Targeted therapy of cognitive deficits in fragile X syndrome

Abstract

Breaking an impasse in finding mechanism-based therapies of neuropsychiatric disorders requires a strategic shift towards alleviating individual symptoms. Here we present a symptom and circuit-specific approach to rescue deficits of reward learning in Fmr1 knockout mice, a model of Fragile X syndrome (FXS), the most common monogenetic cause of inherited mental disability and autism. We use high-throughput, ecologically-relevant automated tests of cognition and social behavior to assess effectiveness of the circuit-targeted injections of designer nanoparticles, loaded with TIMP metalloproteinase inhibitor 1 protein (TIMP-1). Further, to investigate the impact of our therapeutic strategy on neuronal plasticity we perform long-term potentiation recordings and high-resolution electron microscopy. We show that central amygdala-targeted delivery of TIMP-1 designer nanoparticles reverses impaired cognition in Fmr1 knockouts, while having no impact on deficits of social behavior, hence corroborating symptom-specificity of the proposed approach. Moreover, we elucidate the neural correlates of the highly specific behavioral rescue by showing that the applied therapeutic intervention restores functional synaptic plasticity and ultrastructure of neurons in the central amygdala. Thus, we present a targeted, symptom-specific and mechanism-based strategy to remedy cognitive deficits in Fragile X syndrome.

Modelling collective behavior in groups of mice housed under semi-naturalistic conditions

“…To that end, we inject animals with a Tissue Inhibitor of MetalloProteinases (TIMP-1), an enzyme regulating the activity of synaptic plasticity proteins. Changing its physiological levels was previously shown to disrupt the neuronal plasticity in various brain structures [42, 43], including the prefrontal cortex (PFC) [33, 44]. Now, we ask if we can identify changes in behavioral patterns after the mice have been injected with nanoparticles (NP) gradually releasing TIMP-1 (NP-TIMP-1) into the PL [37].…”

MMP-9 plasma level as biomarker of cochlear implantation outcome in cohort study of deaf children

“…The biological mechanism behind MMP-9 responses to cochlear implantation remains unclear. It should be noted, however, that experimental studies have shown that both increased and decreased MMP-9 activity produces alterations in synaptic plasticity, learning, and memory [ 44 , 45 ]. In fact, Wiera et al directly demonstrated deficits in LTP (an electrophysiological model of synaptic plasticity) in gene knockout mice lacking MMP-9 activity, as well as in rats overexpressing the MMP-9 gene in neurons [ 46 ].…”