Regulation of hippocampal mossy fiber-CA3 synapse function by a Bcl11b/C1ql2/Nrxn3(25b+) pathway

Abstract

The transcription factor Bcl11b has been linked to neurodevelopmental and neuropsychiatric disorders associated with synaptic dysfunction. Bcl11b is highly expressed in dentate gyrus granule neurons and is required for the structural and functional integrity of mossy fiber-CA3 synapses. The underlying molecular mechanisms, however, remained unclear. We show that the synaptic organizer molecule C1ql2 is a direct functional target of Bcl11b that regulates synaptic vesicle recruitment and long-term potentiation at mossy fiber-CA3 synapses in vivo and in vitro. Furthermore, we demonstrate C1ql2 to exert its functions through direct interaction with a specific splice variant of neurexin-3, Nrxn3(25b+). Interruption of C1ql2-Nrxn3(25b+) interaction by expression of a non-binding C1ql2 mutant or by deletion of Nrxn3 in the dentate gyrus granule neurons recapitulates major parts of the Bcl11b as well as C1ql2 mutant phenotype, and interferes with C1ql2 targeting to the synapse. Together, this study identifies a novel C1ql2-Nrxn3(25b+)-dependent signaling pathway through which Bcl11b controls mossy fiber-CA3 synapse function. Thus, our findings contribute to the mechanistic understanding of neurodevelopmental disorders accompanied by synaptic dysfunction.

The Role of Bcl11 Transcription Factors in Neurodevelopmental Disorders

“…In line with this, a recent study identified the synaptic organizer molecule C1ql2 as a direct functional target of Bcl11b at the mossy fiber synapses [89]. Interestingly, C1ql2 regulates synaptic vesicle recruitment to the active zone through direct interaction with Nrxn3(25b+), a specific splice variant of neurexin-3 that was linked to NDDs before [89,90]. Changes in synaptic signal transduction, including establishment, transport, and release of synaptic vesicles, as well as alterations on the postsynaptic side are known to be hallmarks of NDDs [91][92][93].…”

“…In addition, the ultrastructural complexity of the synapses is lost, and the synaptic vesicles are disorganized upon the loss of Bcl11b [88]. In line with this, a recent study identified the synaptic organizer molecule C1ql2 as a direct functional target of Bcl11b at the mossy fiber synapses [89]. Interestingly, C1ql2 regulates synaptic vesicle recruitment to the active zone through direct interaction with Nrxn3(25b+), a specific splice variant of neurexin-3 that was linked to NDDs before [89,90].…”

“…The loss of Bcl11b function leads to transcriptional changes of molecular identifier genes followed by a disturbed patch-matrix organization [86]. The function of Bcl11b within the formation of the hippocampus was comprehensively examined [83,[87][88][89]. Bcl11b is expressed in the hippocampus throughout development and in adulthood.…”