Transcriptomic and epigenetic profiles of basal ganglia-cortex networks in developmental epileptic encephalopathies

• Applicants: Professor Dr. Dirk Isbrandt; Professor Dr. Jochen Roeper
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Cognitive, Systems and Behavioural Neurobiology
• Term: from 2022 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 497785435

Neurodevelopmental disorders share many clinical comorbidities such as impaired motor skills and behavioral deficits, suggesting overlapping pathophysiological mechanisms and common disease pathways. The developmental maturation of neuronal circuits through the formation and refining of synaptic connections is paralleled by dynamic changes in intrinsic excitability. Immature cortical networks show self-organization driven by intrinsically generated activity. For the proper maturation of functional architecture, however, sensory stimulation is required. Impaired cortical processing of sensory input, caused, for example, by shifts in the excitatory-inhibitory balance, affects critical developmental windows and triggers maladaptive neuroplasticity. We propose that, similar to these critical periods in sensory development, vulnerable periods may also exist for the development of higher motor functions. Consequently, prophylactic treatment targeted to these vulnerable periods of motor development may be crucial for disease prevention, as we previously showed in a proof-of-concept study in mouse Kv7 encephalopathy. The development and maturation of the basal ganglia, an essential brain network for motor control, has only recently become a research focus in the context of e.g. Attention-Deficit-Hyperactivity Disorder and Autism Spectrum Disease. Here, he roles of cortical excitability and dopamine function are investigated during postnatal development when goal-oriented motor programs begin to manifest and activity-dependent synapse formation occurs. Importantly, cortico-striatal connectivity and its neuromodulation are sensitive to acute and chronic pertubations in the balance of activity in direct and indirect striatal pathways, which in turn appear to control the excitatory innervation of the striatum. However, the developmental interplay of dopamine and cortico-striatal network maturation is not well understood. We hypothesize that disturbed neural network development underlies dysfunction of motor behavior in channelopathies. We postulate that mutations in ion channel genes, through changes in intrinsic neuronal properties altering cortical neuronal and network excitability, also affects the structural and functional maturation of developing subcortical networks such as the basal ganglia. This process then causes persistent functional and structural changes underlying life-long motor dysfunction. Here, we focus on two ion channel families, Kv7/M and HCN/h channels, whose dysfunction causes pronounced behavioral deficits in transgenic mouse models and aim at identifying the effects of perturbed development on the epigenomic and transcriptomic profiles of projection-specific dopamine midbrain neurons as key players of the basal ganglia. Given that neurodevelopmental perturbations result in clinically relevant changes in the adult DA system – also in a projection-selective fashion – we believe that our complementary approach is timely and relevant.

• DFG Programme: Research Grants