Recovery of the full in vivo firing range in post-lesion surviving DA SN neurons associated with Kv4.3-mediated pacemaker plasticity

Dopamine (DA) neurons in the substantia nigra (SN) control several
essential functions, including the voluntary movement, learning and
motivated behavior. Healthy DA SN neurons show diverse firing patterns in
vivo, ranging from slow pacemaker-like activity (1-10 Hz) to transient
high frequency bursts (<100 Hz), interspersed with pauses that can
last hundreds of milliseconds. Recent in vivo patch experiments have
started to reveal the subthreshold mechanisms underlying this
physiological diversity, but the impact of challenges like cell loss on
the in vivo activity of adult DA SN neurons, and how these may relate to
behavioral disturbances, are still largely unknown. We investigated the in
vivoelectrophysiological properties of surviving SN DA neurons after
partial unilateral 6-OHDA lesions, a single-hit, non-progressive model of
neuronal cell loss. We show that mice subjected to this model have an
initial motor impairment, measured by asymmetrical rotations in the open
field test, which recovered over time. At 3 weeks post-lesion, when open
field locomotion was strongly impaired, surviving DA SN neurons showed a
compressed in vivo dynamic firing range, characterized by a 10-fold
reduction of in vivo burst firing compared to controls. This in vivo
phenotype was accompanied by pronounced in vitro pacemaker instability. In
contrast, in the chronic post-lesion phase (>2 months), where
turning symmetry in open field locomotion had recovered, surviving SN DA
neurons displayed the full dynamic range of in vivo firing, including in
vivo bursting, similar to controls. The normalized in vivo firing pattern
was associated with a 2-fold acceleration of stable in vitro pacemaking,
mediated by Kv4.3 potassium channel downregulation. Our findings
demonstrate the existence of a homeostatic pacemaker plasticity mechanism
in surviving DA SN neurons after pronounced cell loss.