A Distinct Subtype of Dopaminergic Interneuron Displays Inverted Structural Plasticity at the Axon Initial Segment

Abstract

The axon initial segment (AIS) is a specialized structure near the start of the axon that is a site of neuronal plasticity. Changes in activity levels in vitro and in vivo can produce structural AIS changes in excitatory cells that have been linked to alterations in excitability, but these effects have never been described in inhibitory interneurons. In the mammalian olfactory bulb (OB), dopaminergic interneurons are particularly plastic, undergoing constitutive turnover throughout life and regulating tyrosine hydroxylase expression in an activitydependent manner. Here we used dissociated cultures of rat and mouse OB to show that a subset of bulbar dopaminergic neurons possess an AIS and that these AIS-positive cells are morphologically and functionally distinct from their AIS-negative counterparts. Under baseline conditions, OB dopaminergic AISs were short and located distally along the axon but, in response to chronic 24 h depolarization, lengthened and relocated proximally toward the soma. These activity-dependent changes were in the opposite direction to both those we saw in non-GABAergic OB neurons and those reported previously for excitatory cell types. Inverted AIS plasticity in OB dopaminergic cells was bidirectional, involved all major components of the structure, was dependent on the activity of L-type Ca V 1 calcium channels but not on the activity of the calcium-activated phosphatase calcineurin, and was opposed by the actions of cyclin-dependent kinase 5. Such distinct forms of AIS plasticity in inhibitory interneurons and excitatory projection neurons may allow considerable flexibility when neuronal networks must adapt to perturbations in their ongoing activity.

Structural and Functional Plasticity at the Axon Initial Segment

“…With chronic depolarization (2 days) via photo-stimulation or high [K + ] o media, all types of excitatory neurons in the culture move the entire AIS distally, resulting in a decrease in their excitability. Importantly, in dissociated culture of the olfactory bulb, chronic depolarization causes reciprocal movements of the AIS in excitatory and inhibitory neurons; the AIS moves proximally in inhibitory interneurons, whereas it moves distally in excitatory neurons (Chand et al, 2015), implying the cell-type-specific nature of the AIS plasticity. These reciprocal movements of the AIS may counterbalance the excess activity in the circuit.…”

“…Key molecules are the calcium-dependent phosphatase calcineurin and cyclin-dependent kinase 5 (cdk5); calcineurin mediates the distal movement of the AIS in hippocampal neurons (Evans et al, 2013), whereas cdk5 mediates the proximal movement in olfactory bulb inhibitory interneurons (Chand et al, 2015). Although the precise mechanisms by which these molecules reorganize the AIS structure remain unknown, the mechanisms may involve post-translational modification of AIS proteins (Yoshimura and Rasband, 2014).…”

Embryonic and postnatal neurogenesis produce functionally distinct subclasses of dopaminergic neuron

“…http://dx.doi.org/10.1101/196006 doi: bioRxiv preprint first posted online Sep. 29, 2017; within the glomerular layer, and roles as diverse as modulating release from olfactory sensory 46 neuron terminals, signal normalisation, contrast enhancement, and temporal decorrelation Here, we build on previous work in vitro (Chand et al, 2015), to show that different classes of OB DA 61 neuron in vivo can be clearly distinguished based on the presence or absence of an axon and its key 62 subcellular specialisation, the axon initial segment (AIS). AIS-positive DA cells are larger, with 63 broader dendritic arborisations, and are exclusively born in early embryonic development.…”

Activity-dependent mismatch between axo-axonic synapses and the axon initial segment controls neuronal output

“…In addition, there is an ongoing debate as to whether axoaxonic synapses depolarize or hyperpolarize postsynaptic pyramidal neurons (14), although in conditions mimicking in vivo-like oscillations, they act mainly as inhibitors of excitability (15). The emerging picture is one where chandelier cells play an important role in modulating neuronal output at the AIS, but the precise way in which this happens remains to be properly established.More recently, longer-term forms of modulation have been described at the AIS in response to chronic alterations in neuronal activity (16)(17)(18)(19)(20). For example, sensory deprivation of chick brainstem auditory neurons caused an increase in the length of the AIS, which was paralleled by an increase in neuronal excitability (18).…”

“…More recently, longer-term forms of modulation have been described at the AIS in response to chronic alterations in neuronal activity (16)(17)(18)(19)(20). For example, sensory deprivation of chick brainstem auditory neurons caused an increase in the length of the AIS, which was paralleled by an increase in neuronal excitability (18).…”