Article

Neuroligin-1-dependent competition regulates cortical synaptogenesis and synapse number.

1] Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA. [2] Max Planck Florida Institute, Jupiter, Florida, USA.
Nature Neuroscience (Impact Factor: 14.98). 11/2012; DOI: 10.1038/nn.3256
Source: PubMed

ABSTRACT Members of the neuroligin family of cell-adhesion proteins are found at excitatory and inhibitory synapses and are mutated in some familial forms of autism spectrum disorders. Although they display synaptogenic properties in heterologous systems, the function of neuroligins in vivo in the regulation of synapse formation and synapse number has been difficult to establish. We found that neuroligin-1 (NL1), which is located at excitatory postsynaptic densities, regulates activity-dependent synaptogenesis and mature synapse number on cortical layer 2/3 pyramidal neurons in vivo. However, synapse number was not sensitive to absolute NL1 levels but instead depended on transcellular differences in the relative amounts of NL1. These effects were independent of the cell-autonomous regulation of NMDA-type glutamate receptors by absolute levels of NL1. Our data indicate that transcellular competitive processes govern synapse formation and number in developing cortex and that NL1 has a central function in these processes.

Download full-text

Full-text

Available from: Jessica L Saulnier, Jul 15, 2014
1 Follower
 · 
172 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuroligin 1 (NLGN1) is a postsynaptic adhesion molecule that determines N-methyl-D-aspartate receptor (NMDAR) function and cellular localization. Our recent work showed that Nlgn1 knockout (KO) mice cannot sustain neuronal activity occurring during wakefulness for a prolonged period of time. Since NMDAR-dependent neuronal activity drives an important vascular response, we used multispectral optical imaging to determine if the hemodynamic response to neuronal stimulation is modified in Nlgn1 KO mice. We observed that Nlgn1 KO mice show a 10% lower response rate to forepaw electrical stimulation compared to wild-type and heterozygote littermates on both the contra- and ipsilateral sides of the somatosensory cortex. Moreover, Nlgn1 mutant mice showed an earlier oxyhemoglobin (HbO) peak response that tended to return to baseline faster than in wild-type mice. Analysis of the time course of the hemodynamic response also showed that heterozygous mice express a faster dynamics of cerebrovascular response in comparison to wild-type. Taken together, these data are indicative of an altered immediate response of the brain to peripheral stimulation in Nlgn1 KO mice, and suggest a role for NLGN1 in the regulation of cerebrovascular responses. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 01/2015; 289. DOI:10.1016/j.neuroscience.2014.12.069 · 3.33 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: During cortical development, synaptic competition regulates the formation and adjustment of neuronal connectivity. It is unknown whether synaptic competition remains active in the adult brain and how inhibitory neurons participate in this process. Using morphological and electrophysiological measurements, we show that expressing a dominant-negative form of the TrkB receptor (TrkB.T1) in the majority of pyramidal neurons in the adult visual cortex does not affect excitatory synapse densities. This is in stark contrast to the previously reported loss of excitatory input which occurs if the exact same transgene is expressed in sparse neurons at the same age. This indicates that synaptic competition remains active in adulthood. Additionally, we show that interneurons not expressing the TrkB.T1 transgene may have a competitive advantage and obtain more excitatory synapses when most neighboring pyramidal neurons do express the transgene. Finally, we demonstrate that inhibitory synapses onto pyramidal neurons are reduced when TrkB signaling is interfered with in most pyramidal neurons but not when few pyramidal neurons have this deficit. This adjustment of inhibitory innervation is therefore not a cell-autonomous consequence of decreased TrkB signaling but more likely a homeostatic mechanism compensating for activity changes at the population level.
    Cerebral Cortex 10/2014; DOI:10.1093/cercor/bhu245 · 8.31 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Rodent models are a key factor in the process of translating psychiatric genetics and genomics findings, allowing us to shed light on how risk-genes confer changes in neurobiology by merging different types of data across fields, from behavioural neuroscience to the burgeoning omics (e.g. genomics, epigenomics, proteomics, etc.). Moreover, they also provide an indispensable first step for drug discovery. However, recent evidence from both clinical and genetic studies highlights possible limitations in the current methods for classifying psychiatric illness, as both symptomology and underlying genetic risk are found to increasingly overlap across disorder diagnoses. Meanwhile, integration of data from animal models across disorders is currently limited. Here, we argue that behavioural neuroscience is in danger of missing informative data because of the practice of trying to ‘diagnose’ an animal model with a psychiatric illness. What is needed is a shift in emphasis, from seeking to ally an animal model to a specific disorder, to one focused on a more systematic assessment of the neurobiological and behavioural outcomes of any given genetic or environmental manipulation.
    European Journal of Neuroscience 05/2014; 39(11). DOI:10.1111/ejn.12607 · 3.67 Impact Factor