Targeting neuronal gap junctions in mouse retina offers neuroprotection in glaucoma

Abstract

The progressive death of retinal ganglion cells and resulting visual deficits are hallmarks of glaucoma, but the underlying mechanisms remain unclear. In many neurodegenerative diseases, cell death induced by primary insult is followed by a wave of secondary loss. Gap junctions (GJs), intercellular channels composed of subunit connexins, can play a major role in secondary cell death by forming conduits through which toxic molecules from dying cells pass to and injure coupled neighbors. Here we have shown that pharmacological blockade of GJs or genetic ablation of connexin 36 (Cx36) subunits, which are highly expressed by retinal neurons, markedly reduced loss of neurons and optic nerve axons in a mouse model of glaucoma. Further, functional parameters that are negatively affected in glaucoma, including the electroretinogram, visual evoked potential, visual spatial acuity, and contrast sensitivity, were maintained at control levels when Cx36 was ablated. Neuronal GJs may thus represent potential therapeutic targets to prevent the progressive neurodegeneration and visual impairment associated with glaucoma.

Pannexin 1 Modulates Axonal Growth in Mouse Peripheral Nerves

“…Such possibilities offer exciting avenues for future experiments. An additional topic of future testing is the relative contributions of Panx1 and pannexin-independent pathways for ATP release, including calcium homeostasis modulator (CALHM) ion channels (Cisneros-Mejorado et al, 2015 ; Ma et al, 2016 ) or ATP signaling through connexins, which play an important role in glial communication in sensory ganglia (Liu et al, 2014 ), and also in the auditory and visual nervous systems (Cowan et al, 2016 ; Hidaka, 2016 ; Akopian et al, 2017 ; Lukashkina et al, 2017 ).…”

Bone Marrow CD133+ Stem Cells Ameliorate Visual Dysfunction in Streptozotocin-induced Diabetic Mice with Early Diabetic Retinopathy

“…The procedures were performed as described previously 27 , 51 – 53 . Briefly, mice ( n =12 eyes per group on Post-D28 and n =10 eyes per group on Post-D56) were dark-adapted overnight for recording under dim red light.…”

“…For quantification of retina layer thickness, all measures were made manually on retina section images using ZEN software (Zeiss). Images were taken at the same distance from the midperipheral regions (150–200 μm from the optic disk) at ×20 magnification as before 53 . Retinal sections were counterstained with DAPI to highlight the different layers of the retina.…”

Connexins in the Central Nervous System: Physiological Traits and Neuroprotective Targets

“…In addition, increased secondary damages via cytotoxicity and inflammatory response, lead to secondary cell death and propagation of neuronal loss (O'Carroll et al, 2013 ; Akopian et al, 2014 ). This mechanism underlies a number of degenerative disorders, including retinopathies, such as glaucoma (Akopian et al, 2014 , 2017 ), traumatic brain injury (Davidson et al, 2015b ; Chen et al, 2016 ), stroke (Nakase et al, 2009 ; Orellana et al, 2014 ) as well as degenerative disorders of the CNS such as Alzheimer's disease (Nagy et al, 1996 ; Orellana et al, 2011b ) and amyotrophic lateral sclerosis (ALS)-related motor neuron loss (Almad et al, 2016 ). These pathological conditions are characterized by reactive astrogliosis, mononuclear phagocytes activation, neuronal injury, and cell death typically linked to affected activity and regulation of main Cxs of the CNS including Cx36, Cx43, Cx30, Cx32, Cx29, and Cx47 (Decrock et al, 2015b ; Belousov et al, 2017 ).…”