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

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 in mice 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. 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 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.

Hippocampal-medial entorhinal circuit is differently organized along the dorsoventral axis in rodents.

The general understanding of hippocampal circuits is that the hippocampus and the entorhinal cortex (EC) are topographically connected through parallel identical circuits along the dorsoventral axis. Our anterograde tracing and in vitro electrophysiology data, however, show a markedly different dorsoventral organization of the hippocampal projection to the medial EC (MEC). While dorsal hippocampal projections are confined to the dorsal MEC, ventral hippocampal projections innervate both dorsal and ventral MEC. Further, whereas the dorsal hippocampus preferentially targets layer Vb (LVb) neurons, the ventral hippocampus mainly targets cells in layer Va (LVa). This connectivity scheme differs from hippocampal projections to the lateral EC, which are topographically organized along the dorsoventral axis. As LVa neurons project to telencephalic structures, our findings indicate that the ventral hippocampus regulates LVa-mediated entorhinal-neocortical output from both dorsal and ventral MEC. Overall, the marked dorsoventral differences in hippocampal-entorhinal connectivity impose important constraints on signal flow in hippocampal-neocortical circuits.

Processing of Hippocampal Network Activity in the Receiver Network of the Medial Entorhinal Cortex Layer V.

The interplay between hippocampus and medial entorhinal cortex (mEC) is of key importance for forming spatial representations. Within the hippocampal-entorhinal loop, the hippocampus receives context-specific signals from layers II/III of the mEC and feeds memory-associated activity back into layer V (LV). The processing of this output signal within the mEC, however, is largely unknown. We characterized the activation of the receiving mEC network by evoked and naturally occurring output patterns in mouse hippocampal-entorhinal cortex slices. Both types of glutamatergic neurons (mEC LVa and LVb) as well as fast-spiking inhibitory interneurons receive direct excitatory input from the intermediate/ventral hippocampus. Connections between the two types of excitatory neurons are sparse, and local processing of hippocampal output signals within mEC LV is asymmetric, favoring excitation of far projecting LVa neurons over locally projecting LVb neurons. These findings suggest a new role for mEC LV as a bifurcation gate for feedforward (telencephalic) and feedback (entorhinal-hippocampal) signal propagation.SIGNIFICANCE STATEMENT Patterned network activity in hippocampal networks plays a key role in the formation and consolidation of spatial memories. It is, however, largely unclear how information is transferred to the neocortex for long-term engrams. Here, we elucidate the propagation of network activity from the hippocampus to the medial entorhinal cortex. We show that patterned output from the hippocampus reaches both major cell types of deep entorhinal layers. These cells are, however, only weakly connected, giving rise to two parallel streams of activity for local and remote signal propagation, respectively. The relative weight of both pathways is regulated by local inhibitory interneurons. Our data reveal important insights into the hippocampal-neocortical dialogue, which is of key importance for memory consolidation in the mammalian brain.