Significance of Protein Synthesis by the Integrated Stress Response in Neuromodulatory Neurons for Adaptive Behavior and Synaptic Plasticity

ABSTRACT Plasticity mechanisms endow the brain with immense capacity to adapt to a wide range of experience and exposures. Protein synthesis, including locally at synapses, is a requirement for many forms of synaptic plasticity. The Integrated Stress Response, ISR, is a highly conserved biochemical pathway that regulates protein synthesis. The ISR markedly shifts which proteins are made by phosphorylating the initiation factor, eIF2alpha. The ISR was named for its effects body-wide - in which it provides a cell stress response mechanism. However, in the brain, the ISR has also been found to be a potent modifier of synaptic plasticity, learning and memory. At a high level of summary, ISR inhibition in the normal brain has been shown to lower the thresholds of experience needed to instantiate long-lasting memory and in some disease settings, such as traumatic brain injury, it rescues cognitive behavioral deficits. Mechanistically, ISR-inhibiting manipulations have been associated with long-lasting potentiation (LTP); while ISR activation is necessary for forms of synaptic depression (LTD). While trying to understand how the ISR contributes to diseases like dementia and dystonia, we recognized major gaps in the basic understanding of brain ISR actions, including when and where it was normally activated. We therefore developed a brain-wide viral reporter, SPOTlight, that gives a two-color readout for ISR activation state. Using SPOTlight, we uncovered a wholly non-canonical modality for the ISR in the brain – involving its constitutive activation in a class of neurons (striatal cholinergic interneurons) where it influences dopaminergic modulation of their firing response. Additionally, cell autonomous ISR inhibition in these cells recapitulated previous “learning enhancement” effects observed with systemic manipulations. These findings either upend, or at least substantially add to, working models for the ISR in plasticity, learning and memory. Here, we propose to advance understanding of how the ISR acts in the brain for neuromodulation, synaptic plasticity, learning and memory. We will focus on 3 knowledge gaps: (1) To what extent does ISR action in neuromodulatory cells, instead of at local synapses undergoing plasticity, explain ISR effects on synaptic plasticity and behavior? (2) What are the molecular mechanisms by which the ISR changes dopamine (D2R) signal transduction outcomes in cholinergic neurons? and (3) Can new ISR reporters be developed with the spatiotemporal resolution needed to resolve when and where the ISR activates protein synthesis under synaptic plasticity conditions? We expect the outcomes of this work to impact both general cell biological principles and specific striatal mechanisms and to have translational relevance for ISR-targeting therapeutic efforts that are underway.