Consequences of HCN/h pacemarker channel deficency for cortico-basal ganglia circuit function
Final Report Abstract
Neurons with pacemaker properties can be found in all basal ganglia nuclei, and they are thought to contribute to the generation of rhythmic local and network activities sustaining normal motor function and behavior. HCN channels, also known as pacemaker channels, are widely expressed in many neuron types with and without pacemaker properties, including in some basal ganglia nuclei and neurons. We hypothesized that a loss of function of HCN channels would change the firing patterns of these neurons, and alter synaptic and network activities, thus affecting both cognitive and motor function. Using a conditional transgenic approach to control HCN-channel activity in forebrain projection neurons, we found that lifelong loss of HCN channel function was associated with a delayed somatomotor development and psychomotor disturbances, including behavioral hyperactivity and stereotypies. Notably, restricting HCN-channel dysfunction to the first three postnatal weeks did not prevent behavioral hyperactivity, indicating developmental changes that are not reversible by simple re-introduction of the HCN-channel function later in life. Importantly, the locomotor hyperactivity could not be ameliorated by the administration of methylphenidate, which is commonly used to treat attention-deficit hyperactivity disorder (ADHD). Instead, HCN-channel-deficient mutants responded to antipsychotics, specifically to D2 dopamine receptor antagonists, suggesting that developmental loss of HCN channels in forebrain projection neurons caused persistent changes in corticobasal ganglia circuits and dopaminergic signaling, such an increase in D2 receptor tone or altered properties of striatal medium spiny neurons. It is tempting to speculate that these changes might also contribute to the altered gait properties. Therefore, we now aim at quantifying the D2 receptor tonus, input/output properties, excitation/inhibition balance, dendritic spine densities, and in vivo activity patterns of medium spiny neurons (MSNs). Furthermore, to prevent the behavioral phenotypes, we aim at chronically modulating the activity of the developing dopaminergic system using pharmacological or chemogenetic approaches.
Publications
- 2018. Embryonic loss of HCN/hchannel function in mouse forebrain results in impaired neural progenitor proliferation and microcephaly. FENS Forum, Abstract: 467
Schlusche AK, Vay SU, Sandke S, Campos Martin R, Kleinenkuhnen N, Florio M, Huttner W, Tresch A, Roeper J, Stockebrand M, Rueger MA, Jakovcevski I, Isbrandt D
- 2018. Loss of I(h) is associated with neurodevelopmental disorders in mice. FENS Forum, Abstract 1807. Berlin
Merseburg A, Neu A, Jakovcevski I, Huang Z, Shah M, Morellini F, Isbrandt D
