GnRH replacement rescues cognition in Down syndrome

Abstract

At the present time, no viable treatment exists for cognitive and olfactory deficits in Down syndrome (DS). We show in a DS model (Ts65Dn mice) that these progressive nonreproductive neurological symptoms closely parallel a postpubertal decrease in hypothalamic as well as extrahypothalamic expression of a master molecule that controls reproduction—gonadotropin-releasing hormone (GnRH)—and appear related to an imbalance in a microRNA-gene network known to regulate GnRH neuron maturation together with altered hippocampal synaptic transmission. Epigenetic, cellular, chemogenetic, and pharmacological interventions that restore physiological GnRH levels abolish olfactory and cognitive defects in Ts65Dn mice, whereas pulsatile GnRH therapy improves cognition and brain connectivity in adult DS patients. GnRH thus plays a crucial role in olfaction and cognition, and pulsatile GnRH therapy holds promise to improve cognitive deficits in DS.

NOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits that can be reversed in infantile mice

“…The consequences of altered minipuberty are largely unknown beyond defects in testicular descent and penile growth (5,6). However, preclinical studies in rodents show that it could not only affect the timing of puberty and reproductive fitness, given that multiple switches are being flipped during minipuberty to induce the mature pattern of GnRH release and correct fertility initiation, but could also affect cognitive abilities (7)(8)(9).…”

Gonadotropin releasing hormone (GnRH): a hormone therapy boosts cognition in Down syndrome and dementia

“… 3 Fourth, a small population of GnRH neurons project to the cortex and hippocampus, regions of the brain that are critical for memory and cognition and have been implicated in the pathology of dementia. 1 , 5 Together, these findings demonstrate that GnRH signaling can be phenotypically, temporally, and spatially correlated with olfactory and cognitive deficits in DS, suggesting GnRH abnormalities may be causally linked to these disease phenotypes. To confirm their hypothesis, the authors characterized the progression of olfactory and cognitive symptoms in a DS mouse model (Ts65Dn mice) and assessed whether they were temporally correlated with any shifts in GnRH signaling.…”

“…A recent study published in Science by Manfredi-Lozano and colleagues suggests that the gonadotropin-releasing hormone (GnRH) could potentially restore cognition in patients with Down syndrome (DS). 1 The findings reveal a new molecular link between dementia and the loss of smell, and a promising therapeutic avenue to combat age-related cognitive decline in DS and other neurodegenerative diseases.…”

Use of pulsatile gonadotropin-releasing hormone (GnRH) in patients with functional hypothalamic amenorrhea (FHA) results in monofollicular ovulation and high cumulative live birth rates: a 25-year cohort

“…It is feasible that this may change as new evidence becomes available: a USA-based multicenter, double-blind, randomized, placebo-controlled trial evaluating three different doses of pulsatile GnRH administered via a subcutaneous pump for ovulation induction in patients with FHA was completed recently (ClinicalTrials.gov Identifier: NCT01976728). The use of pulsatile administration of GnRH has also been explored for other indications, such as in patients with Down syndrome (DS) to improve cognitive function [38].…”