Dendritic A-Current in Rhythmically Active PreBötzinger Complex Neurons in Organotypic Cultures from Newborn Mice

The brainstem preBötzinger complex (preBötC) generates the inspiratory rhythm for breathing. The onset of neural activity that precipitates the inspiratory phase of the respiratory cycle may depend on the activity of type-1 preBötC neurons, which exhibit a transient outward K⁺ current, I_A. Inspiratory rhythm generation can be studied ex vivo because the preBötC remains rhythmically active in vitro, both in acute brainstem slices and organotypic cultures. Advantageous optical conditions in organotypic slice cultures from newborn mice of either sex allowed us to investigate how I_A impacts Ca²⁺ transients occurring in the dendrites of rhythmically active type-1 preBötC neurons. The amplitude of dendritic Ca²⁺ transients evoked via voltage increases originating from the soma significantly increased after an I_A antagonist, 4-aminopyridine (4-AP), was applied to the perfusion bath or to local dendritic regions. Similarly, glutamate-evoked postsynaptic depolarizations recorded at the soma increased in amplitude when 4-AP was coapplied with glutamate at distal dendritic locations. We conclude that I_A is expressed on type-1 preBötC neuron dendrites. We propose that I_A filters synaptic input, shunting sparse excitation, while enabling temporally summated events to pass more readily as a result of I_A inactivation. Dendritic I_A in rhythmically active preBötC neurons could thus ensure that inspiratory motor activity does not occur until excitatory synaptic drive is synchronized and well coordinated among cellular constituents of the preBötC during inspiratory rhythmogenesis. The biophysical properties of dendritic I_A might thus promote robustness and regularity of breathing rhythms.

SIGNIFICANCE STATEMENT Brainstem neurons in the preBötC generate the oscillatory activity that underlies breathing. PreBötC neurons express voltage-dependent currents that can influence inspiratory activity, among which is a transient potassium current (I_A) previously identified in a rhythmogenic excitatory subset of type-1 preBötC neurons. We sought to determine whether I_A is expressed in the dendrites of preBötC. We found that dendrites of type-1 preBötC neurons indeed express I_A, which may aid in shunting sparse non-summating synaptic inputs, while enabling strong summating excitatory inputs to readily pass and thus influence somatic membrane potential trajectory. The subcellular distribution of I_A in rhythmically active neurons of the preBötC may thus be critical for producing well coordinated ensemble activity during inspiratory burst formation.

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