Viral tracing of presynaptic inputs to newly born dentate granule cells in a rodent model of mesial temporal lobe epilepsy

Mesial temporal lobe epilepsy (mTLE) is a common form of epilepsy often resistant to treatment that almost always involves progressive impairment in cognitive function. Hippocampi from patients diagnosed with refractory mTLE show substantial histopathology that includes pyramidal cell loss, astrogliosis, axonal reorganization, and dentate granule cell (DGC) layer dispersion. In the 1990s, seminal discoveries from the laboratories of Rusty Gage, Elizabeth Gould, Arturo Alvarez-Buylla, and Fernando Nottebohm challenged a long-standing notion that the adult brain does not support generation of new neurons (ie, neurogenesis). Proliferative zones where neurogenesis can continue throughout adulthood were identified in the olfactory bulb and hippocampus. Soon after these discoveries, Parent, Lowenstein, and colleagues published a seminal paper showing that prolonged seizure activity (ie, status epilepticus) stimulates neurogenesis in the adult hippocampus. These newborn granule cells (GCs) were quickly implicated in mossy fiber sprouting, a widely recognized reorganization of GC axons seen in epilepsy, and long believed to contribute to a process of epileptogenesis. Some seizure-induced newborn DGCs were subsequently shown, in this journal, to abnormally integrate in the epileptic adult hippocampus. The functional significance of these findings remains an area of active investigation with direct relevance to the emergence of epilepsy and/or cognitive dysfunction in mTLE patients. In this issue of Annals of Neurology, work by Du et al further elucidates the local and long-range inputs to these adult newborn GCs. To better understand newborn GC function, it is necessary to know what “talks to” these neurons (ie, presynaptic inputs). Dendrites on newborn DGCs born under healthy conditions receive synaptic input through perforant path axons from excitatory neurons in entorhinal cortex. Seizure-generated newborn DGCs in the molecular layer, however, extend an additional hilar basal dendrite, and some newborn DGCs aberrantly migrate into the hilus to become ectopic hilar GCs. Understanding whether excitatory or inhibitory input is preferential for healthy pre-existing and seizure-induced newly born DGCs could provide insight into the seizure-induced reorganization of adult hippocampal networks. There exist at least 2 possible scenarios for how seizure-induced newborn DGCs can impact hippocampal function. First, a direct association with epileptogenesis via the creation of de novo excitatory circuits through participation in mossy fiber sprouting is quite appealing as a mechanism of increased recurrent excitation. Recent work from the Parent group found that both neonatal and adult-born DGCs participated in mossy fiber sprouting in the rat pilocarpine mTLE model. Whether newborn DGCs are necessary for mossy fiber sprouting, however, remains controversial, as recent studies using cell-ablation strategies found no impact of newborn DGCs on mossy fiber sprouting. As such, aberrant neurogenesis or mossy fiber sprouting alone may not be sufficient to produce seizures. Second, seizure-induced migration (and functional integration) of newborn DGCs into the hilus could directly contribute to aberrant circuit development and altered network function. These latter reorganizations of the adult hippocampal circuit may play a critical role, not in epileptogenesis per se, but in the progressive emergence of cognitive disabilities associated with mTLE. Whether seizure-induced newborn DGCs receive excitatory, inhibitory, or both types of presynaptic inputs is critical to both possibilities. Whether in a healthy or disease state, unraveling the complexity of brain circuits requires a detailed understanding of the connections between neurons, an emerging neuroscience discipline termed “connectomics. ” Recombinant glycoprotein-deleted rabies virus (RbV) is an important tool for investigating neuronal connections, revealing fine morphological details that were obscured with earlier tracing methodologies. RbV is an RNA virus, not taken up by fibers of passage, that completes its life cycle within the cytoplasm of a primary-infected neuron, contributing to a