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α-Klotho (α-Kl) is a modulator of aging, neuroprotection, and cognition. Transcription of the Klotho gene produces two splice variants-a membrane protein (mKl), which can be cleaved and released into the extracellular milieu, and a truncated secreted form (sKl). Despite mounting evidence supporting a role for α-Kl in brain function, the specific roles of α-Kl isoforms in neuronal development remain elusive. Here, we examined α-Kl protein levels in rat brain and observed region-specific expression in the adult that differs between isoforms. In the developing hippocampus, levels of isoforms decrease after the third postnatal week, marking the end of the critical period for development. We overexpressed α-Kl isoforms in primary cultures of rat cortical neurons and evaluated effects on brain-derived neurotrophic factor (BDNF) signaling. Overexpression of either isoform attenuated BDNF-mediated signaling and reduced intracellular Ca 2+ levels, with mKl promoting a greater effect. mKl or sKl overexpression in hippocampal neurons resulted in a partially overlapping reduction in secondary dendrite branching. Moreover, mKl overexpression increased primary dendrite number. BDNF treatment of neurons overexpressing sKl resulted in a dendrite branching phenotype similar to control neurons. In neurons overexpressing mKl, BDNF treatment restored branching of secondary and higher order dendrites close, but not distal, to the soma. Taken together, the data presented support the idea that sKl and mKl play distinct roles in neuronal development, and specifically, in dendrite morphogenesis., (© 2024. The Author(s).)