CHL1
Neural cell adhesion molecule L1-like protein precursor (Close homolog of L1) [Contains: Processed neural cell adhesion molecule L1-like protein] [CALL]
Publications[править]
Dendritic spines in the developing mammalian neocortex are initially overproduced and then eliminated during adolescence to achieve appropriate levels of excitation in mature networks. We show here that the L1 family cell adhesion molecule Close Homolog of L1 (CHL1) and secreted repellent ligand Semaphorin 3B (Sema3B) function together to induce dendritic spine pruning in developing cortical pyramidal neurons. Loss of CHL1 in null mutant mice in both genders resulted in increased spine density and a greater proportion of immature spines on apical dendrites in the prefrontal and visual cortex. Electron microscopy showed that excitatory spine synapses with postsynaptic densities were increased in the CHL1-null cortex, and electrophysiological recording in prefrontal slices from mutant mice revealed deficiencies in excitatory synaptic transmission. Mechanistically, Sema3B protein induced elimination of spines on apical dendrites of cortical neurons cultured from wild-type but not CHL1-null embryos. Sema3B was secreted by the cortical neuron cultures, and its levels increased when cells were treated with the GABA antagonist gabazine. [i]In vivo[/i] CHL1 was coexpressed with Sema3B in pyramidal neuron subpopulations and formed a complex with Sema3B receptor subunits Neuropilin-2 and PlexinA4. CHL1 and NrCAM, a closely related L1 adhesion molecule, localized primarily to distinct spines and promoted spine elimination to Sema3B or Sema3F, respectively. These results support a new concept in which selective spine elimination is achieved through different secreted semaphorins and L1 family adhesion molecules to sculpt functional neural circuits during postnatal maturation. Dendritic spines in the mammalian neocortex are initially overproduced and then pruned in adolescent life through unclear mechanisms to sculpt maturing cortical circuits. Here, we show that spine and excitatory synapse density of pyramidal neurons in the developing neocortex is regulated by the L1 adhesion molecule, Close Homolog of L1 (CHL1). CHL1 mediated spine pruning in response to the secreted repellent ligand Semaphorin 3B and associated with receptor subunits Neuropilin-2 and PlexinA4. CHL1 and related L1 adhesion molecule NrCAM localized to distinct spines, and promoted spine elimination to Semaphorin 3B and -3F, respectively. These results support a new concept in which selective elimination of individual spines and nascent synapses can be achieved through the action of distinct secreted semaphorins and L1 adhesion molecules.
MeSH Terms
- Aging
- Animals
- Cell Adhesion Molecules
- Cells, Cultured
- Dendritic Spines
- Female
- GABA Agonists
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Nerve Tissue Proteins
- Neuropilin-2
- Patch-Clamp Techniques
- Prefrontal Cortex
- Protein Interaction Mapping
- Pyramidal Cells
- Pyridazines
- Receptors, Cell Surface
- Semaphorins
- Synaptic Transmission
- Visual Cortex
Keywords
- Semaphorin 3B
- autism spectrum disorders
- cell adhesion molecule
- close homolog of L1
- dendritic spine
- spine pruning
In humans, deletions/mutations in the CHL1/CALL gene are associated with mental retardation and schizophrenia. Juvenile CHL1-deficient (CHL1(-/-) ) 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(-/-) mouse are affected during brain maturation and in adulthood. We found that hippocampal, but not neocortical, PV( ) interneurons were reduced with age in CHL1(-/-) 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(-/-) mice. This deficit could be abrogated by a GABAA 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. Close homolog of L1-deficient (CHL1(-/-) ) mice have abnormally high numbers of parvalbumin (PV)-expressing hippocampal interneurons in juvenile animals, but in adult animals a loss of these cells is observed. This loss correlates with an increased density of microglia (M), enhanced interleukin-6 (IL6) production and a deficit in short- and long-term potentiation at CA3-CA1 excitatory synapses. Furthermore, adult CHL1(-/-) mice display behavioral traits similar to those observed in neuropsychiatric disorders of humans.
MeSH Terms
- Aging
- Animals
- Calcium-Binding Proteins
- Cell Adhesion Molecules
- Cerebellum
- Enzyme-Linked Immunosorbent Assay
- Excitatory Postsynaptic Potentials
- Gene Expression Regulation
- Hippocampus
- In Vitro Techniques
- Interleukin-3
- Interleukin-6
- Interneurons
- Mice
- Mice, Transgenic
- Microfilament Proteins
- Microscopy, Electron
- Parvalbumins
- Patch-Clamp Techniques
- Phosphopyruvate Hydratase
- S100 Proteins
- Synapses
Keywords
- close homolog of L1
- hippocampus
- interneu- rons
- long-term potentiation
- parvalbumin
- synaptic plasticity