Neuroligin-2 Deletion Selectively Decreases Inhibitory Synaptic Transmission Originating from Fast-Spiking but Not from Somatostatin-Positive Interneurons

Department of Neuroscience and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 11/2009; 29(44):13883-97. DOI: 10.1523/JNEUROSCI.2457-09.2009
Source: PubMed


Neuroligins are cell adhesion molecules involved in synapse formation and/or function. Neurons express four neuroligins (NL1-NL4), of which NL1 is specific to excitatory and NL2 to inhibitory synapses. Excitatory and inhibitory synapses include numerous subtypes. However, it is unknown whether NL1 performs similar functions in all excitatory and NL2 in all inhibitory synapses, or whether they regulate the formation and/or function of specific subsets of synapses. To address this central question, we performed paired recordings in primary somatosensory cortex of mice lacking NL1 or NL2. Using this system, we examined neocortical microcircuits formed by reciprocal synapses between excitatory neurons and two subtypes of inhibitory interneurons, namely, fast-spiking and somatostatin-positive interneurons. We find that the NL1 deletion had little effect on inhibitory synapses, whereas the NL2 deletion decreased (40-50%) the unitary (cell-to-cell) IPSC amplitude evoked from single fast-spiking interneurons. Strikingly, the NL2 deletion had no effect on IPSC amplitude evoked from single somatostatin-positive inhibitory interneurons. Moreover, the frequency of unitary synaptic connections between individual fast-spiking and somatostatin-positive interneurons and excitatory neurons was unchanged. The decrease in unitary IPSC amplitude originating from fast-spiking interneurons in NL2-deficient mice was due to a multiplicative and uniform downscaling of the amplitude distribution, which in turn was mediated by a decrease in both synaptic quantal amplitude and quantal content, the latter inferred from an increase in the coefficient of variation. Thus, NL2 is not necessary for establishing unitary inhibitory synaptic connections but is selectively required for "scaling up" unitary connections originating from a subset of interneurons.

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Available from: Kimberly Huber, Jun 30, 2015
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    • "Hundreds of papers using diverse approaches have yielded different, often contradictory conclusions . In mice, constitutive triple knockout (KO) of NL1, NL2, and NL3 produced lethality, probably because of impairments in synaptic transmission (Varoqueaux et al., 2006), while constitutive single KOs of individual neuroligins caused robust non-lethal synaptic phenotypes (Chubykin et al., 2007; Jamain et al., 2008; Gibson et al., 2009; Poulopoulos et al., 2009; Etherton et al., 2011; Baudouin et al., 2012; Jedlicka et al., 2013). Neither single nor triple constitutive neuroligin KO mice exhibited a decrease in synapse numbers. "
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    ABSTRACT: Neuroligins are postsynaptic cell-adhesion molecules that bind presynaptic neurexins and are genetically linked to autism. Neuroligins are proposed to organize synaptogenesis and/or synaptic transmission, but no systematic analysis of neuroligins in a defined circuit is available. Here, we show that conditional deletion of all neuroligins in cerebellar Purkinje cells caused loss of distal climbing-fiber synapses and weakened climbing-fiber but not parallel-fiber synapses, consistent with alternative use of neuroligins and cerebellins as neurexin ligands for the excitatory climbing-fiber versus parallel-fiber synapses. Moreover, deletion of neuroligins increased the size of inhibitory basket/stellate-cell synapses but simultaneously severely impaired their function. Multiple neuroligin isoforms differentially contributed to climbing-fiber and basket/stellate-cell synapse functions, such that inhibitory synapse-specific neuroligin-2 was unexpectedly essential for maintaining normal climbing-fiber synapse numbers. Using systematic analyses of all neuroligins in a defined neural circuit, our data thus show that neuroligins differentially contribute to various Purkinje-cell synapses in the cerebellum in vivo. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 08/2015; 87(4). DOI:10.1016/j.neuron.2015.07.020 · 15.05 Impact Factor
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    • "The mechanism by which deletion of Nlgn2 would affect only a subset of perisomatic synapses is currently unknown, but may potentially be explained by the existence of a molecularly heterogeneous synapse population, in which Nlgn2 is either redundant or not present in some synapses. Interestingly, previous studies have reported differential effects of Nlgn2 deletion on mIPSCs in different brain regions , revealing a pronounced decrease in mIPSC frequency and a lesser decrease in amplitude in area CA1 of hippocampus (Poulopoulos et al., 2009), but a decrease in mIPSC amplitude without accompanying changes in frequency in somatosensory cortex (Gibson et al., 2009) and dentate gyrus (Jedlicka et al., 2011). "
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    ABSTRACT: Neuroligin 2 (Nlgn2) is a synaptic adhesion protein that plays a central role in the maturation and function of inhibitory synapses. Nlgn2 mutations have been associated with psychiatric disorders such as schizophrenia, and in mice, deletion of Nlgn2 results in a pronounced anxiety phenotype. To date, however, the molecular and cellular mechanisms linking Nlgn2 deletion to psychiatric phenotypes remain completely unknown. The aim of this study was therefore to define the role of Nlgn2 in anxiety-related neural circuits. To this end, we used a combination of behavioral, immunohistochemical, and electrophysiological approaches in Nlgn2 knockout (KO) mice to expand the behavioral characterization of these mice and to assess the functional consequences of Nlgn2 deletion in the amygdala. Moreover, we investigated the differential activation of anxiety-related circuits in Nlgn2 KO mice using a cFOS activation assay following exposure to an anxiogenic stimulus. We found that Nlgn2 is present at the majority of inhibitory synapses in the basal amygdala, where its deletion affects postsynaptic structures specifically at perisomatic sites and leads to impaired inhibitory synaptic transmission. Following exposure to an anxiogenic environment, Nlgn2 KO mice show a robust anxiety phenotype as well as exacerbated induction of cFOS expression specifically in CaMKII-positive projection neurons, but not in parvalbumin- or somatostatin-positive interneurons. Our data indicate that Nlgn2 deletion predominantly affects inhibitory synapses onto projection neurons in basal amygdala, resulting in decreased inhibitory drive onto these neurons and leading to their excessive activation under anxiogenic conditions. Copyright © 2015. Published by Elsevier Ltd.
    Neuropharmacology 06/2015; DOI:10.1016/j.neuropharm.2015.06.016 · 5.11 Impact Factor
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    • "uroligin ( NL ) homologs ( Nlg1 - Nlg4 ) have been identified in mammals ( Ichtchenko et al . , 1996 ) , with different homologs located in different classes of synapses ( Budreck and Scheiffele , 2007 ; Hoon et al . , 2011 ; Song et al . , 1999 ) . Neuroligin 2 is involved in the formation , differentiation and maturation of inhibitory synapses ( Gibson et al . , 2009 ; Levinson et al . , 2005 ; Poulopou - los et al . , 2009 ) . CaMKII signaling has been shown to be essential for NL to enhance synaptic function ( Chubykin et al . , 2007 ) . We then asked whether NL2 clusters mediate inhibitory synapse formation in response to TGF - b1 . We showed here that TGF - b1 induction of GABAergic synapses is "
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    ABSTRACT: The balance between excitatory and inhibitory synaptic inputs is critical for the control of brain function. Astrocytes play important role in the development and maintenance of neuronal circuitry. Whereas astrocytes-derived molecules involved in excitatory synapses are recognized, molecules and molecular mechanisms underlying astrocyte-induced inhibitory synapses remain unknown. Here, we identified transforming growth factor beta 1 (TGF-β1), derived from human and murine astrocytes, as regulator of inhibitory synapse in vitro and in vivo. Conditioned media derived from human and murine astrocytes induce inhibitory synapse formation in cerebral cortex neurons, an event inhibited by pharmacologic and genetic manipulation of the TGF-β pathway. TGF-β1-induction of inhibitory synapse depends on glutamatergic activity and activation of CaM kinase II, which thus induces localization and cluster formation of the synaptic adhesion protein, Neuroligin 2, in inhibitory postsynaptic terminals. Additionally, intraventricular injection of TGF-β1 enhanced inhibitory synapse number in the cerebral cortex. Our results identify TGF-β1/CaMKII pathway as a novel molecular mechanism underlying astrocyte control of inhibitory synapse formation. We propose here that the balance between excitatory and inhibitory inputs might be provided by astrocyte signals, at least partly achieved via TGF-β1 downstream pathways. Our work contributes to the understanding of the GABAergic synapse formation and may be of relevance to further the current knowledge on the mechanisms underlying the development of various neurological disorders, which commonly involve impairment of inhibitory synapse transmission. GLIA 2014
    Glia 12/2014; 62(12). DOI:10.1002/glia.22713 · 6.03 Impact Factor
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