No abstract

Neural activity enhances adult neurogenesis, enabling experience to influence the construction of new circuits. GABAA receptor-mediated depolarization of newborn neurons in the adult and developing brain promotes glutamatergic synaptic integration since chronic reduction of GABA depolarization impairs morphological maturation and formation of glutamatergic synapses. Here we demonstrate an acute role of GABA depolarization in glutamatergic synaptic integration. Using POMC-GFP reporter mice, we identify a developmental stage when adult generated neurons have glutamatergic synaptic transmission mediated solely by NMDA receptors (NMDARs), representing the initial silent synapses prior to AMPA receptor (AMPAR)-mediated functional transmission. We show that pairing synaptic stimulation with postsynaptic depolarization results in synapse unsilencing that requires NMDAR activation. GABA synaptic depolarization enables activation of NMDARs in the absence of AMPAR-mediated transmission, and is required for synapse unsilencing induced by synaptic activity in vitro as well as a brief exposure to an enriched environment in vivo. The rapid appearance of AMPAR-mediated EPSCs and the lack of maturational changes show that GABA depolarization acutely allows NMDAR activation required for initial synapse unsilencing. Together these results also reveal that adult generated neurons in a critical period for survival use GABA signaling to rapidly initiate functional glutamate-mediated transmission in response to experience.

Neuronal membrane components that bind alpha-bungarotoxin with high affinity have only recently been shown unambiguously to function as nicotinic receptors. Activation of the receptors increases intracellular levels of free calcium in neurons. In the chick ciliary ganglion, where the receptors have been studied in some detail, they have been shown to have a predominantly nonsynaptic location on neurons and may be concentrated on pseudodendrites emerging from the somata. This has raised questions about the physiological significance of the receptors for the neurons. Here we show that activation of the receptors on isolated ciliary ganglion neurons in cell culture produces neurite retraction. Focal application of either nicotine or ACh at low concentrations induces the retraction, and alpha-bungarotoxin blocks the effect. The retraction requires external calcium and is confined to the individual neurite stimulated with agonist. Brief exposure to elevated concentrations of K+ also induces neurite retraction, and both the K(+)-induced and the nicotine-induced retractions can be prevented by the calcium channel blocker omega-conotoxin. The results suggest that activation of the alpha-bungarotoxin-binding nicotinic receptors on neurites triggers activation of voltage-gated calcium channels presumably by depolarizing the membrane, and that together they permit sufficient calcium to enter the neurite to prevent further outgrowth and induce retraction.

Selective serotonin reuptake inhibitor (SSRI) antidepressants are the mainstay treatment for the 10–20% of pregnant and postpartum women who suffer major depression, but the effects of SSRIs on their children’s developing brain and later emotional health are poorly understood. SSRI use during pregnancy can elicit antidepressant withdrawal in newborns and increase toddlers’ anxiety and social avoidance. In rodents, perinatal SSRI exposure increases adult depression- and anxiety-like behavior, although certain individuals are more vulnerable to these effects than others. Our study establishes a rodent model of individual differences in susceptibility to perinatal SSRI exposure, utilizing selectively-bred Low Responder (bLR) and High Responder (bHR) rats that were previously bred for high versus low behavioral response to novelty. Pregnant bHR/bLR females were chronically treated with the SSRI paroxetine (10 mg/kg/day p.o.) to examine its effects on offspring’s emotional behavior and gene expression in the developing brain. Paroxetine treatment had minimal effect on bHR/bLR dams’ pregnancy outcomes or maternal behavior. We found that bLR offspring, naturally prone to an inhibited/anxious temperament, were susceptible to behavioral abnormalities associated with perinatal SSRI exposure (which exacerbated their Forced Swim test immobility), while high risk-taking bHR offspring were resistant. Microarray studies revealed robust perinatal SSRI-induced gene expression changes in the developing bLR hippocampus and amygdala (postnatal days 7–21), including transcripts involved in neurogenesis, synaptic vesicle components, and energy metabolism. These results highlight the bLR/bHR model as a useful tool to explore the neurobiology of individual differences in susceptibility to perinatal SSRI exposure.

Although the absence of the age-regulating klotho protein causes klotho-deficient mice to rapidly develop cognitive impairment and increasing klotho enhances hippocampal-dependent memory, the cellular effects of klotho that mediate hippocampal-dependent memory function are unknown. Here we show premature aging of the klotho-deficient hippocampal neurogenic niche as evidenced by reduced numbers of neural stem cells, decreased proliferation, and impaired maturation of immature neurons. Klotho-deficient neurospheres show reduced proliferation and size that is rescued by supplementation with shed klotho protein. Conversely, 6 month old klotho overexpressing mice exhibit increased numbers of neural stem cells, increased proliferation, and more immature neurons with enhanced dendritic arborization. Protection from normal age-related loss of object location memory with klotho overexpression and loss of spatial memory when klotho is reduced by even half suggest direct, local effects of the protein. Together these data show that klotho is a novel regulator of postnatal neurogenesis affecting neural stem cell proliferation and maturation sufficient to impact hippocampal-dependent spatial memory function.