Figure 2:

Molecular systems that underlie learning regulate recovery after stroke. The peri-infarct cortex acts a hub for molecular events that regulate recovery after stroke. Transcription factor CREB is critical for memory formation. Increasing CREB signaling after stroke improves recovery of motor function. CREB signaling can lead to signaling pathways that enhance BDNF production. BDNF activates Trk signaling and this pathway in turn is positively modulated by AMPA receptor signaling. Slow and persistent (tonic) GABA signaling through the alpha5 receptor at extra synaptic sites dampens stroke recovery. GABA signaling is persistent due to defects in the GABA transporter (GAT1) expressed by astrocytes that function to transport and clear GABA at extrasynaptic sites. Blocking this pathway enhances motor recovery. CREB signaling is impeded by expression of CCR5 early after stroke. Blocking CCR5 signaling increases CREB signaling and signaling via DLK that acts as a regeneration signal for axonal sprouting. Axonal sprouting is further facilitated through reduced signaling via Ephrin A5 expressed on reactive astrocytes and its receptor EphA4 on neurons, that otherwise serve to collapse arrangement of cytoskeletal proteins.