analyses demonstrated higher basal locomoter
activity of NCAM-EC mice and enhanced responses to amphetamine and MK-801
compared to wild type controls. Transgenic mice were deficient in prepulse
inhibition, which was restored by clozapine but not haloperidol. Additionally,
NCAM-EC mice were impaired in contextual and cued fear conditioning. These
results suggested that elevated shedding of NCAM perturbs synaptic connectivity
of GABAergic interneurons, and produces abnormal behaviors that may be relevant
to schizophrenia and other neuropsychiatric disorders.
We show that the neural cell recognition molecule Close
Homolog of L1 (CHL1) is required for neuronal positioning and dendritic growth
of pyramidal neurons in the posterior region of the developing mouse neocortex.
CHL1 was expressed in pyramidal neurons in a high-caudal to low-rostral
gradient within the developing cortex. Deep layer pyramidal neurons of
CHL1-minus mice were shifted to lower laminar positions in the visual and
somatosensory cortex and developed misoriented, often inverted apical
dendrites. Impaired migration of CHL1-minus cortical neurons was suggested by
strikingly slower rates of radial migration in cortical slices, failure to
potentiate integrin-dependent haptotactic cell migration in vitro, and
accumulation of migratory cells in the intermediate and
ventricular/subventricular zones in vivo. The restriction of CHL1 expression
and effects of its deletion in posterior neocortical areas suggests that CHL1
may regulate area-specific neuronal connectivity and, by extension, function in
the visual and somatosensory cortex.