A Therapeutic Potential of Silent Synapses for Ameliorating Critical Period Defects

• Applicants: Professorin Dr. Siegrid Löwel; Professor Dr. Oliver M. Schlüter
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 525940896

Neurodevelopmental disorders such as amblyopia are caused by impaired experience-dependent refinement of neural networks during development. Correcting the sensory defect that causes amblyopia during the critical period (CP) establishes full vision, but treatments after CPs are insufficient. We recently established AMPA receptor-silent synapses as substrates for developmental refinement of excitatory neural networks during CPs. Silent synapses either mature to consolidate a synaptic connection or are pruned, which is observable as a signature of CP plasticity in vivo. Consequently, CPs end with the progressive maturation of silent synapses. In this proposal, we aim to identify the therapeutic potential of silent synapses to increase plasticity in the adult brain with early monocular deprivation (MD) as our amblyopia model. We hypothesize that silent synapses are an essential prerequisite to reorganize excitatory connections to treat amblyopia. We aim to explore molecular mechanisms of silent synapse generation and aim to identify the mechanisms of psychotropic drugs on synapse generation. For translation, we will investigate in vivo signatures of CP plasticity by chronic imaging of layer (L)2/3 pyramidal neuron dendritic spines and assess whether adult induction of silent synapses can correct visual impairments. We recently found that thrombospondin-2 (Thbs2) through its receptor alpha2 delta-1 is required for cocaine-induced generation of silent synapses in the adult nucleus accumbens, indicating that developmental synaptogenic signalling mechanisms are exploited by drugs of abuse. Based on recent findings of dendritic spine induction and amelioration of amblyopia, we hypothesize that the psychotropic drug ketamine will induce silent synapses in the mature brain as substrates for regained plasticity. Furthermore, we found that knocking down PSD-95 in the adult visual cortex increases silent synapse numbers and restores juvenile ocular dominance plasticity after MD. As further mechanistic support of juvenile ocular dominance plasticity, we observed the pruning of L2/3 dendritic spines of PSD-95-deficient neurons in the awake brain. Using a combination of transgenic mice, viral vector-mediated gene transfer, ex vivo visual cortex slice electrophysiology, in vivo intrinsic signal optical imaging, behavioral tests for assessing visual acuity, and two-photon dendritic spine imaging in awake mice, we propose to examine the role of the thrombospondin pathway and the psychoactive drug ketamine in visual cortex silent synapse generation and the potential restoration of compromised visual function in adult mice.

• DFG Programme: Research Grants