Zayd M. Khaliq, Ph.D.

@article{pmid32937133,

title = {Functional Dissection of Basal Ganglia Inhibitory Inputs onto Substantia Nigra Dopaminergic Neurons},

author = {Rebekah C Evans and Emily L Twedell and Manhua Zhu and Jefferson Ascencio and Renshu Zhang and Zayd M Khaliq},

url = {https://pubmed.ncbi.nlm.nih.gov/32937133/},

doi = {10.1016/j.celrep.2020.108156},

issn = {2211-1247},

year  = {2020},

date = {2020-01-01},

urldate = {2020-01-01},

journal = {Cell Rep},

volume = {32},

number = {11},

pages = {108156},

abstract = {Substantia nigra (SNc) dopaminergic neurons respond to aversive stimuli with inhibitory pauses in firing followed by transient rebound activation. We tested integration of inhibitory synaptic inputs onto SNc neurons from genetically defined populations in dorsal striatum (striosome and matrix) and external globus pallidus (GPe; parvalbumin- and Lhx6-positive), and examined their contribution to pause-rebound firing. Activation of striosome projections, which target "dendron bouquets" in the pars reticulata (SNr), consistently quiets firing and relief from striosome inhibition triggers rebound activity. Striosomal inhibitory postsynaptic currents (IPSCs) display a prominent GABA-B receptor-mediated component that strengthens the impact of SNr dendrite synapses on somatic excitability and enables rebounding. By contrast, GPe projections activate GABA-A receptors on the soma and proximal dendrites but do not result in rebounding. Lastly, optical mapping shows that dorsal striatum selectively inhibits the ventral population of SNc neurons, which are intrinsically capable of rebounding. Therefore, we define a distinct striatonigral circuit for generating dopamine rebound.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32870779,

title = {Axonal mechanisms mediating γ-aminobutyric acid receptor type A (GABA-A) inhibition of striatal dopamine release},

author = {Paul F Kramer and Emily L Twedell and Jung Hoon Shin and Renshu Zhang and Zayd M Khaliq},

url = {https://pubmed.ncbi.nlm.nih.gov/32870779/},

doi = {10.7554/eLife.55729},

issn = {2050-084X},

year  = {2020},

date = {2020-01-01},

urldate = {2020-01-01},

journal = {Elife},

volume = {9},

abstract = {Axons of 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 the striatum of adult mice. 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 the positive allosteric modulator diazepam enhanced GABA-A currents on dopaminergic axons and directly inhibited release, but also likely acts by reducing excitation from cholinergic interneurons. Thus, we reveal the mechanisms of GABA-A receptor modulation of dopamine release and provide new insights into the actions of benzodiazepines within the striatum.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30556810,

title = {G protein-coupled receptors in dopamine neurons inhibit the sodium leak channel NALCN},

author = {Fabian Philippart and Zayd M Khaliq},

url = {https://pubmed.ncbi.nlm.nih.gov/30556810/},

doi = {10.7554/eLife.40984},

issn = {2050-084X},

year  = {2018},

date = {2018-01-01},

urldate = {2018-01-01},

journal = {Elife},

volume = {7},

abstract = {Dopamine (D2) receptors provide autoinhibitory feedback onto dopamine neurons through well-known interactions with voltage-gated calcium channels and G protein-coupled inwardly-rectifying potassium (GIRK) channels. Here, we reveal a third major effector involved in D2R modulation of dopaminergic neurons - the sodium leak channel, NALCN. We found that activation of D2 receptors robustly inhibits isolated sodium leak currents in wild-type mice but not in NALCN conditional knockout mice. Intracellular GDP-βS abolished the inhibition, indicating a G protein-dependent signaling mechanism. The application of dopamine reliably slowed pacemaking even when GIRK channels were pharmacologically blocked. Furthermore, while spontaneous activity was observed in nearly all dopaminergic neurons in wild-type mice, neurons from NALCN knockouts were mainly silent. Both observations demonstrate the critical importance of NALCN for pacemaking in dopaminergic neurons. Finally, we show that GABA-B receptor activation also produces inhibition of NALCN-mediated currents. Therefore, we identify NALCN as a core effector of inhibitory G protein-coupled receptors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28264982,

title = {Dopamine Inhibition Differentially Controls Excitability of Substantia Nigra Dopamine Neuron Subpopulations through T-Type Calcium Channels},

author = {Rebekah C Evans and Manhua Zhu and Zayd M Khaliq},

url = {https://pubmed.ncbi.nlm.nih.gov/28264982/},

doi = {10.1523/JNEUROSCI.0117-17.2017},

issn = {1529-2401},

year  = {2017},

date = {2017-01-01},

urldate = {2017-01-01},

journal = {J Neurosci},

volume = {37},

number = {13},

pages = {3704--3720},

abstract = {While there is growing appreciation for diversity among ventral tegmental area dopamine neurons, much less is known regarding functional heterogeneity among the substantia nigra pars compacta (SNc) neurons. Here, we show that calbindin-positive dorsal tier and calbindin-negative ventral tier SNc dopaminergic neurons in mice comprise functionally distinct subpopulations distinguished by their dendritic calcium signaling, rebound excitation, and physiological responses to dopamine D2-receptor (D2) autoinhibition. While dopamine is known to inhibit action potential backpropagation, our experiments revealed an unexpected enhancement of excitatory responses and dendritic calcium signals in the presence of D2-receptor inhibition. Specifically, dopamine inhibition and direct hyperpolarization enabled the generation of low-threshold depolarizations that occurred in an all-or-none or graded manner, due to recruitment of T-type calcium channels. Interestingly, these effects occurred selectively in calbindin-negative dopaminergic neurons within the SNc. Thus, calbindin-positive and calbindin-negative SNc neurons differ substantially in their calcium channel composition and efficacy of excitatory inputs in the presence of dopamine inhibition. Substantia nigra dopaminergic neurons can be divided into two populations: the calbindin-negative ventral tier, which is vulnerable to neurodegeneration in Parkinson's disease, and the calbindin-positive dorsal tier, which is relatively resilient. Although tonic firing is similar in these subpopulations, we find that their responses to dopamine-mediated inhibition are strikingly different. During inhibition, calbindin-negative neurons exhibit increased sensitivity to excitatory inputs, which can then trigger large dendritic calcium transients due to strong expression of T-type calcium channels. Therefore, SNc neurons differ substantially in their calcium channel composition, which may contribute to their differential vulnerability. Furthermore, T-currents increase excitation efficacy onto calbindin-negative cells during dopamine inhibition, suggesting that shared inputs are differentially processed in subpopulations resulting in distinct downstream dopamine signals.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28219982,

title = {Enhanced Sensitivity to Hyperpolarizing Inhibition in Mesoaccumbal Relative to Nigrostriatal Dopamine Neuron Subpopulations},

author = {Rahilla A Tarfa and Rebekah C Evans and Zayd M Khaliq},

url = {https://pubmed.ncbi.nlm.nih.gov/28219982/},

doi = {10.1523/JNEUROSCI.2969-16.2017},

issn = {1529-2401},

year  = {2017},

date = {2017-01-01},

urldate = {2017-01-01},

journal = {J Neurosci},

volume = {37},

number = {12},

pages = {3311--3330},

abstract = {Midbrain dopamine neurons recorded  pause their firing in response to reward omission and aversive stimuli. While the initiation of pauses typically involves synaptic or modulatory input, intrinsic membrane properties may also enhance or limit hyperpolarization, raising the question of how intrinsic conductances shape pauses in dopamine neurons. Using retrograde labeling and electrophysiological techniques combined with computational modeling, we examined the intrinsic conductances that shape pauses evoked by current injections and synaptic stimulation in subpopulations of dopamine neurons grouped according to their axonal projections to the nucleus accumbens or dorsal striatum in mice. Testing across a range of conditions and pulse durations, we found that mesoaccumbal and nigrostriatal neurons differ substantially in rebound properties with mesoaccumbal neurons displaying significantly longer delays to spiking following hyperpolarization. The underlying mechanism involves an inactivating potassium (I) current with decay time constants of up to 225 ms, and small-amplitude hyperpolarization-activated currents (I), characteristics that were most often observed in mesoaccumbal neurons. Pharmacological block of I completely abolished rebound delays and, importantly, shortened synaptically evoked inhibitory pauses, thereby demonstrating the involvement of A-type potassium channels in prolonging pauses evoked by GABAergic inhibition. Therefore, these results show that mesoaccumbal and nigrostriatal neurons display differential responses to hyperpolarizing inhibitory stimuli that favors a higher sensitivity to inhibition in mesoaccumbal neurons. These findings may explain, in part, observations from  experiments that ventral tegmental area neurons tend to exhibit longer aversive pauses relative to SNc neurons. Our study examines rebound, postburst, and synaptically evoked inhibitory pauses in subpopulations of midbrain dopamine neurons. We show that pauses in dopamine neuron firing, evoked by either stimulation of GABAergic inputs or hyperpolarizing current injections, are enhanced by a subclass of potassium conductances that are recruited at voltages below spike threshold. Importantly, A-type potassium currents recorded in mesoaccumbal neurons displayed substantially slower inactivation kinetics, which, combined with weaker expression of hyperpolarization-activated currents, lengthened hyperpolarization-induced delays in spiking relative to nigrostriatal neurons. These results suggest that input integration differs among dopamine neurons favoring higher sensitivity to inhibition in mesoaccumbal neurons and may partially explain  observations that ventral tegmental area neurons exhibit longer aversive pauses relative to SNc neurons.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}