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.

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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). Whereas dorsal hippocampal projections are confined to the dorsal MEC and preferentially target layer Vb (LVb) over layer Va (LVa) neurons, the ventral hippocampus innervates the entire dorsoventral extent of MEC. In the ventral MEC, these projections innervate neurons in both LVa and LVb. In contrast, in the dorsal MEC, ventral hippocampal projections target mainly LVa neurons. As LVa neurons project to telencephalic structures, our findings indicate that the ventral hippocampus regulates LVa-mediated entorhinal-neocortical output from both the dorsal and ventral MEC. Overall, the marked dorsoventral differences in hippocampal-entorhinal connectivity impose important constraints on signal flow in hippocampal-neocortical circuits.

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.