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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Curr Opin Neurobiol. Author manuscript; available in PMC 2012 April 1.
Published in final edited form as:
PMCID: PMC3085653

Mechanisms of excitatory synapse maturation by trans-synaptic organizing complexes


Synapses are specialized cell-cell adhesion contacts that mediate communication within neural networks. During development, excitatory synapses are generated by step-wise recruitment of pre- and postsynaptic proteins to sites of contact. Several classes of synaptic organizing complexes have been identified that function during the initial stages of synapse formation. However, mechanisms underlying the later stages of synapse development are less well understood. In recent years, molecules have been discovered that appear to play a role in synapse maturation. In this review, we highlight recent findings that have provided key insights for understanding postsynaptic maturation of developing excitatory synapses with a focus on recruitment of AMPA receptors to developing synapses.

Keywords: excitatory synapse maturation, AMPA receptor recruitment, trans-synaptic organizing complexes


The developing central nervous system initially generates an abundance of chemical synapses which are later sculpted and refined into the elegant and precise neural networks of the adult brain. The first steps involve several trans-synaptic complexes – collectively referred to as ‘synaptic organizing proteins’ – that initiate and stabilize early synaptic contacts via recruitment of synaptic vesicles to the presynaptic active zone, and N-methyl-D-aspartate (NMDA) receptors to the postsynaptic density [14]. PDZ domain proteins such as PSD-95 serve as scaffolds for recruitment of synaptic components required for synapse development [5]. Initial flurries of excitatory synaptogenesis give way to an abundance of silent NMDA receptor-containing synapses subject to activity-dependent strengthening or elimination. Recruitment of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors to the postsynaptic membrane augments glutamatergic transmission and is a critical process in excitatory synapse maturation [6].

Several studies have investigated AMPA receptor trafficking during synaptic plasticity [711]; however, it is uncertain if similar or distinct mechanisms underlie initial stages of synapse development. AMPA receptors consist of tetramers of different combinations of one or more subunits termed GluA1-4 with distinct biophysical properties, trafficking, and binding partners [8, 12]. The C-terminal PDZ-binding motif interacts with cytoplasmic PDZ domain proteins such as PICK1, GRIP/ABP, and SAP-97 [5]. In addition, the PDZ domain protein PSD-95 interacts with AMPA receptors through stargazin [13], the prototypical transmembrane AMPA receptor regulatory protein (TARP). Recent studies have identified a diverse array of additional transmembrane accessory proteins that modulate AMPA receptor function [14]. The relationship between cytoplasmic AMPA receptor-interacting proteins and transmembrane accessory proteins in mature and developing synapse remains unclear.

Neurexin synaptic organizing complexes and AMPA receptor recruitment

Several trans-synaptic signaling systems have been identified that induce pre- or postsynaptic differentiation when presented to axons or dendrites by expression in non-neuronal cells [14]. Interestingly, recent results have demonstrated that diverse classes of synaptic organizing molecules form complexes of different members (for a recent and thorough review, see [4]). For example, in addition to interaction with neuroligins, neurexins influence presynaptic differentiation via interaction with the leucine-rich repeat transmembrane proteins (LRRTMs) [15**17]. Neurexins are also the presynaptic binding partner of the Cbln1-GluD2 complex, a structurally distinct signaling system that directs synapse formation [18]. Thus, a multifaceted system of trans-synaptic mechanisms underlies synapse development.

Different classes of synaptic organizing complexes differentially influence AMPA receptor recruitment at developing synapses (Figure 1; Table 1). Early studies indicated that synaptic organizing complexes promote formation of structural synapses that are capable of releasing neurotransmitter but are postsynaptically silent, and thus, non-functional, due to the lack of AMPA receptors. For instance, clusters of neuroligin-1 and PSD-95 induced by β-neurexin overlap with NMDA but not AMPA receptors [19] even though in theory, AMPA receptors could be recruited to sites of neurexin-neuroligin induced PSD-95 clusters through stargazin [20]. However, GluA1-containing AMPA receptor clustering at neurexin-neuroligin contact sites can be induced upon glutamate application [21], suggesting that neuroligin-neurexin induced synapse maturation is activity regulated. Indeed, increases in synapse numbers in transfected neurons expressing neuroligins require synaptic activity [22]. In addition, overexpression of neuroligin-1 in hippocampal neurons facilitates recruitment of GluA2-containing AMPA receptors (but not GluA1-containing AMPA receptors, consistent with [21]) to PSD-95 clusters induced by neurexin-coated microspheres in an activity-independent manner [23*], suggesting that AMPA receptor recruitment at neurexin-neuroligin contacts is subunit specific.

Figure 1
AMPA receptor recruitment by select synaptic organizing complexes
Table 1
Modulation of AMPA receptors by select synaptic organizers

Other neurexin-interacting proteins differentially influence AMPA receptor recruitment at developing synapses. Like neuroligins, all LRRTMs induce presynaptic differentiation in axons when expressed in nonneuronal cells [24]. LRRTM2 was further shown to influence postsynaptic differentiation as follows. Coculture of neurons and nonneuronal cells expressing NMDA receptor subunits and LRRTM2 leads to spontaneous currents [24]. Short-hairpin RNA (shRNA)-mediated knockdown of LRRTM2 in dissociated hippocampal neurons resulted in decreased GluA1 content at synapses and a large (>50%) decrease in evoked synaptic currents [15**]. However, miniature excitatory postsynaptic current (mEPSC) amplitudes were only modestly reduced and mEPSC frequency was unchanged upon LRRTM2 knockdown [15**]. Because the reduction in mEPSC amplitude does not seem sufficient to cause the dramatic decrease in excitatory synaptic transmission, these data suggest that LRRTM2 primarily regulates synapse efficacy and plays a minor role postsynaptic AMPA receptor density regulation. Intriguingly, GluA1 and GluA2, as well as NR1, co-precipitate with LRRTM2 when coexpressed in nonneuronal cells, an interaction requiring the extracellular LRR domain [15**]. Thus, it is tempting to speculate that LRRTM2 might function similarly to TARPs to modulate AMPA receptor activity such that interaction with neurexin might then selectively influence AMPA receptor function in a subset of synapses. Like TARPs, LRRTM2 interacts with PSD-95 via a C-terminal ECEV motif [15**, 24]. Deletion of this domain does not impact LRRTM2’s synaptic localization [24]; however, the impact on synaptic AMPA receptors was not tested. Analysis of whether LRRTM2 influences channel gating properties of AMPA receptors like TARPs will provide insight to this interesting possibility.

Neurexins have also recently been identified as the presynaptic binding partner of the Cbln1-GluD2 complex [18] responsible for synapse formation between parallel fibers and Purkinje neurons in the cerebellum [18, 25]. Loss of Cbln1 or GluD2 in vivo leads to reduced numbers of parallel fiber-Purkinje synapses and increased number of free spines [26, 27]. Whether the Cbln1-GluD2-neurexin synaptic organizing complex directly recruits AMPA receptors to developing synapses is unknown; however, an antibody against the putative ligand-binding region of GluD2 destabilizes synaptic AMPA receptors [28], suggesting that GluD2 is involved somehow in AMPA receptor trafficking. Furthermore, expression of GluD2 and GluA1 in nonneuronal cells resulted in glutamate-induced currents and mEPSC-like events that were not observed with GluA1 expression alone [29*]. Still, mEPSC amplitude is unchanged while mEPSC frequency is reduced by 50% in Cbln1 knockout neurons [30]. Together, these data support a model in which the primary role of Cbln1 (perhaps via neurexin) is to promote synapse formation while the secondary role of the GluD2 interaction is to promote synapse maturation. An additional possibility is that the neurexin synaptic organizing complexes function sequentially during synapse development (Figure 2).

Figure 2
Hypothetical time course of neurexin-induced synapse maturation

Synaptic organizing activity of GluA subunits

Narp (neuronal activity-regulated pentraxin receptor), a member of the neuronal pentraxin (NP) family, mediates AMPA receptor clustering at synaptic contacts onto interneurons [31, 32]. Narp (also known as NP2) and NP1 are secreted molecules while NPR (neuronal pentraxin receptor) is an integral membrane protein. All three members are capable of forming hetero-oligomers whereby Narp and NP1 become membrane bound through association with NPR [33]. Interaction of the extracellular N-terminal domain (NTD) of the AMPA receptor GluA4 subunit is required for presynaptically-derived NPR/NP1-mediated GluA4 synaptic recruitment [34]. Synaptic recruitment of GluA4 required coexpression with neuroligin-1 in nonneuronal cells [34], suggesting the tantalizing possibility of a trans-synaptic complex consisting of NP1-NPR-GluA4 to promote synapse maturation via interaction with neuroligin-1. Consistent with this possibility, NP1/2 knockout neurons have reduced AMPA receptor mediated synaptic transmission reflected in an increased number of silent synapses during eye-specific refinement in the retinogeniculate system [35**]. NP1/2 are required for segregation of eye-specific retinal ganglion cell projections to the dorsal lateral geniculate nucleus [36], a process that involves activity-dependent synapse formation and elimination. NPR has also been implicated in AMPA receptor recruitment during homeostatic scaling [37], suggesting dual roles for NPs in synapse maturation and plasticity.

AMPA receptor recruitment activity of other synaptic organizing complexes

The ephrins and Eph receptors are axon guidance and signaling molecules that are increasingly appreciated for their roles in synapse formation and maturation. For example, postsynaptic EphB2 influences AMPA receptor localization through PDZ binding domain interactions [38]. Interestingly, recent experiments implicate a role for postsynaptic ephrins and presynaptic Eph receptors in synapse maturation. EphrinB2 activation by soluble EphB4 selectively stabilizes surface AMPA receptors in dissociated neuronal cultures [39]. mEPSCs recorded from ephrinB2 knockout neurons were decreased in amplitude compared to controls [39**], suggesting that AMPA receptor content was reduced in the absence of ephrinB2. A phosphorylation-dependent interaction between ephrinB2 and GRIP was required for this effect [39]. Similarly, amplitude, but not frequency, of mEPSCs was reduced in ephrinB3 mutants and ephrinB3 mutant mice exhibit reduced AMPA receptor-mediated synaptic transmission [40], suggesting that synapse strength is affected by ephrinB3 loss of function. Together, these findings suggest that ephrinB2 interacts with GRIP to recruit and maintain AMPA receptors at synapses, while ephrinB3 is capable of strengthening excitatory synaptic transmission.

Another axon guidance family of molecules, leukocyte common antigen-related (LAR), appears to be co-opted at the synapse for specialization and development. Presynaptic LAR family protein tyrosine phosphatase receptors (PTRPs) signal through postsynaptic netrin-G ligand NGL-3 to induce excitatory synapse development [41]. While it appears that the LRRs of NGL-3 predominantly induces presynaptic differentiation, it has also been shown to selectively cluster postsynaptic excitatory components, including GluA2 AMPA receptor subunits [42]. In the same study, the investigators found that frequency, but not amplitude, of mEPSCs was reduced with NGL-3 knockdown [42], arguing that this molecule may largely work to establish and maintain nascent excitatory synapses, but whether it functions directly in synaptic strengthening or maturation requires closer investigation. A third LRR domain-containing protein family that may also play a role in synaptic maturation is the synaptic adhesion-like molecules, or SALMs. Coimmunoprecipitation experiments showed that SALM2 interacts with both NMDA and AMPA receptors and regulates the maturation of excitatory synapses [43]. Recent studies showed that SALM5 knockdown reduces both amplitude and frequency of mEPSCs and mIPSCs [44*], suggesting SALM5 promotes both excitatory and inhibitory synaptic differentiation.

Finally, a recent study identified SynDIG1 (synapse differentiation induced gene 1), a conserved type II transmembrane protein, as a novel regulator of excitatory synapse maturation [45**]. SynDIG1 coimmunoprecipitates with AMPA receptor subunits in heterologous cells and brain extracts and knock-down of SynDIG1 in dissociated rat hippocampal neurons reduces AMPA receptor content at developing synapses by ~50% as determined by immunocytochemistry and electrophysiology [45**]. However, SynDIG1 did not influence NMDA receptor containing synapses, suggesting that SynDIG1 is a selective regulator of excitatory synapse maturation. Whether SynDIG1 functions via a trans-synaptic complex to regulate synaptic maturation remains to be determine.

Outlook and open questions

While significant progress in our understanding of postsynaptic maturation has been made, several open questions exist. The spine, for example, is the predominant site of excitatory synapses and a hallmark of synapse maturation. Spine size correlates with the abundance of AMPA receptors, but what is the relationship between AMPA receptor recruitment and spine morphogenesis? The extracellular NTD of the GluA2 subunit is important for the formation, growth and/or maintenance of dendritic spines [46] and involves interaction with N-cadherin [47]. EphB receptors influence motility of dendritic filopodia and spine morphogenesis and are required for synaptogenesis only when filopodia are most abundant and motile [48]. In addition, EphA5-ephrinA5 interaction induces expression of PSD-95-NMDA receptor complexes and morphological spine maturation [49]. Activation of neuregulin-ErbB4 signaling stabilizes synaptic AMPA receptors [50] via extracellular interactions whereas its tyrosine kinase activity is important for dendritic morphological changes [51]. Thus, it is likely that additional molecular mechanisms underlie the coordination of synapse maturation and spine morphogenesis. Additional avenues of research include understanding the relationship between AMPA receptor recruitment during early stages of synapse development and later stages of synapse plasticity. In addition, what is the relationship between the various synaptic organizing proteins, transmembrane AMPA receptor accessory proteins, cytoplasmic AMPA receptor interacting proteins, and AMPA receptor recruitment? Future work is needed to sort these diverse molecular mechanisms into a unifying model of synapse maturation.


We thank members of the Diaz lab for helpful discussions and comments on the manuscript. Research in the laboratory is funded by grants from the National Science Foundation and the National Institutes of Health (NIH) Director’s New Innovator Award Program.


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Papers of particular interest, published within the period of review, have been highlighted as:

* of special interest

** of outstanding interest

1. Dalva MB, McClelland AC, Kayser MS. Cell adhesion molecules: signalling functions at the synapse. Nat Rev Neurosci. 2007;8(3):206–220. [PubMed]
2. McAllister AK. Dynamic aspects of CNS synapse formation. Annu Rev Neurosci. 2007;30:425–450. [PMC free article] [PubMed]
3. Scheiffele P. Cell-cell signaling during synapse formation in the CNS. Annu Rev Neurosci. 2003;26:485–508. [PubMed]
4. Siddiqui TJ, Craig AM. Synaptic organizing complexes. Curr Opin Neurobiol. 2010
5. Kim E, Sheng M. PDZ domain proteins of synapses. Nat Rev Neurosci. 2004;5(10):771–781. [PubMed]
6. Hall BJ, Ghosh A. Regulation of AMPA receptor recruitment at developing synapses. Trends Neurosci. 2008;31(2):82–89. [PubMed]
7. Barry MF, Ziff EB. Receptor trafficking and the plasticity of excitatory synapses. Curr Opin Neurobiol. 2002;12(3):279–286. [PubMed]
8. Bredt DS, Nicoll RA. AMPA receptor trafficking at excitatory synapses. Neuron. 2003;40(2):361–379. [PubMed]
9. Malenka RC. Synaptic plasticity and AMPA receptor trafficking. Ann N Y Acad Sci. 2003;1003:1–11. [PubMed]
10. Sheng M, Lee S Hyoung. AMPA receptor trafficking and synaptic plasticity: major unanswered questions. Neurosci Res. 2003;46(2):127–134. [PubMed]
11. Kessels HW, Malinow R. Synaptic AMPA receptor plasticity and behavior. Neuron. 2009;61(3):340–350. [PubMed]
12. Palmer CL, Cotton L, Henley JM. The molecular pharmacology and cell biology of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Pharmacol Rev. 2005;57(2):253–277. [PMC free article] [PubMed]
13. Chen L, et al. Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature. 2000;408(6815):936–943. [PubMed]
14. Diaz E. Regulation of AMPA receptors by transmembrane accessory proteins. Eur J Neurosci. 2010;32(2):261–268. [PubMed]
15. de Wit J, et al. LRRTM2 interacts with Neurexin1 and regulates excitatory synapse formation. Neuron. 2009;64(6):799–806. [PubMed]
. This study demonstrates that LRRTM2 associates with AMPA receptor subunits and regulates surface expression of AMPA receptors in dissociated hippocampal neurons. In addition, LRRTM2 was shown to regulate synaptic efficacy.
16. Ko J, et al. LRRTM2 functions as a neurexin ligand in promoting excitatory synapse formation. Neuron. 2009;64(6):791–798. [PMC free article] [PubMed]
17. Siddiqui TJ, et al. LRRTMs and neuroligins bind neurexins with a differential code to cooperate in glutamate synapse development. J Neurosci. 2010;30(22):7495–7506. [PMC free article] [PubMed]
18. Uemura T, et al. Trans-synaptic interaction of GluRdelta2 and Neurexin through Cbln1 mediates synapse formation in the cerebellum. Cell. 2010;141(6):1068–1079. [PubMed]
19. Graf ER, et al. Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins. Cell. 2004;119(7):1013–1026. [PMC free article] [PubMed]
20. Schnell E, et al. Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number. Proc Natl Acad Sci U S A. 2002;99(21):13902–13907. [PubMed]
21. Nam CI, Chen L. Postsynaptic assembly induced by neurexin-neuroligin interaction and neurotransmitter. Proc Natl Acad Sci U S A. 2005;102(17):6137–6142. [PubMed]
22. Chubykin AA, et al. Activity-dependent validation of excitatory versus inhibitory synapses by neuroligin-1 versus neuroligin-2. Neuron. 2007;54(6):919–931. [PubMed]
23. Heine M, et al. Activity-independent and subunit-specific recruitment of functional AMPA receptors at neurexin/neuroligin contacts. Proc Natl Acad Sci U S A. 2008;105(52):20947–20952. [PubMed]
. This study demonstrated recruitment of functional GluR2-containing AMPA receptors at neurexin-neuroligin induced synaptic contacts in cultured hippocampal neurons with glutamate un-caging and calcium imaging.
24. Linhoff MW, et al. An unbiased expression screen for synaptogenic proteins identifies the LRRTM protein family as synaptic organizers. Neuron. 2009;61(5):734–749. [PMC free article] [PubMed]
25. Matsuda K, et al. Cbln1 is a ligand for an orphan glutamate receptor delta2, a bidirectional synapse organizer. Science. 2010;328(5976):363–368. [PubMed]
26. Hirai H, et al. Cbln1 is essential for synaptic integrity and plasticity in the cerebellum. Nat Neurosci. 2005;8(11):1534–1541. [PubMed]
27. Kashiwabuchi N, et al. Impairment of motor coordination, Purkinje cell synapse formation, and cerebellar long-term depression in GluR delta 2 mutant mice. Cell. 1995;81(2):245–252. [PubMed]
28. Hirai H, et al. New role of delta2-glutamate receptors in AMPA receptor trafficking and cerebellar function. Nat Neurosci. 2003;6(8):869–876. [PubMed]
29. Kuroyanagi T, Yokoyama M, Hirano T Postsynaptic glutamate receptor delta family contributes to presynaptic terminal differentiation and establishment of synaptic transmission. Proc Natl Acad Sci U S A. 2009;106(12):4912–4916. [PubMed]
. This report showed that HEK cells expressing both glutamate receptor delta2 and GluA1 formed a functional glutamate-gated ion channel with postsynaptic current.
30. Ito-Ishida A, et al. Cbln1 regulates rapid formation and maintenance of excitatory synapses in mature cerebellar Purkinje cells in vitro and in vivo. J Neurosci. 2008;28(23):5920–5930. [PubMed]
31. O'Brien R, et al. Synaptically targeted narp plays an essential role in the aggregation of AMPA receptors at excitatory synapses in cultured spinal neurons. J Neurosci. 2002;22(11):4487–4498. [PubMed]
32. O'Brien RJ, et al. Synaptic clustering of AMPA receptors by the extracellular immediate-early gene product Narp. Neuron. 1999;23(2):309–323. [PubMed]
33. Kirkpatrick LL, et al. Biochemical interactions of the neuronal pentraxins. Neuronal pentraxin (NP) receptor binds to taipoxin and taipoxin-associated calcium-binding protein 49 via NP1 and NP2. J Biol Chem. 2000;275(23):17786–17792. [PubMed]
34. Sia GM, et al. Interaction of the N-terminal domain of the AMPA receptor GluR4 subunit with the neuronal pentraxin NP1 mediates GluR4 synaptic recruitment. Neuron. 2007;55(1):87–102. [PubMed]
35. Koch SM, Ullian EM Neuronal pentraxins mediate silent synapse conversion in the developing visual system. J Neurosci. 2010;30(15):5404–5414. [PubMed]
. This study shows that loss of NP1 and NP2 are required in vivo for normal development of AMPAR-mediated transmission at developing visual system synapses. NP1/2 knock-out neurons from early postnatal thalamus display severely reduced AMPAR-mediated retinogeniculate transmission reflected in an increased number of silent synapses with no change in amplitude or presynaptic release.
36. Bjartmar L, et al. Neuronal pentraxins mediate synaptic refinement in the developing visual system. J Neurosci. 2006;26(23):6269–6281. [PMC free article] [PubMed]
37. Chang MC, et al. Narp regulates homeostatic scaling of excitatory synapses on parvalbumin-expressing interneurons. Nat Neurosci. 2010;13(9):1090–1097. [PMC free article] [PubMed]
38. Kayser MS, et al. Intracellular and trans-synaptic regulation of glutamatergic synaptogenesis by EphB receptors. J Neurosci. 2006;26(47):12152–12164. [PubMed]
39. Essmann CL, et al. Serine phosphorylation of ephrinB2 regulates trafficking of synaptic AMPA receptors. Nat Neurosci. 2008 [PubMed]
. This study demonstrates that ephrinB2 reverse signaling regulates synaptic AMPA receptors via a phosphorylation-dependent interaction with glutamate receptor interacting proteins that link ephrinB ligands and AMPA receptors. In mouse hippocampal neurons from conditional ephrinB2 knockout neurons AMPA receptor internalization was enhanced and synaptic transmission reduced.
40. Antion MD, et al. Ephrin-B3 regulates glutamate receptor signaling at hippocampal synapses. Mol Cell Neurosci. 2010;45(4):378–388. [PMC free article] [PubMed]
41. Kwon SK, et al. Trans-synaptic adhesions between netrin-G ligand-3 (NGL-3) and receptor tyrosine phosphatases LAR, protein-tyrosine phosphatase delta (PTPdelta), and PTPsigma via specific domains regulate excitatory synapse formation. J Biol Chem. 2010;285(18):13966–13978. [PubMed]
42. Woo J, et al. Trans-synaptic adhesion between NGL-3 and LAR regulates the formation of excitatory synapses. Nat Neurosci. 2009;12(4):428–437. [PubMed]
43. Ko J, et al. SALM synaptic cell adhesion-like molecules regulate the differentiation of excitatory synapses. Neuron. 2006;50(2):233–245. [PubMed]
44. Mah W, et al. Selected SALM (synaptic adhesion-like molecule) family proteins regulate synapse formation. J Neurosci. 2010;30(16):5559–5568. [PubMed]
. This study showed that SALM3 and SALM5 synaptic proteins capable of interacting with PSD-95. Aggregation of SALM3, but not SALM5, on dendritic surfaces induces clustering of PSD-95; however, knockdown of SALM5 reduces the frequency and amplitude of mEPSCs and mIPSCs in cultured hippocampal neurons.
45. Kalashnikova E, et al. SynDIG1: an activity-regulated, AMPA- receptorinteracting transmembrane protein that regulates excitatory synapse development. Neuron. 2010;65(1):80–93. [PubMed]
. This study identifies SynDIG1 as a critical regulator of AMPA receptor content at developing synapses in dissociated hippocampal neurons. Overexpression or knockdown of SynDIG1 leads to increased or decreased AMPA receptors at synapses as assessed with immunocytochemistry and electrophysiology.
46. Passafaro M, et al. Induction of dendritic spines by an extracellular domain of AMPA receptor subunit GluR2. Nature. 2003;424(6949):677–681. [PubMed]
47. Saglietti L, et al. Extracellular interactions between GluR2 and N-cadherin in spine regulation. Neuron. 2007;54(3):461–477. [PubMed]
48. Kayser MS, Nolt MJ, Dalva MB. EphB receptors couple dendritic filopodia motility to synapse formation. Neuron. 2008;59(1):56–69. [PMC free article] [PubMed]
49. Akaneya Y, et al. Ephrin-A5 and EphA5 Interaction Induces Synaptogenesis during Early Hippocampal Development. PLoS One. 2010;5(8) [PMC free article] [PubMed]
50. Li B, et al. The neuregulin-1 receptor erbB4 controls glutamatergic synapse maturation and plasticity. Neuron. 2007;54(4):583–597. [PMC free article] [PubMed]
51. Krivosheya D, et al. ErbB4-Neuregulin signaling modulates synapse development and dendritic arborization through distinct mechanisms. J Biol Chem. 2009;283(47):32944–32956. [PubMed]