Abnormalities in the hippocampus are associated with neuropsychiatric diseases characterized by cognitive dysfunction. While the mechanisms underlying hippocampal wiring and plasticity are continually being elucidated, those preserving neuronal positioning and integrity in the hippocampus, once neurons have integrated into the network, remain unknown. The Nguyen lab has recently generated mice postnatally lacking the atypical microtubule-associated / signaling protein Ndel1 in forebrain excitatory neurons (Ndel1 CKO) (Jiang et al., Journal of Neuroscience 2016).

 

Ndel1, the mammalian homolog of NuDE from the filamentous fungus Aspergillus nidulans, is an atypical microtubule (MT)-associated protein (MAP) that was initially investigated in the contexts of neurogenesis and neuronal migration (Nguyen et al., Nat Cell Biol 2003; Shu et al., Neuron 2004; Chansard et al., Cytoskeleton 2011). Constitutive knockout mice for Ndel1 are embryonic lethal, thereby necessitating the creation a conditional knockout to probe the roles of Ndel1 in the postnatal brain.

 

The Nguyen lab discovered a specific postnatal dispersion of CA1 pyramidal cells in dorsal hippocampus of Ndel1 CKO mice that is independent of neuronal migration defects. Dispersed CA1 neurons exhibit fragmented microtubules, primitive dendritic trees, reduced spine density and are intrinsically hyper-excitable. Secondary to pyramidal cell changes is the decreased inhibitory drive onto pyramidal cells from interneurons. Moreover, interneurons in stratum oriens of Ndel1 CKO mice show reduced levels of Reelin, a secreted glycoprotein that normally stabilizes microtubules during brain development and keeps cells aligned in the adult brain. Strikingly, a single injection of Reelin into the hippocampus of Ndel1 CKO mice ameliorates microtubules fragmentation, dendritic/synaptic pathology as well as CA1 dispersion (Jiang et al., Journal of Neuroscience 2016). Furthermore, the spatial learning and memory deficits in the Ndel1 CKO that are associated with deregulation of neuronal cell adhesion, plasticity and neurotransmission genes, can be attenuated with Reelin, and this rescue is correlated with reduced intrinsic hyperexcitability of CA1 pyramidal neurons, and normalized gene deregulation in the hippocampus (Kiroski et al., Cereb Cortex 2020, cover of the September issue). When treated with Reelin, Ndel1 CKO animals that die from an epileptic phenotype, live twice as long as non-treated or vehicle-treated CKO animals (Kiroski et al., Cereb Cortex 2020, cover of the September issue). Thus, Reelin confers striking beneficial effects in the CA1 hippocampus, and at both behavioral and organismal levels.

 

Why is this work important? The levels of Ndel1 and Reelin are decreased in the hippocampus of schizophrenic patients. Ndel1 dysfunction is also associated with major depression, lissencephaly and bipolar disorders. Mutations in Reelin underlie human cases with thickened cortex, pachygyria (indicative of impaired neuronal migration), significant cerebellar hypoplasia. Further, the levels and functions/activities of Reelin are deregulated in Alzheimer disease. By understanding the roles of these two proteins in the postnatal hippocampus, our work provides with a better understanding of the mechanisms underlying hippocampal dysfunction in brain diseases.