Biology subjects

Kottmann, A. H.

Publications and source records attributed to Kottmann, A. H..

6 recordsLinked to original sources

bioRxiv2025

Expression of Angiotensin converting enzyme 2 (ACE2) in the dorsolateral striatum is critical for the temporal coordination of acetylcholine and dopamine, and motor learning.

Neuropeptides are key modulators of adult neurocircuits, balancing their sensitivity to both excitation and inhibition, and fine-tuning fast neurotransmitter action under physiological conditions. We found that the mono-carboxypeptidase angiotensin-converting enzyme 2 (ACE2), which can take part in producing and/or processing of several neuroactive peptides in the mammalian brain and is best known for converting the pro-inflammatory peptide angiotensin II (Ang II) to the stress-ameliorating and neuro-protective peptide angiotensin 1-7 (Ang 1-7), is broadly expressed in the striatum. Cholinergic interneurons (CIN) of the striatum, known to express multiple peptide receptors also co-expressed the corresponding and functionally opposing receptors angiotensin type 1 receptor (AT1R) for Ang II and mas receptor (MasR) for Ang 1-7. Accordingly, the conditional, semi acute ablation and/or local pharmacological inhibition of ACE2 increased the frequency of acetylcholine (ACh) bursts, reduced the amplitude of dopamine (DA)-modulated pausing of CIN activity, and disrupted the temporal coordination of extracellular levels of ACh and DA during burst events. Further, ablation of ACE2 in the DLS biased directional movement and impaired motor skill learning. Coinjection of the AT1R inhibitor losartan and the dopamine D2 receptor (D2R) agonist quinpirole reduced steady state level cholinergic activity in an additive manner, and proximity ligation supported close spatial association of AT1R and D2R on CINs. Together our study provides evidence that striatal produced ACE2 impinges on the dynamics of ACh and DA and impacts action selection and motor learning through functional and structural interactions of peptidergic and dopaminergic signaling on CIN. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/684469v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@13b6cf0org.highwire.dtl.DTLVardef@6d1ef1org.highwire.dtl.DTLVardef@a7e2eorg.highwire.dtl.DTLVardef@e22816_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

neuroscience↗

bioRxiv2025

The GPCR Smoothened on Cholinergic Interneurons Modulates Dopamine-associated Acetylcholine Dynamics

The striatum is a hub for associative learning where fluctuations in dopamine and acetylcholine dynamically regulate behavior. Acetylcholine is released by cholinergic interneurons, which integrate diverse inputs to contextualize dopamine signals and shape behavior. We previously observed that the GPCR Smoothened on cholinergic interneurons suppresses L-DOPA-induced dyskinesias, a motor side-effect resulting from medication elevated dopamine in the Parkinsonian brain. Here, we examine whether Smoothened signaling modulates acetylcholine dynamics, its coordination with dopamine, and motor learning in the healthy brain. We find that cholinergic neuron-specific Smoothened activity bidirectionally modulates acetylcholine inhibition following dopaminergic or cholinergic neuron activity. These effects alter the temporal organization of acetylcholine in the dorsolateral striatum and its coupling to dopamine. Behaviorally, Smoothened ablation from cholinergic neurons promotes motor learning and altered adjustment to changes in the effort or time to obtain reward. These findings identify Smoothened as a bidirectional modulator of striatal dopamine-acetylcholine coordination and striatal learning. HighlightsSonic Hedgehog-Smoothened signaling in striatal cholinergic interneurons bidirectionally regulates dopamine-associated cholinergic pauses without altering dopamine release. Cholinergic Smoothened shapes the timing, duration, and coordination of endogenous dopamine-acetylcholine dynamics in the dorsolateral striatum. Cholinergic Smoothened modulates striatal learning by accelerating motor learning while constraining effort management in an instrumental task. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/662982v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@12531d7org.highwire.dtl.DTLVardef@eb2620org.highwire.dtl.DTLVardef@140479org.highwire.dtl.DTLVardef@31cf0e_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

L-Dopa induced dyskinesias require Cholinergic Interneuron expression of Dopamine 2 receptor.

Striatal cholinergic interneurons (CIN) have been implicated in both, the facilitation as well as the attenuation of L-DOPA-induced dyskinesias (LID). These findings indicate that CIN impinge on formation and expression of LID in a dopamine state dependent manner since LID formation requires prominent oscillations of dopamine at timescales of hours over several years. However, how CIN sense and interpret striatal dopamine levels is not completely understood. CIN express both inhibitory, high affinity, Gi coupled D2 (D2R)- and facilitatory, medium affinity, Gs coupled D5 (D5R)-dopamine receptors. While the systemic ablation of D5R exacerbates LID, the contribution of D2R expression in CIN to LID has not been studied. Here, we produced mice with conditional ablation of D2R from choline acetyltransferase-expressing cells (D2ChATKO) subjected to unilateral 6-hydroxydopamine lesions and chronic L-DOPA dosing. Behavioral assessments revealed that D2ChATKO mice exhibited attenuated LID across escalating L-DOPA doses. Postmortem analyses showed reduced expression of the LID-associated marker p-ERK in CIN in the dorsolateral striatum. Further, quantification of the CIN activity marker p-rpS6240/244 of mice in the L-DOPA ON and OFF state revealed that L-DOPA resulted in an increase of cholinergic activity driven by a subset of mainly dorso-laterally located CIN. D2R ablation from CIN prevented the L-DOPA associated increase in cholinergic activity. Together, these findings indicate that D2R signaling in CIN promotes LID formation, and they highlight CIN D2R as a potential molecular target for mitigating dyskinesias while preserving the therapeutic efficacy of L-DOPA. We discuss our results in the context of recently refined models how CIN contribute to aberrant plasticity in the basal ganglia of mouse models of Parkinsons Disease.

neuroscience↗

bioRxiv2020

Diminished ventral oligodendrocyte precursor generation results in the subsequent over-production of dorsal oligodendrocyte precursors of aberrant morphology and function

Oligodendrocyte precursor cells (OPCs) arise sequentially first from a ventral and then from a dorsal precursor domain at the end of neurogenesis during spinal cord development. Whether the sequential production of OPCs is of physiological significance has not been examined. Here we show that ablating Shh signaling from nascent ventricular zone derivatives and partially from the floor plate results in a severe diminishment of ventral derived OPCs but normal numbers of motor neurons in the postnatal spinal cord. In the absence of ventral vOPCs, dorsal dOPCs populate the entire spinal cord resulting in an increased OPC density in the ventral horns. These OPCs take on an altered morphology, do not participate in the removal of excitatory vGlut1 synapses from injured motor neurons, and exhibit morphological features similar to those found in the vicinity of motor neurons in the SOD1 mouse model of Amyotrophic Lateral Sclerosis (ALS). Our data indicates that vOPCs prevent dOPCs from invading ventral spinal cord laminae and suggests that vOPCs have a unique ability to communicate with injured motor neurons.

neuroscience↗

bioRxiv2020

Dopaminergic Co-transmission with Sonic Hedgehog Inhibits Expression of Abnormal Involuntary Movements

L-Dopa induced dyskinesia (LID) is a debilitating side effect of dopamine replacement therapy for Parkinsons Disease. The mechanistic underpinnings of LID remain obscure. Here we report that diminshed sonic hedgehog (Shh) signaling in the basal ganglia caused by the degeneration of midbrain dopamine neurons (DANs) facilitates the formation and expression of LID. We demonstrate that augmenting Shh signaling with agonists of the Shh effector Smoothened attenuates LID in mouse and macaque models of PD. Employing conditional genetic loss-of-function approaches, we show that reducing Shh secretion from DANs or Smo activity in cholinergic interneurons (CINs) promotes LID. Conversely, the selective expression of constitutively active Smo (SmoM2) in CINs is sufficient to render the sensitized aphakia model of PD resistant to LID. Furthermore, acute depletion of Shh from DANs through prolonged optogenetic stimulation in otherwise intact mice and in the absence of L-Dopa produces LID-like involuntary movements. These findings indicate that augmenting Shh signaling in the L-Dopa treated brain may be a promising and unexpected novel therapeutic approach for mitigating the dyskinetic side effects of long-term treatment with L-Dopa

neuroscience↗

bioRxiv2019

Multiple sources of Shh are critical for the generation and scaling of ventral spinal cord oligodendrocyte precursor populations.

Graded Sonic Hedgehog (Shh) signaling emanating from notochord and floorplate patterns the early neural tube. Soon thereafter, Shh signaling strength within the ventricular zone becomes dis-contiguous and discontinuous along the ventral to dorsal axis suggesting a distribution of Shh that cannot be achieved by diffusion alone. Here we discover that sequential activation of Shh expression by ventricular zone derivatives is critical for counteracting a precocious exhaustion of the Olig2 precursor cell population of the pMN domain at the end of motor neuron genesis and during the subsequent phase of ventral oligodendrocyte precursor production. Selective expression of Shh by motor neurons of the lateral motor column at the beginning of oligodendrogenesis ensures a more yielding pMN domain at limb levels compared to thoracic levels. Thus, patterned expression of Shh by ventricular zone derivatives including earlier born neurons contributes to the scaling of the spinal cord along the anterior - posterior axis by regulating the activity of a select ventricular zone precursor domain at later stages of development.

developmental biology↗