Biology subjects

Twedell, E. L.

Publications and source records attributed to Twedell, E. L..

3 recordsLinked to original sources

bioRxiv2024

Striatal lateral inhibition regulates action selection in a mouse model of levodopa-induced dyskinesia

Striatal medium spiny neurons (MSNs) integrate convergent cortical, thalamic, and dopaminergic inputs to shape motor output. In addition, MSNs form local inhibitory synaptic connections with one another. The function of this striatal lateral inhibition is unknown, but one possibility is in selecting an intended action while suppressing alternatives. The execution of selected movements is disrupted in several movement disorders, including levodopa-induced dyskinesia (LID), a complication of Parkinsons disease (PD) therapy characterized by involuntary movements. Here, we identify chronic changes in the strength of striatal lateral inhibitory synapses in a mouse model of PD/LID. These synapses are also modulated by acute dopamine signaling. Chemogenetic suppression of lateral inhibition originating from dopamine D2 receptor-expressing MSNs lowers the threshold to develop involuntary movements in vivo. By comparing striatal lateral inhibition in health and PD/LID, our findings support a role for this microcircuit in movement selection and suggest its disruption may increase vulnerability to dyskinesia.

neuroscience↗

bioRxiv2020

Axonal mechanisms mediating GABA-A receptor inhibition of striatal dopamine release

Axons of midbrain dopaminergic neurons innervate the striatum where they contribute to movement and reinforcement learning. Past work has shown that striatal GABA tonically inhibits dopamine release, but whether GABA-A receptors directly modulate transmission or act indirectly through circuit elements is unresolved. Here, we use whole-cell and perforated-patch recordings to test for GABA-A receptors on the main dopaminergic neuron axons and branching processes within striatum. Application of GABA depolarized axons, but also decreased the amplitude of axonal spikes, limited propagation and reduced striatal dopamine release. The mechanism of inhibition involved sodium channel inactivation and shunting. Lastly, we show that the positive allosteric modulator diazepam enhanced GABA-A currents on dopaminergic neuron axons and directly inhibited release, but also likely acts by reducing excitatory drive from cholinergic interneurons. Thus, we reveal the mechanisms of GABA-A receptor modulation of dopamine release and provide new insight into the actions of benzodiazepines within the striatum.

neuroscience↗

bioRxiv2019

Functional dissection of basal ganglia inhibitory input onto SNc dopaminergic neurons

Substania nigra (SNc) dopaminergic neurons show a pause-rebound firing pattern in response to aversive events. Because these neurons integrate information from predominately inhibitory brain areas, it is important to determine which inputs functionally inhibit the dopamine neurons and whether this pause-rebound firing pattern can be produced by a solely inhibitory input. Here, we functionally map genetically-defined inhibitory projections from the dorsal striatum (striosome and matrix) and globus pallidus (GPe; parvalbumin and Lhx6) onto SNc neurons. We find that GPe and striosomal inputs both pause firing in SNc neurons, but rebound firing only occurs after inhibition from striosomes. Indeed, we find that striosomes are synaptically optimized to produce rebound and preferentially inhibit a subpopulation of ventral, intrinsically rebound-ready SNc dopaminergic neurons on their reticulata dendrites. Therefore, we describe a self-contained dendrite-specific striatonigral circuit that can produce pause-rebound firing in the absence of excitatory input.

neuroscience↗