A Sensitive Period for GABAergic Interneurons in the Dentate Gyrus in Modulating Sensorimotor Gating

Abstract

Developmental perturbations during adolescence have been hypothesized to be a risk factor for the onset of several neuropsychiatric diseases. However the physiological alterations that result from such insults are incompletely understood. We investigated whether a defined perturbation during adolescence affected hippocampus-dependent sensorimotor gating functions, a proposed endophenotype in several psychiatric diseases, most notably schizophrenia. The developmental perturbation was induced during adolescence in mice using an antimitotic agent, methylazoxymethanol acetate (MAM), during postnatal weeks (PW) 4 -6. MAM-treated mice showed a decrease in hippocampal neurogenesis immediately after treatment, which was restored by PW10 in adulthood. However, the mice treated with MAM during adolescent stages exhibited a persistent sensorimotor gating deficiency and a reduction in prepulse inhibitionrelated activation of hippocampal and prefrontal neurons in adulthood. Cellular analyses found a reduction of GABAergic inhibitory neurons and abnormal dendritic morphology of immature neurons in the dentate gyrus (DG). Interestingly, bilateral infusion of muscimol, a GABA A receptor agonist, into the DG region reversed the prepulse inhibition abnormality in MAM-treated mice. Furthermore, the behavioral deficits together with the decrease in the number of GABAergic neurons in this MAM model were rescued by exposure to an enriched environment during a defined critical adolescent period. These observations suggest a possible role for GABAergic interneurons in the DG during adolescence. This role may be related to the establishment of neural circuitry required for sensorimotor gating. It is plausible that changes in neurogenesis during this window may affect the survival of GABAergic interneurons, although this link needs to be causally addressed.

Seizure frequency correlates with loss of dentate gyrus GABAergic neurons in a mouse model of temporal lobe epilepsy

“…The slope of the regression line was used to estimate the total number of GAD‐positive neurons per dentate gyrus from profile counts for all of the mice. The average number of GAD‐positive neurons per hippocampus in control mice was comparable to that estimated in one previous study (Guo, Koshizaki, et al, ), but higher than that in another (Wei et al, ). The average number of GAD‐positive neurons per dentate gyrus in epileptic mice (5660 ± 70) was 72% of that in controls (7860 ± 300, p < 0.001, Mann–Whitney rank sum test) (Figure c).…”

Fatty acid binding proteins and the nervous system: Their impact on mental conditions

“…4C), and that GABA agonists injection into the DG of these mice (i.e., substitution of reduced GABA inputs) recovers their PPI deficits (Fig. 4D) (Guo et al, 2013). Taken altogether, an excessive excitatory activation (excess output of immature newborn neurons and/or less of GABAergic inhibition in the DG) might affect NAc activity and dopamine release, eventually causing disruption of normal PPI in Fabp7 and Fabp7/5 KO mice.…”

Maternal immune activation alters glutamic acid decarboxylase-67 expression in the brains of adult rat offspring

“…The physiological implications for these increases are unknown. Other studies have found that GABAergic neuronal circuitry is vulnerable during adolescence, with effects persisting into adulthood (Guo et al, 2013). …”