CSP-alpha is essential to maintain the quiescence of radial-glia like stem cells in postnatal neurogenesis

Abstract

Cysteine String Protein-α (CSP-α) is a synaptic co-chaperone that prevents activity-dependent degeneration of nerve terminals. Mutations in the human CSP-α gene cause neuronal ceroid lipofuscinosis characterized by progressive dementia and seizures. Synapses formed onto granule cells by parvalbumin (PV)-expressing basket cells progressively degenerate in CSP-α KO mice. Using electrophysiology in acute hippocampal slices, we have found that the properties of GABA release from basket cells are dysfunctional in CSP-α KO mice. In addition, at the dentate gyrus of CSP-α KO mice, the number of calretinin-expressing neurons is signifi cantly increased. We have systematically used BrdU injections and specific markers to uncover a severe deregulation of adult neurogenesis. We have observed that the pool of radial-glia like stem cells becomes progressively depleted due to hyper-proliferation, likely caused by a loss of stem cell quiescence. Surprisingly, part of these alterations occurs before basket cell synaptic dysfunction is established, suggesting that proliferation increase is partly due to a cell autonomous mechanism. Indeed, in the absence of CSP-α, although the number of neurospheres formed is much higher during the first passages, this number progressively becomes much lower than in controls. Our data are compatible with two types of alterations in adult neurogenesis: circuit-independent and circuit (PV neurons)- dependent mechanisms. Remarkably, our study uncovers an unanticipated requirement of CSP-α to maintain the quiescence of radial-glia like cells in postnatal neurogenesis.