Altered connectomes of adult-born granule cells following engraftment of GABAergic progenitors in the mouse hippocampus

Abstract

Adult neurogenesis occurs in the dentate gyrus (DG) of the rodent hippocampus throughout life, producing new granule cells (GCs) that migrate from a stem cell niche called the subgranular zone (SGZ) into the adjacent granule cell layer (GCL). Seizures associated with temporal lobe epilepsy alter adult neurogenesis and promote the formation of hyperexcitable circuits. Stem cell therapies for treating intractable seizure disorders are based on the premise that transplantation of GABAergic interneurons will strengthen inhibitory connections within the hippocampus and reduce hyperexcitability. Grafts of medial ganglionic eminence (MGE)-derived fetal GABAergic progenitors into the DG of adult mice with pilocarpine-induced TLE have been shown to suppress spontaneous recurrent seizures. In addition, the transplanted cells formed functional inhibitory synaptic connections with hippocampal neurons, including adult-born GCs. However, it is unknown whether MGE grafts change adult-born GC connectivity. To address this question, we compared the first-order monosynaptic inputs to adult-born GCs in TLE mice with or without MGE-derived interneuron grafts. Here we show that TLE increased excitatory inputs from endogenous hippocampal, entorhinal cortex, and medial septum/diagonal band neurons onto adult-born GCs. In contrast, in TLE mice with grafts, these excitatory inputs were reduced, coinciding with transplanted GABAergic interneuron innervation of adult-born GCs. These findings indicate that GABAergic interneuron transplantation into the dentate gyrus may prevent epilepsy-associated alterations in the connectivity of adult-born GCs.

Keywords: Adult neurogenesis; Connectome; Epilepsy; GABAergic graft; Granule cell; Rabies virus.