Skilled Movements Require Non-apoptotic Bax/Bak Pathway-Mediated Corticospinal Circuit Reorganization

Abstract

Early postnatal mammals, including human babies, can perform only basic motor tasks. The acquisition of skilled behaviors occurs later, requiring anatomical changes in neural circuitry to support the development of coordinated activation or suppression of functionally related muscle groups. How this circuit reorganization occurs during postnatal development remains poorly understood. Here we explore the connectivity between corticospinal (CS) neurons in the motor cortex and muscles in mice. Using trans-synaptic viral and electrophysiological assays, we identify the early postnatal reorganization of CS circuitry for antagonistic muscle pairs. We further show that this synaptic rearrangement requires the activity-dependent, non-apoptotic Bax/Bak-caspase signaling cascade. Adult Bax/Bak mutant mice exhibit aberrant co-activation of antagonistic muscle pairs and skilled grasping deficits but normal reaching and retrieval behaviors. Our findings reveal key cellular and molecular mechanisms driving postnatal motor circuit reorganization and the resulting impacts on muscle activation patterns and the execution of skilled movements.

Motor system plasticity after unilateral injury in the developing brain

“…Synaptic interactions, especially competition, may be particularly important during early development when there is an overproduction of synaptic connections in the central nervous system and connections must be eliminated for circuit function. 2 Our findings suggest that the corticospinal motor system effectively oversees development of its downstream subcortical targets through activity or trophic-like interactions and synaptic competition. This could have important implications for perinatal cortical stroke and traumatic injuries, where loss of CST projection from frontal motor areas to the spinal cord may deprive spinal target neurons of signals necessary for their development.…”

“…Factors other than competition may also be important mediators of developmental plasticity – such as cooperative interactions between inputs, which have been contrasted from competitive interactions under different developmental conditions – and of particular importance after injury, the availability of synaptic space. Synaptic interactions, especially competition, may be particularly important during early development when there is an overproduction of synaptic connections in the central nervous system and connections must be eliminated for circuit function …”

“…These motor system circuits depend initially on developmental genetic mechanisms to establish their connections and neural activity-and usedependent synaptic refinement during the early postnatal period to enable motor skills to develop. In this review we consider four key activity-dependent developmental mechanisms that provide insights into how the motor systems establish the proper connections for skilled movement control and how the same mechanisms also inform the mechanisms of motor impairments and developmental plasticity after corticospinal system injury: (1) synaptic competition between the CSTs from each hemisphere; (2) interactions between the CST and spinal cord neurons; (3) synaptic competition between the CST and proprioceptive sensory fibres; and (4) interactions between the developing corticospinal motor system and the rubrospinal tract. Our findings suggest that the corticospinal motor system effectively 'oversees' development of its subcortical targets through synaptic competition and trophic-like interactions and this has important implications for motor impairments after perinatal cortical stroke.…”

“…Descending signals to motoneurons and interneurons mediating voluntary control can be distinguished from muscle and joint sensory signals that provide feedback for movement control. Whereas genetic mechanisms initially establish motor system connections, neural activity‐ and use‐dependent processes refine these connections to enable motor skills to develop …”

“…Whereas genetic mechanisms initially establish motor system connections, neural activity-and use-dependent processes refine these connections to enable motor skills to develop. [2][3][4] To begin to understand the mechanisms by which refinement of motor circuits occurs, we have developed animal models in which we can (1) regulate corticospinal system activity; (2) examine precisely descending motor pathway and proprioceptive fibre connections; (3) determine key characteristics of spinal cord interneurons; and (4) map the functional motor representations in the brain. With these tools we can study activity-based developmental plasticity mechanisms, as well as the relationship of these mechanisms to early brain injury.…”