Abstract
Callosal projections from primary somatosensory cortex (S1) are key for processing somatosensory inputs and integrating sensory-motor information. How the callosal innervation pattern in S1 is formed during early postnatal development is not clear. We found that the normal termination pattern of these callosal projections is disrupted in cortex specific NMDAR mutants. Rather than projecting selectively to the primary/secondary somatosensory cortex (S1/S2) border, axons were uniformly distributed throughout S1. In addition, the density of this projection increased over postnatal life until the mice died by P30. By combining genetic and antibody-mediated loss of function, we demonstrated that it is GluN2B-containing NMDA receptors in target S1 that mediate this guidance phenotype, thus playing a central role in interhemispheric connectivity. Furthermore, we found that this function of NMDA receptors in callosal circuit formation is independent of ion channel function and works with the EPHRIN-B/EPHB system. Thus, NMDAR in target S1 cortex regulates the formation callosal circuits perhaps by modulating EPH-dependent repulsion.
Highlights
Synaptic connections between neurons form circuits that can convey neural information
GluN1 KO mice prematurely innervate S1. To determine when this prominent targeting defect can first be detected, we examined different time points (P0, P3, P5, and P6) corresponding to critical phases of initial corpus callosum (CC) circuit formation – initial axon extension to ipsilateral CC (P0), axons crossing the midline (P3), axons reaching the white matter underneath contralateral S1 (P5), and axons starting to innervate S1 (P6)
We found that antibody injections from P4 to P8 had increased callosal axonal growth into S1 similar to that observed in NMDA receptor (NMDAR) genetic deletion mice (Figure 5A–D)
Summary
Synaptic connections between neurons form circuits that can convey neural information. Abnormalities at any stage of synaptic circuit development can result in neuropsychiatric pathology. The connectivity of the CC is essential for coordinated sensory-motor function and for many higher cognitive processes, and CC pathology is implicated in a variety of developmental disorders (Paul, 2011). Callosal projections originate from pyramidal neurons located in layers II/III, V, and VI and traverse the CC to form synapses with neurons in contralateral homotopic or heterotopic cortical areas. We previously showed (Zhou et al, 2013) that the medial-lateral topography of callosal neurons in the cortex is tightly constrained by the dorsal-ventral (D-V) position of axons within the CC. The axon position within the CC determines its terminal location in the contralateral cortex, with dorsally located axons projecting medially and ventrally located axons projecting laterally. The spatial organization of topographically represented information from one hemisphere is
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