scholarly journals Dopamine D2L Receptor Deficiency Alters Neuronal Excitability and Spine Formation in Mouse Striatum

Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 101
Author(s):  
Gubbi Govindaiah ◽  
Rong-Jian Liu ◽  
Yanyan Wang

The striatum contains several types of neurons including medium spiny projection neurons (MSNs), cholinergic interneurons (ChIs), and fast-spiking interneurons (FSIs). Modulating the activity of these neurons by the dopamine D2 receptor (D2R) can greatly impact motor control and movement disorders. D2R exists in two isoforms: D2L and D2S. Here, we assessed whether alterations in the D2L and D2S expression levels affect neuronal excitability and synaptic function in striatal neurons. We observed that quinpirole inhibited the firing rate of all three types of striatal neurons in wild-type (WT) mice. However, in D2L knockout (KO) mice, quinpirole enhanced the excitability of ChIs, lost influence on spike firing of MSNs, and remained inhibitory effect on spike firing of FSIs. Additionally, we showed mIPSC frequency (but not mIPSC amplitude) was reduced in ChIs from D2L KO mice compared with WT mice, suggesting spontaneous GABA release is reduced at GABAergic terminals onto ChIs in D2L KO mice. Furthermore, we found D2L deficiency resulted in reduced dendritic spine density in ChIs, suggesting D2L activation plays a role in the formation/maintenance of dendritic spines of ChIs. These findings suggest new molecular and cellular mechanisms for causing ChIs abnormality seen in Parkinson’s disease or drug-induced dyskinesias.

2020 ◽  
Author(s):  
Krishnakanth Kondabolu ◽  
Natalie M. Doig ◽  
Olaoluwa Ayeko ◽  
Bakhtawer Khan ◽  
Alexandra Torres ◽  
...  

AbstractThe striatum and subthalamic nucleus (STN) are considered to be the primary input nuclei of the basal ganglia. Projection neurons of both striatum and STN can extensively interact with other basal ganglia nuclei, and there is growing anatomical evidence of direct axonal connections from the STN to striatum. There remains, however, a pressing need to elucidate the organization and impact of these subthalamostriatal projections in the context of the diverse cell types constituting the striatum. To address this, we carried out monosynaptic retrograde tracing from genetically-defined populations of dorsal striatal neurons in adult male and female mice, quantifying the connectivity from STN neurons to spiny projection neurons, GABAergic interneurons, and cholinergic interneurons. In parallel, we used a combination of ex vivo electrophysiology and optogenetics to characterize the responses of a complementary range of dorsal striatal neuron types to activation of STN axons. Our tracing studies showed that the connectivity from STN neurons to striatal parvalbumin-expressing interneurons is significantly higher (~ four-to eight-fold) than that from STN to any of the four other striatal cell types examined. In agreement, our recording experiments showed that parvalbumin-expressing interneurons, but not the other cell types tested, commonly exhibited robust monosynaptic excitatory responses to subthalamostriatal inputs. Taken together, our data collectively demonstrate that the subthalamostriatal projection is highly selective for target cell type. We conclude that glutamatergic STN neurons are positioned to directly and powerfully influence striatal activity dynamics by virtue of their enriched innervation of GABAergic parvalbumin-expressing interneurons.


2020 ◽  
Vol 35 (1) ◽  
pp. 3-14 ◽  
Author(s):  
Anton JM Loonen ◽  
Svetlana A Ivanova

Dystonia is by far the most intrusive and invalidating extrapyramidal side effect of potent classical antipsychotic drugs. Antipsychotic drug-induced dystonia is classified in both acute and tardive forms. The incidence of drug-induced dystonia is associated with the affinity to inhibitory dopamine D2 receptors. Particularly acute dystonia can be treated with anticholinergic drugs, but the tardive form may also respond to such antimuscarinic treatment, which contrasts their effects in tardive dyskinesia. Combining knowledge of the pathophysiology of primary focal dystonia with the anatomical and pharmacological organization of the extrapyramidal system may shed some light on the mechanism of antipsychotic drug-induced dystonia. A suitable hypothesis is derived from the understanding that focal dystonia may be due to a faulty processing of somatosensory input, so leading to inappropriate execution of well-trained motor programmes. Neuroplastic alterations of the sensitivity of extrapyramidal medium-sized spiny projection neurons to stimulation, which are induced by the training of specific complex movements, lead to the sophisticated execution of these motor plans. The sudden and non-selective disinhibition of indirect pathway medium-sized spiny projection neurons by blocking dopamine D2 receptors may distort this process. Shutting down the widespread influence of tonically active giant cholinergic interneurons on all medium-sized spiny projection neurons by blocking muscarinic receptors may result in a reduction of the influence of extrapyramidal cortical-striatal-thalamic-cortical regulation. Furthermore, striatal cholinergic interneurons have an important role to play in integrating cerebellar input with the output of cerebral cortex, and are also targeted by dopaminergic nigrostriatal fibres affecting dopamine D2 receptors.


eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Brooks G Robinson ◽  
Alec F Condon ◽  
Daniela Radl ◽  
Emiliana Borrelli ◽  
John T Williams ◽  
...  

The dopamine D2 receptor has two splice variants, D2S (Short) and D2L (Long). In dopamine neurons, both variants can act as autoreceptors to regulate neuronal excitability and dopamine release, but the roles of each variant are incompletely characterized. In a previous study we used viral receptor expression in D2 receptor knockout mice to show distinct effects of calcium signaling on D2S and D2L autoreceptor function (Gantz et al., 2015). However, the cocaine-induced plasticity of D2 receptor desensitization observed in wild type mice was not recapitulated with this method of receptor expression. Here we use mice with genetic knockouts of either the D2S or D2L variant to investigate cocaine-induced plasticity in D2 receptor signaling. Following a single in vivo cocaine exposure, the desensitization of D2 receptors from neurons expressing only the D2S variant was reduced. This did not occur in D2L-expressing neurons, indicating differential drug-induced plasticity between the variants.


2021 ◽  
Vol 15 ◽  
Author(s):  
Naila Kuhlmann ◽  
Miriam Wagner Valladolid ◽  
Lucía Quesada-Ramírez ◽  
Matthew J. Farrer ◽  
Austen J. Milnerwood

In contrast to the prenatal topographic development of sensory cortices, striatal circuit organization is slow and requires the functional maturation of cortical and thalamic excitatory inputs throughout the first postnatal month. While mechanisms regulating synapse development and plasticity are quite well described at excitatory synapses of glutamatergic neurons in the neocortex, comparatively little is known of how this translates to glutamate synapses onto GABAergic neurons in the striatum. Here we investigate excitatory striatal synapse plasticity in an in vitro system, where glutamate can be studied in isolation from dopamine and other neuromodulators. We examined pre-and post-synaptic structural and functional plasticity in GABAergic striatal spiny projection neurons (SPNs), co-cultured with glutamatergic cortical neurons. After synapse formation, medium-term (24 h) TTX silencing increased the density of filopodia, and modestly decreased dendritic spine density, when assayed at 21 days in vitro (DIV). Spine reductions appeared to require residual spontaneous activation of ionotropic glutamate receptors. Conversely, chronic (14 days) TTX silencing markedly reduced spine density without any observed increase in filopodia density. Time-dependent, biphasic changes to the presynaptic marker Synapsin-1 were also observed, independent of residual spontaneous activity. Acute silencing (3 h) did not affect presynaptic markers or postsynaptic structures. To induce rapid, activity-dependent plasticity in striatal neurons, a chemical NMDA receptor-dependent “long-term potentiation (LTP)” paradigm was employed. Within 30 min, this increased spine and GluA1 cluster densities, and the percentage of spines containing GluA1 clusters, without altering the presynaptic signal. The results demonstrate that the growth and pruning of dendritic protrusions is an active process, requiring glutamate receptor activity in striatal projection neurons. Furthermore, NMDA receptor activation is sufficient to drive glutamatergic structural plasticity in SPNs, in the absence of dopamine or other neuromodulators.


2019 ◽  
Author(s):  
Fran van Heusden ◽  
Anežka Macey-Dare ◽  
Rohan N. Krajeski ◽  
Andrew Sharott ◽  
Tommas Jan Ellender

AbstractHeterogeneous populations of neural progenitors in the embryonic lateral ganglionic eminence (LGE) generate all GABAergic spiny projection neurons (SPNs) found in the striatum. Here we investigate how this diversity in neural progenitors relates to diversity of adult striatal neurons and circuits. Using a combination of in utero electroporation to fluorescently pulse-label striatal neural progenitors in the LGE, brain slice electrophysiology, electrical and optogenetic circuit mapping and immunohistochemistry, we characterise a population of neural progenitors enriched for apical intermediate progenitors (aIPs) and a distinct population of other progenitors (OPs) and their neural offspring. We find that neural progenitor origin has subtle but significant effects on the properties of striatal SPNs. Although aIP and OP progenitors can both generate D1-expressing direct pathway as well as D2-expressing indirect pathway SPNs found intermingled in the striatum, the aIP derived SPNs are found in more medial aspects of the striatum, exhibit more complex dendritic arbors with higher spine density and differentially sample cortical input. Moreover, optogenetic circuit mapping of the aIP derived neurons show that they further integrate within striatal circuits and innervate both local D1 and D2 SPNs. These results show that it is possible to fluorescently pulse-label distinct neural progenitor pools within the LGE and provide the first evidence that neural progenitor heterogeneity can contribute to the diversity of striatal SPNs.


2009 ◽  
Vol 102 (4) ◽  
pp. 2453-2461 ◽  
Author(s):  
Ping Deng ◽  
Zhi-Ping Pang ◽  
Zhigang Lei ◽  
Zao C. Xu

Protein kinase C (PKC) plays critical roles in neuronal activity and is widely expressed in striatal neurons. However, it is not clear how PKC activation regulates the excitability of striatal cholinergic interneurons. In the present study, we found that PKC activation significantly inhibited A-type potassium current ( IA), but had no effect on delayed rectifier potassium currents. Consistently, application of PKC activator caused an increase of firing in response to depolarizing currents in cholinergic interneurons, which was persistent in the presence of both excitatory and inhibitory neurotransmission blockers. These excitatory effects of PKC could be partially mimicked and occluded by blockade of IA with potassium channel blocker 4-aminopyridine. In addition, immunostaining demonstrated that PKCα, but not PKCγ and PKCε, was expressed in cholinergic interneurons. Furthermore, activation of group I metabotropic glutamate receptors (mGluRs) led to an inhibition of IA through a PKC-dependent pathway. These data indicate that activation of PKC, most likely PKCα, increases the neuronal excitability of striatal cholinergic interneurons by down-regulating IA. Group I mGluR-mediated IA inhibition might be important for the glutamatergic regulation of cholinergic tone in the neostriatum.


Author(s):  
Е.И. Захарова ◽  
З.И. Сторожева ◽  
А.Т. Прошин ◽  
М.Ю. Монаков ◽  
А.М. Дудченко

Цель - исследование холинергической синаптической организации функций обучения и памяти у крыс с разными когнитивными способностями. Методы. Крыс обучали на пространственной обстановочной модели в водном лабиринте Морриса. Через 2-3 сут. после окончания тренировок животных декапитировали, из неокортекса и гиппокампа с помощью центрифугирования выделяли субфракции синаптических мембран и синаптоплазмы легких и тяжелых синаптосом. В синаптических субфракциях определяли активность ключевого фермента холинергических нейронов холинацетилтрансферазы (ХАТ). Сравнивали результаты тестирования (время достижения скрытой платформы) и активность фермента у способных и неспособных к обучению крыс. Результаты. Были выявлены: 1) различия в холинергической организации исследованных функций в процессе обучения у способных и неспособных к обучению крыс, в том числе: положительные корреляции активности ХАТ в синапсах проекционных нейронов неокортекса у способных крыс со временем достижения платформы на промежуточных этапах обучения и в синапсах проекционных нейронов гиппокампа у неспособных крыс на позднем этапе обучения; разнонаправленные корреляции активности ХАТ в синапсах, предположительно, интернейронов гиппокампа (фракция тяжелых синаптосом) у способных и неспособных крыс на начальном и позднем этапах обучения; 2) индивидуальность холинергической организации функций на всех этапах обучения. Выводы. Полученные данные свидетельствуют в пользу представлений о специфике холинергической организации функций пространственного обстановочного обучения у крыс с выраженными и слабыми способностями к обучению, а также избирательной роли холинергических интернейронов гиппокампа на исходном этапе обучения и в консолидации памяти. In order to expand the knowledge about neuronal organization of the cognitive functions required for understanding plastic processes in the brain, we investigated the cholinergic synaptic organization of learning and memory functions in rats with different cognitive abilities. Methods. Rats were trained on a contextual situation model in the Morris water maze. At 2-3 days after the end of training, animals were decapitated, and subfractions of synaptic membranes and synaptoplasm of light and heavy synaptosomes were isolated from the cortex and the hippocampus by centrifugation. In synaptic subfractions, activity of the key enzyme of cholinergic neurons, choline acetyltransferase, was measured. We compared the test results (latent period to reach the hidden platform) and the enzyme activity in capable (lower quartile) and incapable of learning rats (upper quartile). Results. The following was found: 1) differences in the cholinergic organization of studied functions in capable and uncapable of learning rats during training, including: positive correlations of choline acetyltransferase activity in synapses of projection neurons in the cortex of capable rats with latency to reach the platform at intermediate stages of training and in the hippocampus ofincapable rats at late stages of training; multidirectional correlations of choline acetyltransferase activity in synapses of hippocampal, presumably, interneurons (heavy synaptosomes) in capable and incapable rats at early and late stages of training; 2) distinctness of the cholinergic organization of functions at all stages of training. Conclusions. The study demonstrated for the first time a specificity of the cholinergic organization of functions in spatial situational learning of rats with strong and poor learning abilities and a selective role of hippocampal cholinergic interneurons at the initial stage of learning and in memory consolidation.


2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Qingying Tang ◽  
Shuxia Chen ◽  
Hui Wu ◽  
Honghua Song ◽  
Yongjun Wang ◽  
...  

AbstractCongenital hypothyroidism (CH), a common neonatal endocrine disorder, can result in cognitive deficits if delay in diagnose and treatment. Dentate gyrus (DG) is the severely affected subregion of the hippocampus by the CH, where the dentate granule cells (DGCs) reside in. However, how CH impairs the cognitive function via affecting DGCs and the underlying mechanisms are not fully elucidated. In the present study, the CH model of rat pups was successfully established, and the aberrant dendrite growth of the DGCs and the impaired cognitive behaviors were observed in the offspring. Transcriptome analysis of hippocampal tissues following rat CH successfully identified that calcium/calmodulin-dependent protein kinase IV (CaMKIV) was the prominent regulator involved in mediating deficient growth of DGC dendrites. CaMKIV was shown to be dynamically regulated in the DG subregion of the rats following drug-induced CH. Interference of CaMKIV expression in the primary DGCs significantly reduced the spine density of dendrites, while addition of T3 to the primary DGCs isolated from CH pups could facilitate the spine growth of dendrites. Insights into relevant mechanisms revealed that CH-mediated CaMKIV deficiency resulted in the significant decrease of phosphorylated CREB in DGCs, in association with the abnormality of dendrites. Our results have provided a distinct cell type in hippocampus that is affected by CH, which would be beneficial for the treatment of CH-induced cognitive deficiency.


2009 ◽  
Vol 102 (2) ◽  
pp. 1287-1295 ◽  
Author(s):  
Jaime G. Mancilla ◽  
Paul B. Manis

Individual neurons have been shown to exhibit target cell-specific synaptic function in several brain areas. The time course of the postsynaptic conductances (PSCs) strongly influences the dynamics of local neural networks. Cartwheel cells (CWCs) are the most numerous inhibitory interneurons in the dorsal cochlear nucleus (DCN). They are excited by parallel fiber synapses, which carry polysensory information, and in turn inhibit other CWCs and the main projection neurons of the DCN, pyramidal cells (PCs). CWCs have been implicated in “context-dependent” inhibition, producing either depolarizing (other CWCs) or hyperpolarizing (PCs) post synaptic potentials. In the present study, we used paired whole cell recordings to examine target-dependent inhibition from CWCs in neonatal rat DCN slices. We found that CWC inhibitory postsynaptic potentials (IPSPs) onto PCs are large (1.3 mV) and brief (half-width = 11.8 ms), whereas CWC IPSPs onto other CWCs are small (0.2 mV) and slow (half-width = 36.8 ms). Evoked IPSPs between CWCs exhibit paired-pulse facilitation, while CWC IPSPs onto PCs exhibit paired-pulse depression. Perforated-patch recordings showed that spontaneous IPSPs in CWCs are hyperpolarizing at rest with a mean estimated reversal potential of −67 mV. Spontaneous IPSCs were smaller and lasted longer in CWCs than in PCs, suggesting that the kinetics of the receptors are different in the two cell types. These results reveal that CWCs play a dual role in the DCN. The CWC-CWC network interactions are slow and sensitive to the average rate of CWC firing, whereas the CWC-PC network is fast and sensitive to transient changes in CWC firing.


2009 ◽  
Vol 29 (11) ◽  
pp. 3033-3044 ◽  
Author(s):  
Garret R. Anderson ◽  
Rafael Lujan ◽  
Kirill A. Martemyanov

ABSTRACT Neurotransmitter signaling via G protein coupled receptors is crucially controlled by regulators of G protein signaling (RGS) proteins that shape the duration and extent of the cellular response. In the striatum, members of the R7 family of RGS proteins modulate signaling via D2 dopamine and μ-opioid receptors controlling reward processing and locomotor coordination. Recent findings have established that R7 RGS proteins function as macromolecular complexes with two subunits: type 5 G protein β (Gβ5) and R7 binding protein (R7BP). In this study, we report that the subunit compositions of these complexes in striatum undergo remodeling upon changes in neuronal activity. We found that under normal conditions two equally abundant striatal R7 RGS proteins, RGS9-2 and RGS7, are unequally coupled to the R7BP subunit, which is present in complex predominantly with RGS9-2 rather than with RGS7. Changes in the neuronal excitability or oxygenation status resulting in extracellular calcium entry, uncouples RGS9-2 from R7BP, triggering its selective degradation. Concurrently, released R7BP binds to mainly intracellular RGS7 and recruits it to the plasma membrane and the postsynaptic density. These observations introduce activity-dependent remodeling of R7 RGS complexes as a new molecular plasticity mechanism in striatal neurons and suggest a general model for achieving rapid posttranslational subunit rearrangement in multisubunit complexes.


Sign in / Sign up

Export Citation Format

Share Document