Dendrites Of Medium Spiny Neurons Research Articles

Dopamine-independent development and maintenance of mouse striatal medium spiny neuron dendritic spines

Striatal medium spiny neurons (MSNs) and striatal dopamine (DA) innervation are profoundly important for brain function such as motor control and cognition. A widely accepted theory posits that striatal DA loss causes (or leads to) MSN dendritic atrophy. However, examination of the literature indicates that the data from Parkinson's disease (PD) patients and animal PD models were contradictory among studies and hard to interpret. Here we have re-examined the potential effects of DA activity on MSN morphology or lack thereof. We found that in 15-day, 4- and 12-month old Pitx3 null mutant mice that have severe DA denervation in the dorsal striatum while having substantial residual DA innervation in the ventral striatum, MSN dendrites and spine numbers were similar in dorsal and ventral striatum, and also similar to those in normal mice. In 15-day, 4- and 12-month old tyrosine hydroxylase knockout mice that cannot synthesize L-dopa and thus have no endogenous DA in the entire brain, MSN dendrites and spine numbers were also indistinguishable from age-matched wild-type (WT) mice. Furthermore, in adult WT mice, unilateral 6-OHDA lesion at 12 months of age caused an almost complete striatal DA denervation in the lesioned side, but MSN dendrites and spine numbers were similar in the lesioned and control sides. Taken together, our data indicate that in mice, the development and maintenance of MSN dendrites and spines are DA-independent such that DA depletion does not trigger MSN dendritic atrophy; our data also suggest that the reported MSN dendritic atrophy in PD may be a component of neurodegeneration in PD rather than a consequence of DA denervation.

Direct administration of ifenprodil and citalopram into the nucleus accumbens inhibits cue-induced nicotine seeking and associated glutamatergic plasticity.

Nicotine use disorder has been associated with glutamatergic alterations within the basal ganglia that might contribute to relapse. Specifically, initiation of cue-induced nicotine seeking produces rapid, transient synaptic potentiation (t-SP) in nucleus accumbens core (NAcore) medium spiny neurons (MSNs), defined as increases in spine head diameter and AMPA to NMDA current ratios (A/N). Ifenprodil, which inhibits nicotine reinstatement when administered systemically, antagonizes GluN2B-containing NMDA receptors, has affinity for serotonin receptors, and blocks serotonin transporters (SERT). The mechanisms underlying its therapeutic efficacy, however, remain unknown. Using pharmacological and genetic approaches, the current study examined the role of NAcore GluN2B receptors as well as SERT in mediating cue-induced nicotine seeking and associated MSN structure and physiology. Prior to reinstatement, rats received intra-NAcore injections of either ifenprodil, citalopram or artificial cerebral spinal fluid (15min prior), or GluN2B or control siRNAs (3 consecutive days prior). Rats were sacrificed after a 15-min cue-induced reinstatement session for dendritic spine analysis, western blotting or whole-cell electrophysiology. Intra-NAcore ifenprodil blocked nicotine-seeking behavior and promoted a higher frequency of shorter spines on MSN dendrites. However, a decrease in membrane-bound GluN2B receptor expression did not prevent cue-induced nicotine seeking or associated MSN cell physiology. Interestingly, intra-NAcore citalopram, an SSRI, prevented cue-induced nicotine seeking. Together, these results indicate that the therapeutic effects of ifenprodil on cue-induced nicotine seeking may, in part, be due to its actions at SERT rather than GluN2B, which may be specific to nicotine-seeking as opposed to other drugs of abuse.

Correlative study using structural MRI and super-resolution microscopy to detect structural alterations induced by long-term optogenetic stimulation of striatal medium spiny neurons

Striatal medium spiny neurons (MSNs) control motor function. Hyper- or hypo-activity of MSNs coincides with basal ganglia-related movement disorders. Based on the assumption that lasting alterations in neuronal activity lead to structural changes in the brain, understanding these structural alterations may be used to infer MSN functional abnormalities. To infer MSN function from structural data, understanding how long-lasting alterations in MSN activity affect brain morphology is essential. To address this, we utilized a simplified model of functional induction by stimulating MSNs expressing channelrhodopsin 2 (ChR2). Subsequent structural alterations which induced long-term activity changes in these MSNs were investigated in the striatal pathway and its associated regions by diffusion tensor imaging (DTI) and histological assessment with super-resolution microscopy. DTI detected changes in the striatum, substantia nigra, and motor cortex. Histological assessment found a reduction in the diameter of myelinated cortical axons as well as MSN dendrites and axons. The structural changes showed a high correlation between DTI parameters and histological data. These results demonstrated that long-term neural activation in the MSNs alters the diameter of MSN and cortical neurons fibers. This study provides a tool for understanding the causal relationship between functional and structural alterations.

Selective effects of Δ9-tetrahydrocannabinol on medium spiny neurons in the striatum.

Derivatives from the Cannabis plant are the most commonly abused illegal substances in the world. The main psychoactive component found in the plant, Δ-9-tetrahydrocannabinol (THC), exerts its effects through the endocannabinoid system. Manipulations of this system affect some types of learning that seem to be dependent on dorsal striatum synaptic plasticity. Dendritic spines exhibit important synaptic functional attributes and a potential for plasticity, which is thought to mediate long-lasting changes in behaviour. To study the possible structural plasticity changes that prolonged THC administration might exert in the dorsal striatum, adult, male C57BL6/J mice were intraperitoneally injected with THC (10mg/kg) or vehicle for 15 days followed by a 7-day drug-free period. Using single cell intracellular injections of Lucifer Yellow, confocal microscopy, and 3D reconstruction of labelled neurons, we studied dendritic spine density and spine size in medium spiny neurons (MSNs) of the anterior dorsolateral striatum (aDLS) and posterior dorsomedial striatum (pDMS). We found that the THC treatment increased dendritic spine density in the distal part of the dendrites of MSNs in the pDMS, but no changes were found in the rest of the parameters analysed in either region studied. We also observed that dendritic spines of MSNs of pDMS presented lower volume and surface area values than MSNs of the aDLS. These results seem to indicate that THC could induce structural plasticity alterations in the circuits involving pDMS MSNs.

Effects of location and extent of spine clustering on synaptic integration in striatal medium spiny neurons—a computational study

The nucleus accumbens (NAc) is known widely for its role in the reward circuit, which is dysregulated in a number of psychological disorders. Recent evidence also suggests the contribution of this structure in spatial and gustatory memories. Because of its role in different types of memories, similar to the hippocampus, we assumed the formation of spine clusters, which are engrams of memory, to be present on dendrites of medium spiny neurons (MSNs). We found that the activation of clustered inputs resulted in sublinear summation when clusters were present on the same branch and also when inputs were distributed on different branches. The size, as well as the location of clusters, was found to affect the summation. With an increase in cluster size and distance from soma, the summation was increasingly sublinear. When the temporal integration window was measured for clustered spines, it was found to be narrower as compared to that for a single spine. Also, distally located clusters resulted in a wider temporal window, as compared to proximal clusters. Our results suggest that depending on the location of clusters, the modes of integration will differ in MSNs possessing clustered spines.

Nicotine-induced and D1-receptor-dependent dendritic remodeling in a subset of dorsolateral striatum medium spiny neurons

Nicotine is one of the most addictive substances known, targeting multiple memory systems, including the ventral and dorsal striatum. One form of neuroplasticity commonly associated with nicotine is dendrite remodeling. Nicotine-induced dendritic remodeling of ventral striatal medium spiny neurons (MSNs) is well-documented. Whether MSN dendrites in the dorsal striatum undergo a similar pattern of nicotine-induced structural remodeling is unknown. A morphometric analysis of Golgi-stained MSNs in rat revealed a natural asymmetry in dendritic morphology across the mediolateral axis, with larger, more complex MSNs found in the dorsolateral striatum (DLS). Chronic nicotine produced a lasting (at least 21day) expansion in the dendritic complexity of MSNs in the DLS, but not dorsomedial striatum (DMS). Given prior evidence that MSN subtypes can be distinguished based on dendritic morphology, MSNs were segregated into morphological subpopulations based on the number of primary dendrites. Analysis of these subpopulations revealed that DLS MSNs with more primary dendrites were selectively remodeled by chronic nicotine exposure and remodeling was specific to the distal-most portions of the dendritic arbor. Co-administration of the dopamine D1 receptor (D1R) antagonist SCH23390 completely reversed the selective effects of nicotine on DLS MSN dendrite morphology, supporting a causal role for dopamine signaling at D1 receptors in nicotine-induced dendrite restructuring. Considering the functional importance of the DLS in shaping and expressing habitual behavior, these data support a model in which nicotine induces persistent and selective changes in the circuit connectivity of the DLS that may promote and sustain addiction-related behavior.

Dopamine synapse is a neuroligin-2–mediated contact between dopaminergic presynaptic and GABAergic postsynaptic structures

Midbrain dopamine neurons project densely to the striatum and form so-called dopamine synapses on medium spiny neurons (MSNs), principal neurons in the striatum. Because dopamine receptors are widely expressed away from dopamine synapses, it remains unclear how dopamine synapses are involved in dopaminergic transmission. Here we demonstrate that dopamine synapses are contacts formed between dopaminergic presynaptic and GABAergic postsynaptic structures. The presynaptic structure expressed tyrosine hydroxylase, vesicular monoamine transporter-2, and plasmalemmal dopamine transporter, which are essential for dopamine synthesis, vesicular filling, and recycling, but was below the detection threshold for molecules involving GABA synthesis and vesicular filling or for GABA itself. In contrast, the postsynaptic structure of dopamine synapses expressed GABAergic molecules, including postsynaptic adhesion molecule neuroligin-2, postsynaptic scaffolding molecule gephyrin, and GABAA receptor α1, without any specific clustering of dopamine receptors. Of these, neuroligin-2 promoted presynaptic differentiation in axons of midbrain dopamine neurons and striatal GABAergic neurons in culture. After neuroligin-2 knockdown in the striatum, a significant decrease of dopamine synapses coupled with a reciprocal increase of GABAergic synapses was observed on MSN dendrites. This finding suggests that neuroligin-2 controls striatal synapse formation by giving competitive advantage to heterologous dopamine synapses over conventional GABAergic synapses. Considering that MSN dendrites are preferential targets of dopamine synapses and express high levels of dopamine receptors, dopamine synapse formation may serve to increase the specificity and potency of dopaminergic modulation of striatal outputs by anchoring dopamine release sites to dopamine-sensing targets.

GABAA receptor activity shapes the formation of inhibitory synapses between developing medium spiny neurons.

Basal ganglia play an essential role in motor coordination and cognitive functions. The GABAergic medium spiny neurons (MSNs) account for ~95% of all the neurons in this brain region. Central to the normal functioning of MSNs is integration of synaptic activity arriving from the glutamatergic corticostriatal and thalamostriatal afferents, with synaptic inhibition mediated by local interneurons and MSN axon collaterals. In this study we have investigated how the specific types of GABAergic synapses between the MSNs develop over time, and how the activity of GABAA receptors (GABAARs) influences this development. Isolated embryonic (E17) MSNs form a homogenous population in vitro and display spontaneous synaptic activity and functional properties similar to their in vivo counterparts. In dual whole-cell recordings of synaptically connected pairs of MSNs, action potential (AP)-activated synaptic events were detected between 7 and 14 days in vitro (DIV), which coincided with the shift in GABAAR operation from depolarization to hyperpolarization, as detected indirectly by intracellular calcium imaging. In parallel, the predominant subtypes of inhibitory synapses, which innervate dendrites of MSNs and contain GABAAR α1 or α2 subunits, underwent distinct changes in the size of postsynaptic clusters, with α1 becoming smaller and α2 larger over time, while both the percentage and the size of mixed α1/α2-postsynaptic clusters were increased. When activity of GABAARs was under chronic blockade between 4–7 DIV, the structural properties of these synapses remained unchanged. In contrast, chronic inhibition of GABAARs between 7–14 DIV led to reduction in size of α1- and α1/α2-postsynaptic clusters and a concomitant increase in number and size of α2-postsynaptic clusters. Thus, the main subtypes of GABAergic synapses formed by MSNs are regulated by GABAAR activity, but in opposite directions, and thus appear to be driven by different molecular mechanisms.

Long-term effects of cocaine experience on neuroplasticity in the nucleus accumbens core of addiction-prone rats

Repeated exposure to drugs of abuse is associated with structural plasticity in brain reward pathways. Rats selectively bred for locomotor response to novelty differ on a number of neurobehavioral dimensions relevant to addiction. This unique genetic animal model was used here to examine both pre-existing differences and long-term consequences of repeated cocaine treatment on structural plasticity. Selectively bred high-responder (bHR) and low-responder (bLR) rats received repeated saline or cocaine injections for 9 consecutive days. Escalating doses of cocaine (7.5, 15 and 30mg/kg) were administered on the first (day 1) and last (day 9) days of treatment and a single injection of the intermediate dose (15mg/kg) was given on days 2–8. Motor activity in response to escalating doses of cocaine was compared on the first and last days of treatment to assess the acute and sensitized response to the drug. Following prolonged cocaine abstinence (28days), spine density was examined on terminal dendrites of medium spiny neurons in the nucleus accumbens core. Relative to bLRs, bHRs exhibited increased psychomotor activation in response to both the acute and repeated effects of cocaine. There were no differences in spine density between bHR and bLR rats under basal conditions or following repeated saline treatment. However, spine density differed markedly between these two lines following prolonged cocaine abstinence. All spine types were decreased in cocaine-treated bHRs, while only mushroom spines were decreased in bLRs that received cocaine. Changes in spine density occurred specifically near the branch point of terminal dendrites. These findings indicate that structural plasticity associated with prolonged cocaine abstinence varies markedly in two selected strains of rats that vary on numerous traits relevant to addiction. Thus, genetic factors that contribute to individual variation in the behavioral response to cocaine also influence cocaine-induced structural plasticity.

Striatal plasticity and medium spiny neuron dendritic remodeling in parkinsonism

Current approaches to Parkinson's Disease (PD) are largely based on our current understanding of the mechanisms that contribute to the death of nigrostriatal dopamine neurons. However, our understanding of the consequences of the loss of dopamine on the striatal target cells of nigrostriatal neurons is much less advanced. In particular, the compensatory changes that occur in striatal medium spiny neurons (MSNs) that have lost their normal dopamine input remains poorly understood. The compensatory changes may have either positive or negative effects. Among the alterations that occur in striatal cells of the dopamine-denervated striatum are dystrophic changes in the dendrites of MSNs, with a loss of dendritic length and dendritic spine number. Dendritic spines are the targets of convergent nigrostriatal dopamine and corticostriatal glutamate axons, and integrate these convergent signals to determine the nature of striatal output. The loss of these spines in the dopamine-denervated state may protect the MSN from overt excitotoxic death, but at the price of compromising MSN function. The loss of dendritic spines is thought be responsible for the gradual decrease in levodopa efficacy in late-stage PD, suggesting that therapeutic interventions need to be developed that target key downstream signaling complexes in medium spiny neurons.

BDNF heterozygous mice demonstrate age-related changes in striatal and nigral gene expression

TrkB receptors mediate the effects of BDNF on striatal medium spiny neurons and mesencephalic dopamine neurons. The effect of partial BDNF gene deletion on locomotor activity and the gene expression of these neurons was evaluated at 3, 12, and 24 months of age in BDNF heterozygous (BDNF(LacZ/neo+)) and wildtype mice. BDNF(LacZ/neo+) mice displayed less spontaneous horizontal activity than wildtypes at 3 and 24 months of age. Whereas striatal preproenkephalin and preprodynorphin mRNA and mesencephalic tyrosine hydroxylase mRNA levels were significantly lower at all ages in BDNF(LacZ/neo+) mice, GAD67 mRNA was only lower at 24 months. In contrast, BDNF(LacZ/neo+) mice expressed more trkB mRNA in the striatum at 3 months and less at 24 months of age than wildtypes. Total striatal cell number in the two genotypes was not different at 12 months of age, whereas Golgi staining revealed that the spine density on distal dendrites of medium spiny neurons was less in BDNF(LacZ/neo+) mice than in wildtypes at 24 months of age. These data indicate that endogenous BDNF is required to maintain the normal phenotype and functioning of striatal projection neurons and mesencephalic dopamine neurons and that exaggerated dysfunction of these neurons and a concomitant decline in locomotor behavior occurs during aging.

State-Dependent Calcium Signaling in Dendritic Spines of Striatal Medium Spiny Neurons

Striatal medium spiny neurons (MSNs) in vivo undergo large membrane depolarizations known as state transitions. Calcium (Ca) entry into MSNs triggers diverse downstream cellular processes. However, little is known about Ca signals in MSN dendrites and spines and how state transitions influence these signals. Here, we develop a novel approach, combining 2-photon Ca imaging and 2-photon glutamate uncaging, to examine how voltage-sensitive Ca channels (VSCCs) and ionotropic glutamate receptors contribute to Ca signals in MSNs. We find that upstate transitions switch the VSCCs available in dendrites and spines, decreasing T-type while enhancing L-type channels. Moreover, these transitions change the dominant synaptic Ca source from Ca-permeable AMPA receptors to NMDA receptors. Finally, pairing bAPs with synaptic inputs generates additional synaptic Ca signals due to enhanced Ca influx through NMDA receptors. By altering the sources, amplitude, and kinetics of spine Ca signals, state transitions may gate synaptic plasticity and gene expression in MSNs.

The location of persistent amphetamine-induced changes in the density of dendritic spines on medium spiny neurons in the nucleus accumbens and caudate-putamen.

Repeated intermittent treatment with amphetamine increases the density of dendritic spines on medium spiny neurons (MSNs) in the nucleus accumbens (NAcc). The purpose of this study was two-fold: (1) to determine whether amphetamine has similar effects on MSNs in the caudate-putamen (CPu) and (2) to determine if this effect is localized to distal dendrites, the site of convergence of dopamine (DA) and glutamate synapses in the striatum. An amphetamine treatment regimen that produced behavioral sensitization increased the density of dendritic spines on MSNs in both the NAcc and dorsolateral CPu. This effect was long lasting, because it was evident 3.5 months after the discontinuation of drug treatment. The increase in spine density was confined to distal dendrites of MSNs, and was not apparent on dendrites close to the cell body. It is concluded that amphetamine may preferentially reorganize synapses at the site of DA-glutamate interaction in the striatum, which may alter DA-glutamate signaling and thereby contribute to some of the persistent behavioral and psychological consequences of repeated exposure to psychostimulant drugs.

Regulation of the Subcellular Distribution of m4 Muscarinic Acetylcholine Receptors in Striatal NeuronsIn Vivoby the Cholinergic Environment: Evidence for Regulation of Cell Surface Receptors by Endogenous and Exogenous Stimulation

Our aim was to determine how the cholinergic environment influences, in vivo, the membrane abundance and the intracellular trafficking of the muscarinic receptor m4 (m4R). Immunohistochemistry at light and electron microscopic level was used to detect the subcellular localization of m4R in several populations of striatal cholinoceptive neurons, including cholinergic neurons and medium spiny neurons. (1) In control rats, in cholinergic neurons, m4R is mostly restricted to intracytoplasmic sites involved in its synthesis, especially endoplasmic reticulum. In contrast, m4R is preferentially located at the plasma membrane in cell bodies and dendritic shafts and spines of medium spiny neurons. The density of m4R was greater at the membrane of perikarya in patches (striatal areas with low acetylcholine activity) than in matrix (striatal areas with high acetylcholine activity). (2) Stimulation of muscarinic receptor with oxotremorine provokes translocation of m4R from the membrane to endosomes in perikarya and dendrites of medium spiny neurons but has no influence on the localization of m4R in the cytoplasm of cholinergic cell bodies. Our results suggest that the intraneuronal trafficking and the abundance of membrane-bound m4R in vivo is under regulation of the cholinergic environment. The m4R subcellular compartmentalization depends on the phenotype of the cholinoceptive neuron and on its neurochemical environment. Such regulation, by modulating availability of receptor for endogenous and exogenous ligands, may play key roles in the response of target neurons.