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PubMed2006

Dopamine presynaptically and heterogeneously modulates nucleus accumbens medium-spiny neuron GABA synapses in vitro.

BACKGROUND: The striatal complex is the major target of dopamine action in the CNS. There, medium-spiny GABAergic neurons, which constitute about 95% of the neurons in the area, form a mutually inhibitory synaptic network that is modulated by dopamine. When put in culture, the neurons reestablish this network. In particular, they make autaptic connections that provide access to single, identified medium-spiny to medium-spiny neuron synaptic connections. RESULTS: We examined medium-spiny neuron autaptic connections in postnatal cultures from the nucleus accumbens, the ventral part of the striatal complex. These connections were subject to presynaptic dopamine modulation. D1-like receptors mediated either inhibition or facilitation, while D2-like receptors predominantly mediated inhibition. Many connections showed both D1 and D2 modulation, consistent with a significant functional colocalization of D1 and D2-like receptors at presynaptic sites. These same connections were subject to GABAA, GABAB, norepinephrine and serotonin modulation, revealing a multiplicity of modulatory autoreceptors and heteroreceptors on individual varicosities. In some instances, autaptic connections had two components that were differentially modulated by dopamine agonists, suggesting that dopamine receptors could be distributed heterogeneously on the presynaptic varicosities making up a single synaptic (i.e. autaptic) connection. CONCLUSION: Differential trafficking of dopamine receptors to different presynaptic varicosities could explain the many controversial studies reporting widely varying degrees of dopamine receptor colocalization in medium-spiny neurons, as well as more generally the diversity of dopamine actions in target areas. Longer-term changes in the modulatory actions of dopamine in the striatal complex could be due to plasticity in the presynaptic distribution of dopamine receptors on medium-spiny neuron varicosities.

Animals↗

PubMed1998

Postinjury magnesium sulfate treatment is not markedly neuroprotective for striatal medium spiny neurons after perinatal hypoxia/ischemia in the rat.

Hypoxic/ischemic (H/I) brain injury is thought to be mediated via the N-methyl-D-aspartate receptor complex, which can be blocked by the magnesium ion. Striatal medium spiny neurons abundantly express N-methyl-D-aspartate receptors and are known to be injured after H/I. Thus, the aim of this study was to investigate the effect of postinjury magnesium treatment on the total number of medium spiny neurons in the striatum after perinatal H/I injury in the rat. Anesthetized postnatal day (PN) 7 rats underwent common carotid artery ligation followed 2 h later by exposure to hypoxia for 1.5 h. Contralateral hemispheres served as controls as did animals exposed to normoxia. Immediately after hypoxia or normoxia, the magnesium groups received s.c. injections of 300 mg/kg MgSO4. Control, hypoxic or normoxic animals received NaCl injections. This continued daily until PN13. Eleven matched-for-weight H/I pups were injected in total. A power calculation showed that 11 pups per treatment group would permit detection of a treatment difference of 32% or more. Animals were killed on PN18, and 40-micron serial sections were cut through each entire striatum. The total number of the predominant medium spiny neurons within each striatum was stereologically determined via the use of an unbiased optical dissector/Cavalieri combination. It was found that postinjury magnesium treatment did not improve neuronal survival by 32% or more in the striatum. The results suggest that magnesium treatment after perinatal H/I damage in the rat is not markedly neuroprotective for striatal medium spiny neurons.

Animals↗

PubMed2004

Adenovirally expressed noggin and brain-derived neurotrophic factor cooperate to induce new medium spiny neurons from resident progenitor cells in the adult striatal ventricular zone.

Neurogenesis from endogenous progenitor cells in the adult forebrain ventricular wall may be induced by the local viral overexpression of cognate neuronal differentiation agents, in particular BDNF. Here, we show that the overexpression of noggin, by acting to inhibit glial differentiation by subependymal progenitor cells, can potentiate adenoviral BDNF-mediated recruitment of new neurons to the adult rat neostriatum. The new neurons survive at least 2 months after their genesis in the subependymal zone and are recruited primarily as GABAergic DARPP-32+ medium spiny neurons in the caudate-putamen. The new medium spiny neurons successfully project to the globus pallidus, their usual developmental target, extending processes over several millimeters of the normal adult striatum. Thus, concurrent suppression of subependymal glial differentiation and promotion of neuronal differentiation can mobilize endogenous subependymal progenitor cells to achieve substantial neuronal addition to otherwise non-neurogenic regions of the adult brain.

Adenoviridae↗

PubMed2001

Coordinated expression of muscarinic receptor messenger RNAs in striatal medium spiny neurons.

The postsynaptic effects of acetylcholine in the striatum are largely mediated by muscarinic receptors. Two of the five cloned muscarinic receptors (M1 and M4) are expressed at high levels by the medium spiny neurons-the principal projection neurons of the striatum. Previous studies have suggested that M4 muscarinic receptors are found primarily in medium spiny neurons that express substance P and participate in the "direct" striatonigral pathway. This view is difficult to reconcile with electrophysiological studies suggesting that nearly all medium spiny neurons exhibit responses characteristic of M4 receptors. To explore this apparent discrepancy, the coordinated expression of M1-M5 receptor messenger RNAs in identified medium spiny neurons was assayed using single-cell reverse transcription-polymerase chain reaction techniques. Nearly all medium spiny neurons had detectable levels of M1 receptor messenger RNA. Although M4 receptor messenger RNA was detected more frequently in substance P-expressing neurons (70%), it was readily seen in a substantial population of enkephalin-expressing neurons (50%). To provide a quantitative estimate of transcript abundance, quantitative reverse transcription-polymerase chain reaction experiments were performed. These studies revealed that M4 messenger RNA was expressed by both substance P and enkephalin neurons, but was roughly five-fold higher in abundance in substance P-expressing neurons. This quantitative difference provides a means of reconciling previous estimates of M4 receptor distribution and function.

Animals↗

PubMed1994

Two distinct glutamatergic synaptic inputs to striatal medium spiny neurones of neonatal rats and paired-pulse depression.

Excitatory postsynaptic currents (EPSCs) were recorded from the medium spiny neurones of neonatal rat striatal slices using the whole-cell patch clamp method. EPSCs were selectively elicited in the presence of picrotoxin with a glass stimulating pipette placed in the striatum. We found two distinct unitary EPSCs that were evoked by stimulation of single presynaptic fibres. The major type of EPSC, termed 'S-type', failed frequently and had a small mean amplitude (2.05 pA). They probably represented cortical afferents. The other type of unitary EPSC, the 'H-type', seldom failed and was 13 times larger than the S-type. Spontaneous EPSCs with amplitudes similar to those of H-type EPSCs could be induced. H-type EPSCs were mediated by both non-NMDA and NMDA receptors. The two types of EPSCs could be evoked in the same neurons. The intensity of stimulation for H-type EPSCs was higher than that for S-type EPSCs. H-type EPSCs could be polysynaptically activated, suggesting the presence of glutamatergic interneurones in the striatum that generated H-type EPSCs. H-type EPSCs displayed particularly long-lasting paired-pulse depression, while that displayed by the S-type EPSCs was short. The paired-pulse depression of both EPSCs was Ca2+ dependent and involved presynaptic mechanisms. We have demonstrated that the medium spiny neurones of neonatal rats receive two different glutamatergic input systems having different amplitudes, origins and paired-pulse depression, reminiscent of cerebellar Purkinje cells. This suggests that the two types of EPSCs also play distinctive roles in striatal neuronal circuitry.

Animals↗

PubMed1994

Quantal properties of S-type glutamatergic synaptic input to the striatal medium spiny neuron from neonate rat.

We investigated the quantal properties of the small glutamatergic EPSPs (S-type EPSPs) in the striatal medium spiny neurons using the whole-cell recording method. Amplitudes of unitary glutamatergic EPSCs displayed a single peak at about 4.7 pA that was unaffected by decreasing external Ca2+. This indicates that afferent fibers contact the medium spiny neuron with only a few, possibly one, release sites which generate no more than one quantum of EPSCs at a time.

Animals↗

PubMed2005

Periadolescent nicotine administration produces enduring changes in dendritic morphology of medium spiny neurons from nucleus accumbens.

The objective of the current study was to examine how periadolescent nicotine exposure affects dendritic morphology of medium spiny neurons from the nucleus accumbens shell. Male Long-Evans hooded rats were chronically administered nicotine or saline for a period extending from postnatal day 22 (p22) to p69. Nicotine and saline administration was via subcutaneously implanted osmotic pumps. At p144, 75 days after conclusion of nicotine administration, brains were processed for Golgi-Cox staining. Medium spiny neurons from the nucleus accumbens shell were digitally reconstructed. It was found that neurons from nicotine-treated animals possessed significantly longer dendrites and a greater number of dendritic segments than control animals. A branch order analysis indicated that differences in dendritic length and segment number were most pronounced in third and fourth order segments. A subsequent behavioral experiment suggests that the observed anatomical changes are associated with enduring psychomotor differences. These findings indicate that periadolescent exposure to nicotine can result in long-lasting structural changes in the nucleus accumbens shell and are consistent with behavioral data suggesting that adolescent nicotine exposure may result in vulnerability to nicotine addiction in adulthood.

Age Factors↗

PubMed1997

D1 receptor activation enhances evoked discharge in neostriatal medium spiny neurons by modulating an L-type Ca2+ conductance.

Most in vitro studies of D1 dopaminergic modulation of excitability in neostriatal medium spiny neurons have revealed inhibitory effects. Yet studies made in more intact preparations have shown that D1 receptors can enhance or inhibit the responses to excitatory stimuli. One explanation for these differences is that the effects of D1 receptors on excitability are dependent on changes in the membrane potential occurring in response to cortical inputs that are seen only in intact preparations. To test this hypothesis, we obtained voltage recordings from medium spiny neurons in slices and examined the impact of D1 receptor stimulation at depolarized and hyperpolarized membrane potentials. As previously reported, evoked discharge was inhibited by D1 agonists when holding at negative membrane potentials (approximately -80 mV). However, at more depolarized potentials (approximately -55 mV), D1 agonists enhanced evoked activity. At these potentials, D1 agonists or cAMP analogs prolonged or induced slow subthreshold depolarizations and increased the duration of barium- or TEA-induced Ca2+-dependent action potentials. Both effects were blocked by L-type Ca2+ channel antagonists (nicardipine, calciseptine) and were occluded by the L-type channel agonist BayK 8644-arguing that the D1 receptor-mediated effects on evoked activity at depolarized membrane potential were mediated by enhancement of L-type Ca2+ currents. These results reconcile previous in vitro and in vivo studies by showing that D1 dopamine receptor activation can either inhibit or enhance evoked activity, depending on the level of membrane depolarization.

Animals↗

PubMed2006

Presynaptic I1-imidazoline receptors reduce GABAergic synaptic transmission in striatal medium spiny neurons.

Imidazoline receptors are expressed widely in the CNS. In the present study, whole-cell patch-clamp recordings were made from medium spiny neurons in dorsal striatum slices from the rat brain, and the roles of I1-imidazoline receptors in the modulation of synaptic transmission were studied. Moxonidine, an I1-imidazoline receptor agonist, decreased the GABAA receptor-mediated IPSCs in a concentration-dependent manner. However, glutamate-mediated EPSCs were hardly affected. The depression of IPSCs by moxonidine was antagonized by either idazoxan or efaroxan, which are both imidazoline receptor antagonists containing an imidazoline moiety. In contrast, yohimbine and SKF86466 (6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine), which are alpha2-adrenergic receptor antagonists with no affinity for imidazoline receptors, did not affect the moxonidine-induced inhibition of IPSCs. Moxonidine increased the paired-pulse ratio and reduced the frequency of miniature IPSCs without affecting their amplitude, indicating that this agent inhibits IPSCs via presynaptic mechanisms. Moreover, the sulfhydryl alkylating agent N-ethylmaleimide (NEM) significantly reduced the moxonidine-induced inhibition of IPSCs. Thus, the activation of presynaptic I1-imidazoline receptors decreases GABA-mediated inhibition of medium spiny neurons in the striatum, in which NEM-sensitive proteins such as G(i/o)-type G-proteins play an essential role. The adenylate cyclase activator forskolin partly opposed IPSC inhibition elicited by subsequently applied moxonidine. Furthermore, the protein kinase C (PKC) activator phorbol 12,13-dibutyrate attenuated and the PKC inhibitor chelerythrine potentiated the moxonidine-induced inhibition of IPSCs. These results suggest that IPSC inhibition via presynaptic I1-imidazoline receptors involves intracellular adenylate cyclase activity and is influenced by static PKC activity in the striatum.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed2003

Heterogeneity of spike frequency adaptation among medium spiny neurones from the rat striatum.

The main neuronal population of the striatum is composed of the medium spiny neurones (MSNs). In fact several sub-populations of MSNs can be distinguished according to the striatal compartment (striosomes and matrix) to which they belong, their afferents and their sites of projection, their biochemical markers and their morphologies. However, these cells are generally described as an electrophysiological homogeneous population. Using brain slices from the rat and whole cell patch clamp recordings, we show that at P(15) 28% of the MSNs display a spike frequency adaptation. While the mean frequency adaptation ratio for non-adapting cells was 1.07+/-0.01 it reached 2.66+/-0.09 in adapting MSNs and the incidence of this frequency adaptation phenotype appeared to be stable during post-natal development. Single-cell RT-PCR analysis of mRNAs for mu opioid receptors, enkephalin and substance P precursors suggested that adapting MSNs are present in both striatal compartments as well as in the direct and indirect pathways of the matrix. Adapting neurones were also distinguished from non-adapting cells by a lower membrane time constant, a higher AP threshold, a reduced delay to the first spike and a higher initial firing rate. Micro-domains differing by their magnitude of adaptation could be distinguished within the spike frequency adaptation process.A subgroup of MSNs exists, showing a marked spike frequency adaptation together with other distinct properties, such as shorter delay to first spike and membrane time constant, and higher initial frequency and action potential threshold. In conclusion, when strong cortical inputs are delivered in coincidence, adapting MSNs could not only transmit faster the first AP but also exert a sort of cutoff of the transmission due to their spike frequency adaptation process.

Action Potentials↗

PubMed2000

D2 dopamine receptors in striatal medium spiny neurons reduce L-type Ca2+ currents and excitability via a novel PLC[beta]1-IP3-calcineurin-signaling cascade.

In spite of the recognition that striatal D(2) receptors are critical determinants in a variety of psychomotor disorders, the cellular mechanisms by which these receptors shape neuronal activity have remained a mystery. The studies presented here reveal that D(2) receptor stimulation in enkephalin-expressing medium spiny neurons suppresses transmembrane Ca(2+) currents through L-type Ca(2+) channels, resulting in diminished excitability. This modulation is mediated by G(beta)(gamma) activation of phospholipase C, mobilization of intracellular Ca(2+) stores, and activation of the calcium-dependent phosphatase calcineurin. In addition to providing a unifying mechanism to explain the apparently divergent effects of D(2) receptors in striatal medium spiny neurons, this novel signaling linkage provides a foundation for understanding how this pivotal receptor shapes striatal excitability and gene expression.

Action Potentials↗

PubMed1996

The role of adenosine A2a receptors in regulating GABAergic synaptic transmission in striatal medium spiny neurons.

We demonstrated an adenosine A2a receptor-mediated disinhibition of medium spiny projection neurons using intracellular recording and the whole-cell patch-clamp recording applied to these cells, visually identified in thin rat striatal slices. The A2a receptor agonist 2-[p-(2-carboxyethyl) phenylethylamino]-5'-N- ethylcarboxamido adenosine (CGS-21680; 0.3-10 microM) suppressed GABAergic synaptic transmission onto these cells in a manner inhibited by the A2a receptor-selective antagonist (E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine (0.1-1.0 microM). The A1 receptor antagonists had no effect on the CGS-21680-induced suppression. Analysis of spontaneous miniature inhibitory synaptic currents indicated that suppression of intrastriatal GABAergic synaptic transmission was attributable to presynaptic, but not postsynaptic, A2a receptors. Therefore, the A2a receptor may regulate striatal output activity by relieving GABA-mediated inhibition of the medium spiny projection neurons, which explains the ability of purinergic agents to affect motor control.

Adenosine↗

PubMed2004

The nitric oxide-guanylyl cyclase signaling pathway modulates membrane activity States and electrophysiological properties of striatal medium spiny neurons recorded in vivo.

Nitric oxide (NO)-releasing interneurons are believed to regulate the activity of striatal medium spiny neurons (MSNs) that contain the NO effector enzyme guanylyl cyclase (GC). The involvement of NO-GC signaling in modulating steady-state membrane activity of striatal MSNs was examined using in vivo intracellular recordings in rats. Intrastriatal infusion of a neuronal NO synthase inhibitor or a NO scavenger via reverse microdialysis consistently decreased the amplitude of spontaneously occurring depolarized plateau potentials (up events). Intrastriatal infusion of a NO scavenger also decreased the amplitude of EPSPs evoked during electrical stimulation of the orbital prefrontal cortex. The effect of the NO scavenger on spontaneous up events was partially reversed by coperfusion with a cell-permeable cGMP analog. Intracellular injection of MSNs with a soluble GC inhibitor resulted in large decreases in the following: (1) spontaneous up-event amplitude, (2) responsiveness to depolarizing current, (3) action potential amplitude, and (4) input resistance. These effects were partially reversed by coinjection of cGMP. Conversely, intracellular injection of a phosphodiesterase inhibitor increased MSN neuron membrane excitability. These results indicate that, in the intact animal, the NO signaling pathway exerts a powerful tonic modulatory influence over the membrane activity of striatal MSNs via the activation of GC and stimulation of cGMP production.

Animals↗

PubMed1980

Medium spiny neuron projection from the rat striatum: an intracellular horseradish peroxidase study.

The morphological features of striatal projection neurons and the responses of these neurons to electrical stimulation of the substantia nigra were studied in rats through the methods of intracellular recording and intracellular labeling with the enzyme horseradish peroxidase. Under urethane anesthesia, single striatal neurons were first analyzed for responsiveness to nigral stimuli and then filled electrophoretically with the enzyme in order to permit subsequent serial reconstruction. The axon of the medium spiny neuron was found to form an extensive collateral plexus within the striatum before entering the globus pallidus or the internal capsule. These medium spiny projection neurons responded to nigral stimuli with monosynaptic excitation.

Animals↗

PubMed2006

Striatal plasticity in parkinsonism: dystrophic changes in medium spiny neurons and progression in Parkinson's disease.

Striatal dopamine loss in Parkinson's Disease (PD) sets into play a variety of compensatory responses to help counter dopamine depletion. Most of these changes involve surviving dopamine neurons, but there are also changes in striatal medium spiny neurons (MSNs), which are the major target of dopamine axons. Among these changes are decreases in MSN dendritic length and spine density, which may dampen excessive corticostriatal glutamatergic drive onto MSNs that occurs secondary to dopamine loss. An increasing knowledge of dendritic changes in PD suggests strategies for tracking progressive worsening of symptoms and is opening new ideas on novel therapeutic strategies for PD.

Animals↗

PubMed2003

Continuous low-dose treatment with brain-derived neurotrophic factor or neurotrophin-3 protects striatal medium spiny neurons from mild neonatal hypoxia/ischemia: a stereological study.

This study aimed to investigate whether continuous, low-dose, intracerebral infusion of either brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3) could protect against striatal neuronal loss in mild neonatal hypoxic/ischaemic brain injury. Continuous, low-dose, intracerebral treatment is likely to minimise unwanted side effects of a single high dose and lengthen the time window for neuroprotection. A milder, albeit brain damage-inducing, hypoxic/ischaemic injury paradigm was used since this situation is likely to produce the highest survival rates and thus the greatest prevalence. Anaesthetised postnatal day 7 rats were each stereotaxically implanted with a brain infusion kit connected to a micro-osmotic pump. The pump continuously infused either BDNF (4.5 microg/day), NT-3 (12 microg/day), or vehicle solution into the right striatum for 3 days from postnatal day 7. The intrastriatal presence of BDNF or NT-3 was verified immunohistochemically. On postnatal day 8, the rats underwent right common carotid artery ligation followed by hypoxic exposure for 1.5 h. Animals were weighed daily thereafter and killed 1 week later on postnatal day 14. The total number of medium spiny neurons within the right striatum was stereologically determined using an optical disector/Cavalieri combination. Other measures of neuroprotection such as brain weight and striatal infarct volume were also undertaken. BDNF or NT-3 significantly increased the total number of surviving medium spiny neurons by 43% and 33% respectively. This significant neuroprotection was not evident when brain weight, striatal volume, striatal infarct volume, and neuronal density measures for NT-3, were compared. These measures therefore missed the protective effect demonstrated by the total neuronal count. This suggests that stereological measurement of total neuronal number is needed to detect neuroprotection at 1 week after low-dose, continuously infused, neurotrophin treatment and mild hypoxic/ischaemic injury. The results also suggest that lower treatment doses may be more useful than previously thought. BDNF may be particularly useful since it fostered both neuroprotection and normal weight gain. The ability to rescue striatal neurons from death may contribute toward a potential short-term, low-dose neurotrophin treatment for mild perinatal hypoxic/ischaemic brain injury in humans.

Animals↗

PubMed2026

Loss of interruption in the HTT CAG repeat is associated with somatic expansion and loss of medium spiny neurons in Huntington's disease.

Synonymous loss-of-interruption variants in the expanded CAG repeat sequence of Huntingtin (HTT) accelerate the clinical onset and progression of Huntington's disease (HD). Medium spiny neurons (MSNs) are gradually lost in HD and undergo selective somatic CAG expansion, but it is unclear how somatic expansion relates to MSN pathology. Here, we show that MSNs with large (111-150 CAG) and very large (>150 CAG) somatic expansions are rare in early manifest HD but accumulate in proportion with duration of disease. In patients with the deleterious CAG-CCG loss-of-interruption (CAG-CCG LOI) modifier, the proportion of MSNs with large and very large expansions is increased ∼5-fold despite reduced small somatic expansions in blood, and caudate MSN counts are reduced. Our findings suggest that increased somatic CAG expansion contributes to accelerated striatal MSN pathology and onset of HD but that MSNs with very large genomic CAG expansions can persist among surviving neurons of the HD brain.

Huntington’s disease↗

PubMed2006

Phenotype of striatofugal medium spiny neurons in parkinsonian and dyskinetic nonhuman primates: a call for a reappraisal of the functional organization of the basal ganglia.

The classic view of anatomofunctional organization of the basal ganglia is that striatopallidal neurons of the "indirect" pathway express D2 dopamine receptors and corelease enkephalin with GABA, whereas striatopallidal neurons of the "direct" pathway bear D1 dopamine receptors and corelease dynorphin and substance P with GABA. Although many studies have investigated the pathophysiology of the basal ganglia after dopamine denervation and subsequent chronic levodopa (L-dopa) treatment, none has ever considered the possibility of plastic changes leading to profound reorganization and/or biochemical phenotype modifications of medium spiny neurons. Therefore, we studied the phenotype of striatal neurons in four groups of nonhuman primates, including the following: normal, parkinsonian, parkinsonian chronically treated with L-dopa without exhibiting dyskinesia, and parkinsonian chronically treated with L-dopa exhibiting overt dyskinesia. To identify striatal cells projecting to external (indirect) or internal (direct) segments of the globus pallidus, the retrograde tracer cholera toxin subunit B (CTb) was injected stereotaxically into the terminal areas. Using immunohistochemistry techniques, brain sections were double labeled for CTb and dopamine receptors, opioid peptides, or the substance P receptor (NK1). We also used HPLC-RIA to assess opioid levels throughout structures of the basal ganglia. Our results suggest that medium spiny neurons retain their phenotype because no variations were observed in any experimental condition. Therefore, it appears unlikely that dyskinesia is related to a phenotype modification of the striatal neurons. However, this study supports the concept of axonal collateralization of striatofugal cells that project to both globus pallidus pars externa and globus pallidus pars interna. Striatofugal pathways are not as segregated in the primate as previously considered.

Animals↗