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Neurexin Dysfunction in Adult Neurons Results in Autistic-Like Behavior in Mice

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Neurexin Dysfunction in Adult Neurons Results in Autistic-Like Behavior in Mice Cell Reports Report Neurexin Dysfunction in Adult Neurons Results in Autistic-like Behavior in Mice Luis G. Rabaneda,1 Estefanı´a Robles-Lanuza,1 Jose´ Luis Nieto-Gonza´ lez,1,2 and Francisco G. Scholl1,* 1Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocı´o/CSIC/Universidad de Sevilla and Departamento de Fisiologı´a Me´ dica y Biofı´sica, Universidad de Sevilla, Campus del Hospital Universitario Virgen del Rocı´o, Avenida Manuel Siurot s/n, Sevilla 41013, Spain 2Centro de Investigacio´ n Biome´ dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Campus del Hospital Universitario Virgen del Rocı´o, Avenida Manuel Siurot s/n, Sevilla 41013, Spain *Correspondence: [email protected] http://dx.doi.org/10.1016/j.celrep.2014.06.022 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). SUMMARY The neurexin family of synaptic plasma membrane proteins forms one class of ASD-associated genes. Neurexins are en- Autism spectrum disorders (ASDs) comprise a group coded by three genes (NRXN1, NRXN2, and NRXN3), each of of clinical phenotypes characterized by repetitive which generates long a- and short b-neurexin proteins from behavior and social and communication deficits. alternative promoters (Tabuchi and Su¨ dhof, 2002; Ushkaryov Autism is generally viewed as a neurodevelopmental et al., 1992). Deletions and truncating mutations in the NRXN1 a b disorder where insults during embryonic or early gene affecting and isoforms have been linked to autism postnatal periods result in aberrant wiring and func- and other neurodevelopmental disorders (Ching et al., 2010; Gauthier et al., 2011; Schaaf et al., 2012; Szatmari et al., tion of neuronal circuits. Neurexins are synaptic 2007). Moreover, point mutations specific to the NRXN1b proteins associated with autism. Here, we generated gene have been identified in ASD patients (Camacho-Garcia b D transgenic Nrx1 C mice in which neurexin function et al., 2012, 2013). Neurexins couple presynaptic signaling is selectively impaired during late postnatal stages. with binding to postsynaptic partners, such as neuroligins Whole-cell recordings in cortical neurons show an (NLGNs) (Dean et al., 2003; Su¨ dhof, 2008). The identification impairment of glutamatergic synaptic transmission of mutations in NLGN and SHANK genes in ASD pointed to glu- in the bNrx1DC mice. Importantly, mutant mice tamatergic dysfunction of the NRNX-NLGN-SHANK pathway in exhibit autism-related symptoms, such as increased autism (Durand et al., 2007; Jamain et al., 2003; Laumonnier self-grooming, deficits in social interactions, and et al., 2004). altered interaction for nonsocial olfactory cues. The Current genetic data support that hypofunction of neurexin autistic-like phenotype of bNrx1DC mice can be isoforms is a risk factor in autism. However, the brain regions and the developmental stage in which loss of neurexin function reversed after removing the mutant protein in aged leads to autistic-like behaviors are not known. In rodents, neu- animals. The defects resulting from disruption of rexin mRNAs are expressed throughout the developing and neurexin function after the completion of embryonic mature CNS (Ehrmann et al., 2013; Iijima et al., 2011; Pu¨ schel and early postnatal development suggest that and Betz, 1995), which raises the question of whether autism- functional impairment of mature circuits can trigger related symptoms can emerge from neurexin dysfunction after autism-related phenotypes. the development has been completed. The manipulation of neu- rexins is challenging because of their genetic complexity and INTRODUCTION high number of isoforms (Treutlein et al., 2014). In multifactorial disorders, such as ASD, a combination of DNA variants in a num- Autism spectrum disorder (ASD) is a complex neurodevelop- ber of genes contributes to the clinical presentation. This poses mental syndrome characterized by restricted and stereotyped difficulties when the role of individual mutations is assessed in behavior patterns, difficulty with social interactions, and deficits animal models. Therefore, a dominant-negative approach is in verbal/nonverbal communication. ASD symptoms typically well suited to address the effect of impaired neurexin function emerge in early childhood and persist through adulthood, sug- in vivo. In this study, we generated transgenic mice that express gesting ASD origin could stem from prenatal impairment that a neurexin-1b mutant in postnatal neurons of brain regions impli- develops into enduring postnatal manifestations. Alternatively, cated in autism, such as cortex and striatum (Parikshak et al., dysfunction of postnatal neuronal networks at symptom onset 2013; Shepherd, 2013; Willsey et al., 2013). Neurexin-1b mutant may define the clinical phenotype for this disorder. Thus, it mice showed impaired glutamatergic transmission in pyramidal remains unclear whether there are early critical periods where cortical neurons and autism-related phenotype. Importantly, autism develops or if postnatal dysfunction of neuronal circuits the autism phenotype was reversed in young as well as older is sufficient to produce autism-related phenotypes. mice upon inhibiting the expression of mutant neurexin-1b. Our 338 Cell Reports 8, 338–346, July 24, 2014 ª2014 The Authors data indicate that neurexin dysfunction in postnatal forebrain inducible manner using the Tet-off system (Figure 1D). First, neurons recapitulates the core symptoms of autism, which can we obtained a mouse line (TRE-HAbnrx1DC) that expresses be reversed in adult animals when normal neurexin function is the HA-bnrx1DC transgene under the control of the tetracy- resumed. cline-responsive promoter element (TRE). TRE-HAbnrx1DC mice did not express HA-bnrx1DC protein in the brain, showing RESULTS no escape of the transgene (Figure 1E). It has been shown that expression of neurexin-1 (-S4) transcripts is maximal in fore- Characterization of the Neurexin-1b Mutant Protein brain regions, including cortex (Ehrmann et al., 2013; Iijima Cytoplasmic-tail deletion mutants have been previously shown et al., 2011). Therefore, to direct the expression of HA-bnrx1DC to inhibit the synaptic function of neurexin variants in cultured protein to forebrain neurons, we crossed TRE-HAbnrx1DC mice neurons (Choi et al., 2011; Dean et al., 2003; Futai et al., 2007). with CaMKIIa-tTA mice that express the tetracycline trans- The shared cytoplasmic tail of neurexins interacts with presyn- activator (tTA) in postnatal glutamatergic neurons of the fore- aptic scaffolding proteins (Butz et al., 1998), whereas alternative brain (Mayford et al., 1996). Double-transgenic CaMKIIa-tTA; splicing at the extracellular domain modulates the binding to TRE-HAbnrx1DC mice (bNrx1DC mice) expressed HA-bnrx1DC postsynaptic partners, such that maximal binding to neuroligins protein in forebrain neurons of the cortex and striatum and is exhibited by neurexin-1b variants lacking an insertion at splice showed no detectable expression in the midbrain and cere- site 4 (-S4) (Boucard et al., 2005; Comoletti et al., 2006; Dean bellum (Figures 1E and 1F). Compared with endogenous neu- et al., 2003). Thus, to uncouple neurexin-1b function, we gener- rexin-1b, exogenous HA-bnrx1DC protein is expressed at ated a hemagglutinin (HA)-tagged deletion mutant of neurexin- 100%–200% in cortex and striatum (Figure 1F). Importantly, 1b (-S4) that lacks the cytoplasmic tail (Figure 1A). First, we expression of HA-bnrx1DC turns on only in the third postnatal analyzed the distribution of the HA-bnrx1DC protein, as it has week (Figure 1G). Thus, in our mouse model, neurexin function been suggested that C-terminal sequences are required for syn- is unperturbed over the first 2 postnatal weeks when extensive aptic targeting of neurexin-1a (Fairless et al., 2008). The cell-sur- synapse formation takes place. Upon onset, HA-bnrx1DC face localization of the HA-bnrx1DC protein was confirmed expression is maintained throughout adulthood (Figure 1G) in nonpermeabilized human embryonic kidney 293T (HEK293T) but can be suppressed by doxycycline (Dox) feeding of the cells (Figure S1A). Then, we studied the synaptic recruitment of mutant mice (Figure 1H). HA-bnrx1DC induced by neuroligin-1 (NL1) in nonneuronal cells (Scheiffele et al., 2000). HA-bnrx1DC concentrated at synaptic Synaptic Defects in bNrx1DC Mice contacts mediated by VSV-NL1 at similar levels as wild-type Neurexins have been proposed to participate in synapse forma- HA-bnrx1 (Figure 1B). The enrichment of the glutamatergic syn- tion and function by a presynaptic mechanism (Dean et al., aptic vesicle marker vGluT1 to NL1 synapses was not affected 2003; Missler et al., 2003). Therefore, an inhibitory effect in glu- by the expression of HA-bnrx1DC(Figure 1B), indicating that tamatergic synapses was predicted as a consequence of the the cytoplasmic tail of neurexin-1b is dispensable for the recruit- expression of the neurexin-1b mutant in cortical glutamatergic ment of synaptic vesicles, consistent with a recent report (Gokce neurons. Immunoblot experiments of cortical synaptosomes re- and Su¨ dhof, 2013). vealed that HA-bnrx1DC is mostly expressed at presynaptic We reasoned that HA-bnrx1DC mutant might compete with fractions (Figures 2A and 2B), in agreement with a presynaptic endogenous neurexins for the binding to postsynaptic partners role of neurexin proteins. Because the expression of the neu- but affect other presynaptic parameters such as synapse func- rexin-1b mutant begins at
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