Table 1 Comprehensive list of potential causes for loss of optogenetic expression over time.

Direct Nerve Damage

Phototoxicity

Light-induced thermal damage

Axonal death + Wallerian Degeneration

Khan et al.¹³, Chen et al.³⁹

Cytotoxicity

Excitotoxicity

Optogenetic pore-induced electrostatic damage

Neuronal death via apoptosis

Beppu et al.¹⁵,Perny et al.¹⁶, Lignani et al.⁴⁰, Feldbauer et al.⁴¹

ChR2 toxicity

Toxicity of opsin build-up & aggregation

Neuronal death via apoptosis

Zimmerman et al.⁹, Gradinaru et al.¹⁰, Miyashita et al.⁶, Li et al.⁴²

EYFP toxicity

Toxicity of reporter build-up & aggregation

Neuronal death via apoptosis

Ansari et al.²², Taghizadeh et al.²⁴

Immunogenicity

AAV immunogenicity

Adaptive immune response to virus

Neuronal+ muscular death via CTL

Montgomery et al.¹, Mingozzi et al.¹⁹, Sack et al.⁴³, Kohro et al.¹⁷

ChR2 immunogenicity

Adaptive immune response to opsin

Neuronal death via CTL

None^#

EYFP immunogenicity

Adaptive immune response to reporter

Neuronal death via CTL

Ansari et al.²², Stripecke et al.²³ Kohro et al.¹⁷

Protein Loss-of-Expression

Episomal DNA loss

rAAV DNA broken down or lost during division

Neuron likely healthy, no longer expresses

McCarty et al.⁴⁴, Fisher et al.⁴⁵

Epigenetic silencing

rAAV DNA silenced/methylated (no longer transcribed)

Neuron likely healthy, no longer expresses

Robertson et al.⁴⁶, Okada et al.⁴⁷, Migliaccio et al.⁴⁸

Transgene protein degradation or mRNA lysis/downregulation

Recombinant protein ubiquitinated and discarded via proteosome or no longer translated

Neuron likely healthy, no longer expresses

Jennings et al.⁴⁹, Kong et al.⁵⁰

Anatomical

Anatomical

More scattering in thick tissue

Neuron healthy, still expresses

Jacques et al.⁵¹, Maimon et al.⁴