The human brain contains billions of neurons working together to process the vast array of information we receive from our environment. These neurons communicate at junctions known as synapses, where chemical packages called vesicles released from one neuron stimulate a response in another. This synaptic communication is crucial for our ability to think, learn and remember.

However, this activity depends on a complex interplay of proteins, whose balance and location within the neuron are tightly controlled. Any disruption to this delicate equilibrium can cause significant problems, including neurodevelopmental and neuropsychiatric disorders, such as schizophrenia and intellectual disability.

One key regulator of activity at the synapse is a protein called Bcl11b, which has been linked to conditions affected by synaptic dysfunction. It plays a critical role in maintaining specific junctions known as mossy fibre synapses, which are important for learning and memory. One of the genes regulated by Bcl11b is C1ql2, which encodes for a synaptic protein. However, it is unclear what molecular mechanisms Bcl11b uses to carry out this role.

To address this, Koumoundourou et al. explored the role of C1ql2 in mossy fibre synapses of adult mice. Experiments to manipulate the production of C1ql2 independently of Bcl11b revealed that C1ql2 is vital for recruiting vesicles to the synapse and strengthening synaptic connections between neurons. Further investigation showed that C1ql2’s role in this process relies on interacting with another synaptic protein called neurexin-3. Disrupting this interaction reduced the amount of C1ql2 at the synapse and, consequently, impaired vesicle recruitment.

These findings will help our understanding of how neurodevelopmental and neuropsychiatric disorders develop. Bcl11b, C1ql2 and neurexin-3 have been independently associated with these conditions, and the now-revealed interactions between these proteins offer new insights into the molecular basis of synaptic faults. This research opens the door to further study of how these proteins interact and their roles in brain health and disease.

Disruptions in synaptic structure and function have been identified as a major determinant in the manifestation of various neurodevelopmental and neuropsychiatric disorders, such as autism spectrum disorder, schizophrenia, and intellectual disability (Hayashi-Takagi, 2017; Lepeta et al., 2016; Zoghbi and Bear, 2012). The need to understand how synaptic function is compromised in these disorders has accentuated the importance of studying the regulatory mechanisms of physiological synaptic function. These mechanisms involve cell adhesion molecules at both the pre- and post-synaptic side that act as synaptic organizers, whose unique combination determines the structural and functional properties of the synapse. Many such proteins have already been identified and our understanding of their complex role in synapse assembly and function has significantly increased over the last years (de Wit and Ghosh, 2016; O’Rourke et al., 2012; Südhof, 2017). Furthermore, recent advances in the genetics of neurodevelopmental and neuropsychiatric disorders have implicated genes encoding for several of the known synaptic proteins, supporting a role for these molecules in the pathogenesis of corresponding disorders (Südhof, 2021; Torres et al., 2017; Wang et al., 2018).

The sensitivity of the functional specification of the synapse to the combination of distinct synaptic proteins and their relative expression levels suggests that genetically encoded programs define at least facets of the synaptic properties in a cell-type-specific manner (Südhof, 2017). Several of the synaptic proteins have been shown to promote formation of functional pre- and postsynaptic assemblies when presented in non-neuronal cells (Dalva et al., 2000; Dean et al., 2003; Scheiffele et al., 2000), showing that their ability to specify synapses is in part independent of signaling processes and neuronal activity and supporting the idea that synaptic function is governed by cues linked to cellular origin (Gomez et al., 2021). Thus, the investigation of synaptic organizers and their function in health and disease should be expanded to the transcriptional programs that regulate their expression.

Bcl11b (also known as Ctip2) is a zinc finger transcription factor that has been implicated in various disorders of the nervous system including Alzheimer’s and Huntington’s disease, and schizophrenia (Kunkle et al., 2016; Song et al., 2022; Whitton et al., 2018; Whitton et al., 2016). Patients with BCL11B mutations present with neurodevelopmental delay, overall learning deficits as well as impaired speech acquisition and autistic features (Eto et al., 2022; Lessel et al., 2018; Punwani et al., 2016; Yang et al., 2020). Bcl11b is expressed in several neuron types, including the dentate gyrus granule neurons (DGN) of the hippocampus. Expression of Bcl11b in the DGN starts during embryonic development and persists into adulthood (Simon et al., 2020). We have previously demonstrated that Bcl11b plays a crucial role in the development of the hippocampal mossy fiber system, adult hippocampal neurogenesis as well as hippocampal learning and memory (Simon et al., 2016; Simon et al., 2012). In the mature hippocampus, Bcl11b is critical for the structural and functional integrity of mossy fiber synapses (MFS), the connections between DGN and CA3 pyramidal neurons (De Bruyckere et al., 2018). MFS have a critical role in learning and memory stemming from their unique structural and functional properties, such as an enormous pool of releasable synaptic vesicles (SV), and reliable presynaptic short- and long-term plasticity (Nicoll and Schmitz, 2005; Rollenhagen and Lübke, 2010). Conditional ablation of Bcl11b in murine DGN impairs presynaptic recruitment of SV and abolishes mossy fiber long-term potentiation (MF-LTP; De Bruyckere et al., 2018). The molecular mechanisms, however, through which the transcriptional regulator Bcl11b controls highly dynamic properties of the MFS remained elusive.

In the present study, we show that the secreted synaptic organizer molecule C1ql2, a member of the C1q-like protein family (Yuzaki, 2017), is a functional target of Bcl11b in murine DGN. Reintroduction of C1ql2 in Bcl11b mutant DGN rescued the localization and docking of SV to the active zone (AZ), as well as MF-LTP that was abolished upon Bcl11b ablation. Knock-down (KD) of C1ql2 in wildtype animals recapitulated a major part of the MFS phenotype observed in Bcl11b mutants. Furthermore, we show that C1ql2 requires direct interaction with a specific neurexin-3 isoform, Nrxn3(25b+), a member of a polymorphic family of presynaptic cell adhesion molecules (Reissner et al., 2013; Südhof, 2017), to recruit SV in vitro and in vivo. Finally, we observe that localization of C1ql2 along the mossy fiber tract depends on C1ql2-Nrxn3(25b+) interaction. Taken together, this study identifies a novel Bcl11b/C1ql2/Nrxn3(25b+)-dependent regulatory mechanism that is essential for the control of MFS function. Recent genetic studies suggested its single components to be associated with neurodevelopmental and neuropsychiatric disorders characterized by synaptic dysfunction. Our data, for the first time, demonstrate these molecules to be interconnected in one regulatory pathway. Thus, our findings provide new mechanistic insight into the pathogenesis of corresponding human disorders.

There is emerging evidence that the zinc finger transcription factor Bcl11b is involved in the pathogenesis of neurodevelopmental as well as neuropsychiatric disorders that are frequently associated with synaptic dysfunction. Previous work from our group demonstrated Bcl11b to be essential for synapse function in the mossy fiber circuit of the adult murine hippocampus. The underlying molecular mechanisms downstream of Bcl11b, however, remained elusive. In the present study, we uncover a novel C1ql2-dependent regulatory pathway through which Bcl11b controls the structural as well as functional integrity of hippocampal MFS in adult mice. We show that SV recruitment to the AZ of MFS, as well as the expression of MF-LTP, depend on C1ql2, which is a direct functional target of Bcl11b. Reintroduction of C1ql2 into Bcl11b mutant DGN restores defective SV recruitment and LTP expression. KD of C1ql2 in DGN recapitulates the impaired SV recruitment and loss of LTP observed in Bcl11b mutants. Finally, we show that C1ql2 controls SV recruitment through a direct interaction with presynaptic Nrxn3(25b+), while LTP depends on C1ql2 signals independent of Nrxn3 interaction. Recent studies suggested Nrxn3, as well as C1ql2, to be associated with neuropsychiatric disorders (Hishimoto et al., 2007; Hu et al., 2013; Huggett and Stallings, 2020a; Marballi et al., 2022). Our study for the first time identifies a Bcl11b/C1ql2/Nrxn3-dependent signaling pathway in the control of basic structural and functional properties of MFS. Analysis of this regulatory pathway in mice may provide important novel insights into the pathogenesis of neurodevelopmental and neuropsychiatric disorders.

We have previously shown that conditional ablation of Bcl11b in the adult hippocampus leads to structural and functional changes of MFS characterized by an overall reduction in synapse numbers, loss of bouton complexity, misdistribution of SV as well as loss of MF-LTP (De Bruyckere et al., 2018). Here, we found that reintroduction of the synaptic organizer protein C1ql2, which is a direct transcriptional target of Bcl11b and is downregulated in Bcl11b mutant DGN (De Bruyckere et al., 2018), was able to rescue major part of the Bcl11b mutant phenotype at the MFS. Restoring C1ql2 expression in Bcl11b cKO DGN led to a complete rescue of the SV distribution and docking, as well as LTP at the MFS, while synapse numbers and ultrastructural complexity of boutons remained unchanged. Furthermore, KD of C1ql2 in WT DGN recapitulated the Bcl11b phenotype with impaired SV recruitment and loss of LTP, supporting the specificity of C1ql2 function. MF-LTP, which manifests as a long-term increase in presynaptic vesicle release probability (P_r) (Shahoha et al., 2022), directly depends on the distribution of SV in the proximity of the AZ. Recent studies have shown that the increase in P_r involves the recruitment of new AZ and an increase in the number of docked and tethered vesicles, corresponding to the readily releasable pool of SV (Orlando et al., 2021; Vandael et al., 2020). The perturbed SV recruitment in both Bcl11b cKO and C1ql2 KD mice could thus potentially explain the loss of LTP in both conditions. Indeed, the reintroduction of C1ql2 in Bcl11b cKO DGN specifically rescued SV recruitment and LTP, while synapse numbers and ultrastructural complexity of MFB remained unchanged. Whether the regulation of SV distribution by C1ql2 and the expression of MF-LTP are directly and causally linked remains to be determined. Additional factors have been suggested to contribute to the increase in P_r, including a tighter coupling between Ca²⁺ channels and SV (Midorikawa and Sakaba, 2017) and the accumulation of Ca²⁺ channels near release sites (Fukaya et al., 2021). It cannot, therefore, be excluded that C1ql2 regulates MF-LTP through one of these alternative mechanisms. Aiming to narrow in on the nature of the mechanism through which Bcl11b regulates MF-LTP, we used forskolin to induce LTP in Bcl11b cKO. MF-LTP relies on presynaptic mechanisms (Castillo, 2012; Zalutsky and Nicoll, 1990) and is mediated by the second messenger cAMP, which is produced by AC in response to Ca²⁺ influx through voltage-gated Ca²⁺ channels (Li et al., 2007) and KARs (Lauri et al., 2001; Schmitz et al., 2003). By using forskolin to directly activate AC, we bypassed these initial steps, and still found a reduction of LTP in Bcl11b cKO mice, similarly to HFS. These results strongly suggest that the loss of LTP is caused by a process downstream of the initial presynaptic Ca²⁺ influx following stimulation. We note that, in the present experiments, we did not observe the decrease in input-output relation in Bcl11b cKO as reported in De Bruyckere et al., 2018. After excluding technical differences, e.g., different methods of data analysis, we conclude that the discrepancy is best explained by differences in the population of presynaptic fibers. In the present study, mossy fiber responses were specifically identified by testing for frequency facilitation and sensitivity to mGluR antagonists, whereas in the previous study, this purification was not done (De Bruyckere et al., 2018). It is not immediately obvious why the reduction in synapse numbers and misdistribution of SV in Bcl11b cKO animals does not affect basal synaptic transmission. While a modest displacement of SV might fail to noticeably influence synaptic transmission due to the low initial P_r at MFS, causing only a fraction of release-ready vesicles to be initially released, the reduction in synapse numbers might indeed be expected to reflect in the input-output relationship. It might be that synapses that are preferentially eliminated in Bcl11b mutants are predominantly silent or have weak coupling strength, such that their loss has only a minimal effect on synaptic transmission. Further investigation is needed to elucidate this apparent discrepancy. Together, our results suggest Bcl11b to be an important synaptic regulator that controls the structure and function of adult MFS through both C1ql2-dependent, as well as -independent transcriptional programs.

C1ql proteins are complement-related factors that are synthesized by the presynapse and secreted into the synaptic cleft. Within the hippocampus, C1ql2 and –3 protein expression overlaps and is highly restricted to DGN (Iijima et al., 2010) and the corresponding mossy fiber system, including MF-CA3 synapses. C1ql2 and –3 were previously suggested to form functional heteromers that can cluster postsynaptic KAR on MFS. Selective deletion of either C1ql2 or –3 in mice was reported to have no overt mutant hippocampal phenotype, suggesting functional compensation for both proteins (Matsuda et al., 2016). Using shRNA-mediated selective KD of C1ql2 in DGN as well as rescue of the Bcl11b mutation by the reintroduction of C1ql2 into mutant DGN, we observed a novel, presynaptic function for C1ql2 in the recruitment of SV and the expression of LTP in MFS. This function was specific to C1ql2 since overexpression of C1ql3 in Bcl11b mutant DGN was unable to rescue the synapse phenotype. Furthermore, another study has identified all four C1ql proteins, including C1ql2, as ligands for the postsynaptic Brain-specific angiogenesis inhibitor 3 (BAI3). Addition of any of the four C1ql proteins to cultured hippocampal neurons led to a loss of excitatory synapses, a function inhibited by the presence of BAI3 (Bolliger et al., 2011). In our study, we show that neither loss of C1ql2 nor overexpression of C1ql2 affects the number of MFS, supporting the notion that synaptic organizers have synapse-specific functions. This highlights the role of C1ql2 as a synaptic organizer and adds a new layer of understanding to its function at the MFS.

Previous in vitro studies suggested that C1ql2 function at the MFS involves interaction with Nrxn3 isoforms containing the splice site 5 25b sequence (SS5^25b) (Matsuda et al., 2016). Nrxns are synaptic cell adhesion molecules that mediate various synaptic properties (Reissner et al., 2013; Südhof, 2017), including the recruitment of SV and dense-core vesicles (Dean et al., 2003; Ferdos et al., 2021; Quinn et al., 2017; Rui et al., 2017). This prompted us to analyze, whether C1ql2-dependent SV recruitment in MFS requires a direct interaction with Nrxn3(25b+) in vitro and in vivo. Expression of C1ql2 in HEK293 cells co-cultured with GFP-Nrxn3α(25+)-expressing hippocampal neurons was able to recruit Nrxn3α(25b+) and vGlut1 at contact points, while C1ql2.K262E, a C1ql2 variant with an amino-acid replacement that perturbs the interaction with Nrxn3(25b+), was no longer able to recruit neuronal vGlut1. Furthermore, clustering of vGlut1 by C1ql2-secreting HEK293 cells was reduced in neurons harboring a pan-neurexin mutation, a phenotype that was rescued by the selective reintroduction of Nrxn3α(25b+). Finally, the introduction of C1ql2.K262E in Bcl11b cKO DGN in vivo was unable to rescue SV recruitment, while the silencing of Nrxns in DGN in vivo perturbed SV recruitment to a similar extent as in Bcl11b cKO and C1ql2 KD. Based on these findings, we anticipated the overexpression of C1ql2.K262E in Bcl11b cKO DGN to be unable to rescue MF-LTP. Unexpectedly, the introduction of C1ql2.K262E into Bcl11b cKO fully rescued MF-LTP. This raises the possibility that C1ql2 can influence MF-LTP through additional, yet uncharacterized mechanisms, independent of SV recruitment or direct interaction with Nrxn3(25b+). We cannot exclude, however, that the expression of a mutant C1ql2 variant created an additional gain-of-function effect that circumvented SV recruitment and allowed the rescue of MF-LTP in our experimental system. The latter is supported by the fact that within the first 10 min after HFS, fEPSP slopes for C1ql2.K262E were significantly elevated compared to controls, an effect that was not seen after C1ql2 re-expression. Together, our data provide comprehensive experimental evidence that the direct interaction of C1ql2 with Nrxn3(25b+) is essential for SV recruitment at the MFS. Finally, we observed that an abolished interaction between C1ql2 and Nrxn3(25b+) was associated with reduced localization of the C1ql2 protein along the MF tract. This raises the possibility that C1ql2-Nrxn3 interaction might be involved in surface presentation of C1ql2, transportation, or stabilization at the MFS. The C1q domain can form stable, higher order oligomers (Ressl et al., 2015). Neurexins, on the other hand, are highly mobile outside and inside of synaptic terminals (Klatt et al., 2021; Neupert et al., 2015). Thus, the interaction of C1ql2 with Nrxn3(25b+) may reciprocally augment the accumulation of both proteins at synaptic sites.

Neurexin mRNAs are subjected to extensive alternative splicing that leads to the expression of thousands of isoforms with differential expression patterns (Treutlein et al., 2014; Ullrich et al., 1995) that act in a type-specific manner on synaptic functions (Dai et al., 2019; Schreiner et al., 2014; Traunmüller et al., 2016). Nrxn3 splice variants have been shown to regulate the function and plasticity of glutamatergic and GABAergic synapses through various mechanisms (Aoto et al., 2013; Dai et al., 2019; Lloyd et al., 2023; Trotter et al., 2023). The Nrxn3 splice site SS5 is a major contributor to the high number of Nrxn3 isoforms (Schreiner et al., 2014). One such isoform was recently found to be highly expressed in GABAergic interneurons at the DG, where it regulates dendritic inhibition (Hauser et al., 2022). Our findings on the role of Nrxn3 isoforms containing SS5^25b in the recruitment of SV at the MFS through interaction with C1ql2 add to the understanding of the synapse-specific mechanisms of action of Nrxns.

Perturbations in synaptic structure and function are major determinants of various neuropsychiatric and neurodevelopmental disorders (Hayashi-Takagi, 2017; Lepeta et al., 2016; Zoghbi and Bear, 2012). Emerging evidence from recent genetic studies suggests such disorders to be linked to various genes encoding for synaptic proteins (Südhof, 2021; Torres et al., 2017; Wang et al., 2018). Decoding the molecular mechanisms of synaptic organization and stability and their transcriptional regulation would therefore be expected to contribute to the mechanistic understanding of neuropsychiatric and neurodevelopmental disorders. The transcription factor Bcl11b has been linked to neurodevelopmental (Lessel et al., 2018), neurodegenerative (Kunkle et al., 2016; Song et al., 2022) and neuropsychiatric disorders (Whitton et al., 2018; Whitton et al., 2016). BCL11B mutations in humans are associated with neurodevelopmental delay, overall learning deficits as well as impaired speech acquisition and autistic features (Eto et al., 2022; Lessel et al., 2018; Punwani et al., 2016; Yang et al., 2020). Moreover, conditional ablation of Bcl11b selectively in the adult murine hippocampus results in impaired learning and memory behavior (Simon et al., 2016). NRXN3 single-nucleotide polymorphisms (SNP) have been implicated in schizophrenia (Hu et al., 2013) and addiction (Hishimoto et al., 2007), with one recorded SNP located close to SS5 altering the expression of Nrxn3(25b+). Interestingly, recent studies have also associated C1QL2 with schizophrenia (Marballi et al., 2022) as well as cocaine addiction (Huggett and Stallings, 2020b). In this study we demonstrate that Bcl11b, through its transcriptional target C1ql2, modulates the synaptic organization of MFS by controlling the recruitment of SV at AZ. This regulatory mechanism depends on a direct interaction of C1ql2 with Nrxn3(25b+). Importantly, SV trafficking and altered release probability have been implicated in neurological and neuropsychiatric disorders (Egbujo et al., 2016; Lepeta et al., 2016; Zhu et al., 2021). Thus, the identification of the Bcl11b/C1ql2/Nrxn3(25b+)-dependent signaling module in this study provides a new entry point for future mechanistic analyses of synaptopathies. Moreover, the existence of such cell-type-specific signaling modules reveals how a fundamental transcription factor with diverse functions such as Bcl11b can be implicated in the pathogenesis of brain disorders characterized by synaptic dysfunction.

All data generated or analysed during this study are included in the manuscript and supporting files; source data files have been provided for all Figures.

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Author details

1. Artemis Koumoundourou

   Institute of Molecular and Cellular Anatomy, Ulm University, Ulm, Germany

   Contribution

   Conceptualization, Formal analysis, Investigation, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-8917-5717

2. Märt Rannap

   Institute of Physiology and Pathophysiology, Faculty of Medicine, Heidelberg University, Heidelberg, Germany

   Contribution

   Formal analysis, Investigation, Writing – original draft

   Competing interests

   No competing interests declared

3. Elodie De Bruyckere

   Institute of Molecular and Cellular Anatomy, Ulm University, Ulm, Germany

   Contribution

   Investigation

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-6056-376X

4. Sigrun Nestel

   Department of Neuroanatomy, Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, Freiburg, Germany

   Contribution

   Investigation

   Competing interests

   No competing interests declared

5. Carsten Reissner

   Institute of Anatomy and Molecular Neurobiology, University of Münster, Münster, Germany

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-5496-9971

6. Alexei V Egorov

   Institute of Physiology and Pathophysiology, Faculty of Medicine, Heidelberg University, Heidelberg, Germany

   Contribution

   Investigation

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4899-8407

7. Pengtao Liu

   1. School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
   2. Centre for Translational Stem Cell Biology, Hong Kong, China

   Contribution

   Resources

   Competing interests

   No competing interests declared

8. Markus Missler

   Institute of Anatomy and Molecular Neurobiology, University of Münster, Münster, Germany

   Contribution

   Resources, Writing – original draft

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8008-984X

9. Bernd Heimrich

   Department of Neuroanatomy, Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, Freiburg, Germany

   Contribution

   Investigation, Methodology, Writing – original draft

   Competing interests

   No competing interests declared

10. Andreas Draguhn

    Institute of Physiology and Pathophysiology, Faculty of Medicine, Heidelberg University, Heidelberg, Germany

    Contribution

    Conceptualization, Supervision, Writing – original draft

    Competing interests

    No competing interests declared

11. Stefan Britsch

    Institute of Molecular and Cellular Anatomy, Ulm University, Ulm, Germany

    Contribution

    Conceptualization, Supervision, Funding acquisition, Writing – original draft, Writing – review and editing

    For correspondence

    stefan.britsch@uni-ulm.de

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0003-4379-3322

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