Suppression of Adult Neurogenesis Increases the Acute Effects of Kainic Acid

Abstract

Adult neurogenesis, the generation of new neurons in the adult brain, occurs in the hippocampal dentate gyrus (DG) and the olfactory bulb (OB) of all mammals, but the functions of these new neurons are not entirely clear. Originally, adult-born neurons were considered to have excitatory effects on the DG network, but recent studies suggest a net inhibitory effect. Therefore, we hypothesized that selective removal of newborn neurons would lead to increased susceptibility to the effects of a convulsant. This hypothesis was tested by evaluating the response to the chemoconvulsant kainic acid (KA) in mice with reduced adult neurogenesis, produced either by focal X-irradiation of the DG, or by pharmacogenetic deletion of dividing radial glial precursors. In the first 4 hrs after KA administration, when mice have the most robust seizures, mice with reduced adult neurogenesis had more severe convulsive seizures, exhibited either as a decreased latency to the first convulsive seizure, greater number of convulsive seizures, or longer convulsive seizures. Nonconvulsive seizures did not appear to change or they decreased. Four-21 hrs after KA injection, mice with reduced adult neurogenesis showed more interictal spikes (IIS) and delayed seizures than controls. Effects were greater when the anticonvulsant ethosuximide was injected 30 min prior to KA administration; ethosuximide allows forebrain seizure activity to be more easily examined in mice by suppressing seizures dominated by the brainstem. These data support the hypothesis that reduction of adult-born neurons increases the susceptibility of the brain to effects of KA.

Adult Hippocampal Neurogenesis, Fear Generalization, and Stress

“…These observations are consistent with a study showing that ablation of adult hippocampal neurogenesis diminished sparseness of activation in the DG in mice only under conditions of high interference(Burghardt et al, 2012). Further, albeit indirect support, for a link between adult hippocampal neurogenesis and GABAergic inhibition comes from studies showing that blockade of adult hippocampal neurogenesis decreases seizure threshold, vesicular GABA transporter VGAT and baseline inhibitory synaptic transmission in the DG while increasing gamma burst activity(Singer et al, 2011;Lacefield et al, 2012;Iyengar et al, 2015). A recent study used optogenetics in slices from mice in which adult-born DGCs were labeled at different stages of maturation with channelrhodopsin to examine the extent of feed-back inhibition recruited by adultborn DGCs.…”

Increased gyrification and aberrant adult neurogenesis of the dentate gyrus in adult rats

“…Notably, there is evidence that aberrant neurogenesis leads to hyperexcitability and epilepsy (Cho et al 2015), even without SE (Koyama et al 2012; Pun et al 2012; Myers et al 2013). Importantly, there are studies which suggest that some neurons born after SE, possibly those that mature normally rather than abnormally, may quiet the DG network after SE rather than promote seizures (Jakubs et al 2006), consistent with the evidence that normal adult-born neurons reduce evoked seizures (Iyengar et al 2015). …”

Long-term Fate Mapping to Assess the Impact of Postnatal Isoflurane Exposure on Hippocampal Progenitor Cell Productivity

“…Consistent with this idea, experimental manipulations that transiently deplete adult-generated granule cells have been shown to produce a variety of behavioral deficits, including disruption of hippocampal dependent memory, 50-52 impaired responses to anti-depressant medications 53-55 and altered responses to convulsant drugs. 56,57 Deficiencies in recollection memory have recently been observed five to ten years following anesthesia and surgery in infancy, 58 possibly reflecting long-term consequences of transient hippocampal disruption. Animal and human studies designed to detect such transient deficits should be carefully timed with regard to the exposure period to optimize the chances of observing an effect.…”