Biology subjects

Nawy, S.

Publications and source records attributed to Nawy, S..

4 recordsLinked to original sources

bioRxiv2024

A toolbox for ablating excitatory and inhibitory synapses

Recombinant optogenetic and chemogenetic proteins are potent tools for manipulating neuronal activity and controlling neural circuit function. However, there are few analogous tools for manipulating the structure of neural circuits. Here, we introduce three rationally designed genetically encoded tools that use E3 ligase-dependent mechanisms to trigger the degradation of synaptic scaffolding proteins, leading to functional ablation of synapses. First, we developed a constitutive excitatory synapse ablator, PFE3, analogous to the inhibitory synapse ablator GFE3. PFE3 targets the RING domain of the E3 ligase Mdm2 and the proteasome-interacting region of Protocadherin 10 to the scaffolding protein PSD-95, leading to efficient ablation of excitatory synapses. In addition, we developed a light-inducible version of GFE3, paGFE3, using a novel photoactivatable complex based on the photocleavable protein PhoCl2c. paGFE3 degrades Gephyrin and ablates inhibitory synapses in response to 400 nm light. Finally, we developed a chemically inducible version of GFE3, chGFE3, which degrades inhibitory synapses when combined with the bio-orthogonal dimerizer HaloTag ligand-trimethoprim. Each tool is specific, reversible, and capable of breaking neural circuits at precise locations.

neuroscience↗

bioRxiv2024

Retinal bipolar cells borrow excitability from electrically coupled inhibitory interneurons to amplify excitatory synaptic transmission

Bipolar cells (BCs) carry visual information from photoreceptors in the outer retina to retinal ganglion cells (RGCs) in the inner retina. Most BCs lack voltage-gated Na+ (NaV) channels and action potentials. Instead, voltage signals spread passively from input to output synapses. Despite this, we find that blocking NaV channels reduces synaptic output of On-cone bipolar cells (On-CBCs). These cells borrow NaV channel-mediated excitability from electrically coupled A2 amacrine cells to amplify excitatory output, allowing voltage changes to be transmitted more effectively to downstream RGCs in dim light. Because neighboring On-CBCs form electrical synapses onto the same A2 cell, a spatially adjacent group of On-CBCs is more effective than a dispersed set for recruiting A2 cell electrical excitability and driving post-synaptic RGCs. This mechanism filters the neural representation of an image to highlight shapes over spatially uncorrelated stimuli, a sophisticated feature detection property that is well-suited for object recognition.

neuroscience↗

bioRxiv2023

Retinoic acid-dependent loss of synaptic output from bipolar cells impairs visual information processing in inherited retinal degeneration.

In retinitis pigmentosa (RP), rod and cone photoreceptors degenerate, depriving downstream neurons of light-sensitive input, leading to vision impairment or blindness. Although downstream neurons survive, some undergo morphological and physiological remodeling. Bipolar cells (BCs) link photoreceptors, which sense light, to retinal ganglion cells (RGCs), which send information to the brain. While photoreceptor loss disrupts input synapses to BCs, whether BC output synapses remodel has remained unknown. Here we report that synaptic output from BCs plummets in RP mouse models of both sexes owing to loss of voltage-gated Ca2+ channels. Remodeling reduces the reliability of synaptic output to repeated optogenetic stimuli, causing RGC firing to fail at high stimulus frequencies. Fortunately, functional remodeling of BCs can be reversed by inhibiting the retinoic acid receptor (RAR). RAR inhibitors targeted to BCs present a new therapeutic opportunity for mitigating detrimental effects of remodeling on signals initiated either by surviving photoreceptors or by vision-restoring tools. Significance StatementPhotoreceptor degenerative disorders such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD) lead to vision impairment or blindness. Vision mediated by surviving photoreceptors or artificial vision restoration technologies, rely on bipolar cells retaining normal function despite photoreceptor death. We find that in two animal models of RP, synaptic transmission from both rod and cone bipolar cells is severely impaired owing to diminished voltage-gated calcium current, preventing postsynaptic amacrine cells and retinal ganglion cells from properly receiving and encoding visual information. We find that an inhibitor of the retinoic acid receptor restores both the calcium current and synaptic release from bipolar cells. These discoveries about bipolar cells reveal a new functional deficit in blindness and a potential therapeutically important solution.

neuroscience↗

bioRxiv2019

Ocular hypertension drives remodeling of AMPA receptors in select populations of retinal ganglion cells

AMPA receptors in the CNS are normally impermeable to Ca2+ but aberrant expression of Ca2+-permeable AMPA receptors (CP-AMPARs) occurs in pathological conditions such as ischemia or epilepsy, or in degenerative diseases such as ALS. Here we show that select populations of retinal ganglion cells (RGCs) similarly express high levels of CP-AMPARs in a mouse model of glaucoma. CP-AMPAR expression increased dramatically in both On and transient Off RGCs, and this increase was prevented by genomic editing of the GluA2 Q/R site. On RGCs with elevated CP-AMPAR levels displayed profound synaptic depression, which was reduced by selectively blocking CP-AMPARs, buffering Ca2+ with BAPTA, or with the CB1 antagonist AM251, suggesting that depression was mediated by a retrograde transmitter which might be triggered by influx of Ca2+ through CP-AMPARs. Thus OHT alters the composition of AMPARs and modulates patterns of synaptic activity in select populations of RGCs.

neuroscience↗