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Mouse Neurexin-1 Deletion Causes Correlated Electrophysiological And Mouse neurexin-1␣ deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments Mark R. Ethertona,1, Cory A. Blaissb,1, Craig M. Powellb,c, and Thomas C. Su¨ dhof a,d,e,f,g,2 aDepartment of Molecular and Cellular Physiology and dHoward Hughes Medical Institute, Stanford University, 1050 Arastradero Road, CA 94304; and Departments of bNeurology, cPsychiatry, eNeuroscience, and fMolecular Genetics, and gHoward Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390 Contributed by Thomas C. Su¨dhof, September 9, 2009 (sent for review August 2, 2009) Deletions in the neurexin-1␣ gene were identified in large-scale patients carry neurexin-1␣ deletions. Thus, understanding the unbiased screens for copy-number variations in patients with biology of neurexin-1␣ and its role in the pathogenesis of ASDs autism or schizophrenia. To explore the underlying biology, we and schizophrenia assumes added importance. In view of the studied the electrophysiological and behavioral phenotype of mice human clinical genetics data, we have now performed an lacking neurexin-1␣. Hippocampal slice physiology uncovered a in-depth analysis of the synaptic phenotype produced by the defect in excitatory synaptic strength in neurexin-1␣ deficient neurexin-1␣ deletion in mice, and examined the behavioral mice, as revealed by a decrease in miniature excitatory postsyn- consequences of this deletion. Based on the viability of aptic current (EPSC) frequency and in the input-output relation of neurexin-1␣ KO mice and on the human condition, we ex- evoked postsynaptic potentials. This defect was specific for exci- pected a limited phenotype without incapacitating impair- tatory synaptic transmission, because no change in inhibitory ments. Indeed, our data show that neurexin-1␣ KO mice synaptic transmission was observed in the hippocampus. Behav- exhibit a discrete, but significant, electrophysiological pheno- ioral studies revealed that, compared with littermate control mice, type that is associated with pervasive behavioral abnormali- neurexin-1␣ deficient mice displayed a decrease in prepulse inhi- ties, which in turn, are suggestive of some features of cognitive bition, an increase in grooming behaviors, an impairment in nest- diseases. building activity, and an improvement in motor learning. However, neurexin-1␣ deficient mice did not exhibit any obvious changes in Results social behaviors or in spatial learning. Together, these data indi- Deletion of Neurexin-1␣ Reduces Spontaneous Excitatory Synaptic ␣ cate that the neurexin-1 deficiency induces a discrete neural Transmission. We first used whole-cell voltage-clamp recordings phenotype whose extent correlates, at least in part, with impair- to measure spontaneous miniature excitatory postsynaptic cur- ments observed in human patients. rents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) in hippocampal CA1 pyramidal neurons in the presence ͉ ͉ ͉ ͉ autism neuroligin schizophrenia synaptic cell-adhesion synapse of TTX (Fig. 1 A–C). Neurexin-1␣ KO mice exhibited a significant, and selective, decrease in mEPSC frequency without a change in eurexins are neuronal cell-surface proteins that were iden- mIPSC frequency, indicating a potential impairment in excitatory Ntified as receptors for ␣-latrotoxin, a presynaptic toxin that synaptic transmission or excitatory synapse number (Fig. 1B). Also, triggers massive neurotransmitter release (1–3). Neurexins are no change in the mEPSC or mIPSC amplitude was observed, which largely presynaptic proteins that form a transsynaptic cell- suggests that deletion of neurexin-1␣ did not alter the quantal size adhesion complex with postsynaptic neuroligins (4, 5). Verte- or postsynaptic receptor numbers (Fig. 1C). brates express three neurexin genes, each of which includes two To further test the effect of neurexin-1␣ deletion on sponta- ␣ promoters that direct the synthesis of the longer -neurexins and neous neurotransmission, we assessed the excitatory/inhibitory ␤ the shorter -neurexins (6, 7). Neurexins are expressed in all balance of individual neurons in the CA1 region of the hip- neurons, and are subject to extensive alternative splicing, gen- pocampus. Specifically, we used whole-cell voltage-clamp re- Ͼ erating 1,000 splice variants, some of which exhibit highly cordings to monitor spontaneous miniature events in the same regulated developmental and spatial expression patterns (8). neuron both at the chloride-reversal potential (Ϫ60 mV; to The properties of neurexins suggested that they function as measure mEPSCs) and at the glutamatergic current reversal synaptic recognition molecules (1), and mediate transsynaptic potential (0 mV; to measure mIPSCs) in artificial cerebrospinal interactions via binding to neuroligins (4). In support of this ␣ fluid containing only TTX. Using this approach (Fig. 1 D–F), we overall concept, -neurexin triple KO mice exhibit major im- confirmed that neurexin-1␣ KO neurons exhibited a reduced pairments in synaptic transmission that manifest largely, but not ␣ mEPSC frequency that resulted in a shift in the excitatory/ exclusively, as presynaptic changes (9–13). Importantly, -neur- inhibitory balance of individual CA1 pyramidal neurons to favor exin KO mice do not display a major decrease in the number of decreased excitatory input. In summary, these findings suggest excitatory synapses, and only a moderate decrease in inhibitory that deletion of neurexin-1␣ impairs excitatory synaptic trans- synapses (9, 13). Thus, neurexins appear to be essential compo- mission in the hippocampus. nents of synaptic function whose roles extend to several different components of synapses. In recent years, enormous progress in human genetics has Author contributions: M.R.E., C.A.B., C.M.P., and T.C.S. designed research; M.R.E. and C.A.B. led to the identification of multiple genes that are linked to performed research; M.R.E., C.A.B., C.M.P., and T.C.S. analyzed data; and M.R.E., C.A.B., autism spectrum disorders (ASDs) and schizophrenia. Inter- C.M.P., and T.C.S. wrote the paper. estingly, copy-number variations in the neurexin-1␣ gene (but The authors declare no conflict of interest. not the neurexin-1␤ gene) were repeatedly observed in pa- 1M.R.E. and C.A.B. contributed equally to this work. tients with ASDs (14–21) and schizophrenia (22–25). Because 2To whom correspondence should be addressed. E-mail: [email protected]. ␣ 0.5% of all ASD cases appear to harbor neurexin-1 gene This article contains supporting information online at www.pnas.org/cgi/content/full/ deletions, and ASDs are highly prevalent, thousands of ASD 0910297106/DCSupplemental. 17998–18003 ͉ PNAS ͉ October 20, 2009 ͉ vol. 106 ͉ no. 42 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0910297106 Downloaded by guest on October 1, 2021 A mEPSCs mIPSCs A Neurexin-1α WT Neurexin-1α KO Neurexin- 1a WT 0.5 mV Neurexin- 5 ms 1a KO 20 pA 50 pA B C 1 s 0.4 s B WT 1.0 1.0 4 * 0.8 0.8 1.0 ** p<0.05 0.6 0.6 KO 2 0.4 0.4 0.5 α Neurexin-1a WT Neurexin-1a WT Neurexin-1 WT α Linear Fit Slope/Slice 0.2 a 0.2 a Slope (mV/ms) fEPSP Neurexin-1 KO Cumulative Probability Cumulative Neurexin-1 KO Probability Cumulative Neurexin-1 KO WT, n=9; KO, n=9 WT, n=11; KO, n=9 WT, n=9; KO, n=8 0 0 0 0 0246 0 200 400 600 00.10.20.3 WT KO mEPSC Inter-event Interval (s) mIPSC Inter-event Interval (ms) Fiber-volley Amplitude (mV) C 0.4 1.0 1.0 DENeurexin-1α WT Neurexin-1α KO NMDA 0.8 0.8 0.2 0.6 0.6 AMPA 30 pA 0 0.4 0.4 20 ms ratio NMDA/AMPA WT KO Neurexin-1a WT Neurexin-1a WT 0.2 a 0.2 a α Cumulative Probability Cumulative Cumulative Probability Cumulative Neurexin-1 KO Neurexin-1 KO Neurexin-1 WT FGNeurexin-1α WT WT, n=9; KO, n=9 WT, n=11; KO, n=9 α 0 0 1.4 Neurexin-1 KO 0204060 0 50 100 150 200 250 WT, n=9; KO, n=6 NEUROSCIENCE mEPSC Amplitude (pA) mIPSC Amplitude (pA) 1.2 D mEPSCs (-60 mV) mIPSCs (0 mV) Neurexin-1α KO Neurexin- 1.0 1a WT Paired-Pulse Ratio 0.5 mV 00.20.40.6 Neurexin- 100 ms Inter-stimulus Interval (s) 1a KO 30 pA 30 pA ␣ 0.5 s 0.5 s Fig. 2. Neurexin-1 KO mice exhibit a decrease in excitatory synaptic * strength in the CA1 region of the hippocampus. (A) Sample traces for extra- E 15 cellular field EPSP recordings performed in stratum radiatum of CA1 region of n.s. hippocampus. (B) Summary graph of input-output measurements. The slope 20 of the fEPSP is plotted as a function of the fiber-volley amplitude (WT, three 10 mice per nine slices; KO, three mice per eight slices). Linear fit slopes were n.s. n.s. calculated for WT (4.815 Ϯ 0.285) and KO (3.616 Ϯ 0.296) slices and were significantly different (P ϭ 0.011, unpaired Student’s t test). (C) Summary 15 5 graph of linear fit slopes for WT and KO input-output curves. (D and E) Sample Neurexin-1a WT Neurexin-1a WT a a traces and summary graph for whole-cell voltage clamp recordings of NMDA/ Neurexin-1 KO mIPSC Amplitude (pA) Neurexin-1 KO AMPA ratio in CA1 pyramidal neurons (WT, three mice per six cells; KO, three mIPSC Frequency (Hz) mIPSC Frequency WT, n=8; KO, n=8 WT, n=8; KO, n=8 0 10 mice per eight cells). (F and G) Sample traces and summary graph for paired- 012345 51015 mEPSC Frequency (Hz) mEPSC Amplitude (pA) pulse facilitation measurements (fEPSP2/fEPSP1) recorded at various inter- stimulus intervals (WT, three mice per nine slices; KO, three mice per six slices).
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