Abstract
Treatments that stimulate neuronal excitability enhance motor performance after stroke. cAMP-response-element binding protein (CREB) is a transcription factor that plays a key role in neuronal excitability. Increasing the levels of CREB with a viral vector in a small pool of motor neurons enhances motor recovery after stroke, while blocking CREB signaling prevents stroke recovery. Silencing CREB-transfected neurons in the peri-infarct region with the hM4Di-DREADD blocks motor recovery. Reversing this inhibition allows recovery to continue, demonstrating that by manipulating the activity of CREB-transfected neurons it is possible to turn off and on stroke recovery. CREB transfection enhances remapping of injured somatosensory and motor circuits, and induces the formation of new connections within these circuits. CREB is a central molecular node in the circuit responses after stroke that lead to recovery from motor deficits.
Highlights
Treatments that stimulate neuronal excitability enhance motor performance after stroke. cAMP-response-element binding protein (CREB) is a transcription factor that plays a key role in neuronal excitability
To determine the role of CREB in motor recovery after stroke, we increased its expression in a small pool of neurons in motor and premotor cortex anterior to the site of the stroke (Fig. 1a, b; Supplementary Fig. 1)
A photothrombotic stroke was produced in the forelimb motor cortex. This model produces long-lasting behavioral deficits in motor function[8,16,17,18,19,20] in which motor and premotor sites play a causal role in motor recovery[17,18,19,20]. In this lentiviral gene delivery, CREB-eGFP expression is under the regulation of the excitatory neuron-specific αCaMKII promoter along with enhanced green fluorescent protein (CaMKIIa_HA/ AlstR_CREB/eGFP, referred as lenti-CREB; Fig. 1c)
Summary
Treatments that stimulate neuronal excitability enhance motor performance after stroke. cAMP-response-element binding protein (CREB) is a transcription factor that plays a key role in neuronal excitability. Silencing CREB-transfected neurons in the peri-infarct region with the hM4Di-DREADD blocks motor recovery. In rodent models of stroke, pharmacogenetic treatments that enhance neuronal excitability in peri-infarct cortex adjacent to the stroke promote motor recovery[7,8]. Stroke recovery is associated with dramatic spine plasticity in the peri-infarct cortex, with an increase in spine density over baseline values in some regions[6]. These data indicate that CREB-dependent transcription has a critical role in the modulation of neuronal excitability and in long-lasting alterations in circuit structure during cortical plasticity and memory. We hypothesized that CREB function in a localized network of motor cortical neurons near the stroke site might enhance motor recovery by facilitating remapping of local cortical networks
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