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.
    Full-text · Article · Aug 2015 · Neuron
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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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    Full-text · Article · Jun 2015 · Neuropharmacology
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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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