Fluoxetine induces input-specific hippocampal dendritic spine remodeling along the septotemporal axis in adulthood and middle age.

Fluoxetine, a selective serotonin-reuptake inhibitor (SSRI), is known to induce structural rearrangements and changes in synaptic transmission in hippocampal circuitry. In the adult hippocampus, structural changes include neurogenesis, dendritic, and axonal plasticity of pyramidal and dentate granule neurons, and dedifferentiation of dentate granule neurons. However, much less is known about how chronic fluoxetine affects these processes along the septotemporal axis and during the aging process. Importantly, studies documenting the effects of fluoxetine on density and distribution of spines along different dendritic segments of dentate granule neurons and CA1 pyramidal neurons along the septotemporal axis of hippocampus in adulthood and during aging are conspicuously absent. Here, we use a transgenic mouse line in which mature dentate granule neurons and CA1 pyramidal neurons are genetically labeled with green fluorescent protein (GFP) to investigate the effects of chronic fluoxetine treatment (18 mg/kg/day) on input-specific spine remodeling and mossy fiber structural plasticity in the dorsal and ventral hippocampus in adulthood and middle age. In addition, we examine levels of adult hippocampal neurogenesis, maturation state of dentate granule neurons, neuronal activity, and glutamic acid decarboxylase-67 expression in response to chronic fluoxetine in adulthood and middle age. Our studies reveal that while chronic fluoxetine fails to augment adult hippocampal neurogenesis in middle age, the middle-aged hippocampus retains high sensitivity to changes in the dentate gyrus (DG) such as dematuration, hypoactivation, and increased glutamic acid decarboxylase 67 (GAD67) expression. Interestingly, the middle-aged hippocampus shows greater sensitivity to fluoxetine-induced input-specific synaptic remodeling than the hippocampus in adulthood with the stratum-oriens of CA1 exhibiting heightened structural plasticity. The input-specific changes and circuit-level modifications in middle-age were associated with modest enhancement in contextual fear memory precision, anxiety-like behavior and antidepressant-like behavioral responses.

Prospective Cohort Study of Nephrogenic Systemic Fibrosis in Patients With Stage 3-5 Chronic Kidney Disease Undergoing MRI With Injected Gadobenate Dimeglumine or Gadoteridol.

OBJECTIVE: The purpose of this study was to determine the incidence of nephrogenic systemic fibrosis (NSF) in patients with chronic kidney disease (CKD) and moderate-to-severe impairment of kidney function who had not previously been exposed to gadolinium-based contrast agents (GBCAs) or referred to undergo contrast-enhanced MRI with gadobenate dimeglumine or gadoteridol. SUBJECTS AND METHODS: Two multicenter prospective cohort studies evaluated the incidence of unconfounded NSF in patients with stage 3 CKD (estimated glomerular filtration rate [eGFR] in cohort 1, 30-59 mL/min/1.73 m(2)) or stage 4 or 5 CKD (eGFR in cohort 2, < 30 mL/min/1.73 m(2)) after injection of gadobenate dimeglumine (study A) or gadoteridol (study B). A third study (study C) determined the incidence of NSF in patients with stage 4 or 5 CKD who had not received a GBCA in the 10 years before enrollment. Monitoring for signs and symptoms suggestive of NSF was performed via telephone at 1, 3, 6, and 18 months, with clinic visits occurring at 1 and 2 years. RESULTS: For studies A and B, the populations evaluated for NSF comprised 363 and 171 patients, respectively, with 318 and 159 patients in cohort 1 of each study, respectively, and with 45 and 12 patients in cohort 2, respectively. No signs or symptoms of NSF were reported or detected during the 2 years of patient monitoring. Likewise, no cases of NSF were reported for any of the 405 subjects enrolled in study C. CONCLUSION: To our knowledge, and consistent with reports in the literature, no association of gadobenate dimeglumine or gadoteridol with unconfounded cases of NSF has yet been established. Study data confirm that both gadoteridol and gadobenate dimeglumine properly belong to the class of GBCAs considered to be associated with the lowest risk of NSF.

Modulating Neuronal Competition Dynamics in the Dentate Gyrus to Rejuvenate Aging Memory Circuits.

The neural circuit mechanisms underlying the integration and functions of adult-born dentate granule cell (DGCs) are poorly understood. Adult-born DGCs are thought to compete with mature DGCs for inputs to integrate. Transient genetic overexpression of a negative regulator of dendritic spines, Kruppel-like factor 9 (Klf9), in mature DGCs enhanced integration of adult-born DGCs and increased NSC activation. Reversal of Klf9 overexpression in mature DGCs restored spines and activity and reset neuronal competition dynamics and NSC activation, leaving the DG modified by a functionally integrated, expanded cohort of age-matched adult-born DGCs. Spine elimination by inducible deletion of Rac1 in mature DGCs increased survival of adult-born DGCs without affecting proliferation or DGC activity. Enhanced integration of adult-born DGCs transiently reorganized adult-born DGC local afferent connectivity and promoted global remapping in the DG. Rejuvenation of the DG by enhancing integration of adult-born DGCs in adulthood, middle age, and aging enhanced memory precision.