Medium Spiny Neurons

Cross references:  Basal Ganglia    Striatum     Substantia Nigra  
Ventral Tegmental Area   GABA  ,  Medium Spiny Neurons  ,  Lamprey GABA  ,  
GABA/Glycine Inhibition   ,  Tonic Inhibition  ,  Behavioral Disinhibition    
Inhibition of Locomotion in Lampreys .          Locomotion Sequence  
Locomotion Sequence Revision      Dictionary   

Medium spiny neuron (Wiki)    
    "Medium spiny neurons (MSN), also known as spiny projection neurons, are a special type of GABA-ergic inhibitory cell representing 90-95% (depending upon species) of the neurons within the striatum of the basal ganglia. The dorsal striatal MSNs play a key role in initiating and controlling movements of the body, limbs, and eyes. The ventral striatal MSNs play a key role in motivation, reward, reinforcement, and aversion. Medium spiny neurons have dopamine receptors, where dopamine has a dual action on MSNs; it inhibits the (D2-type) MSNs in the indirect pathway and excites (D1-type) MSNs in the direct pathway. Consequently, when dopamine is lost from the striatum, the indirect
pathway becomes overactive and the direct pathway becomes underactive.
  Confocal microscopy Z   projection of medium spiny neurons (MSNs) in the mouse striatum. The neurons were labeled using the matrisome MSN mouse Gpr101-Cre[1] in combination with a dtTomato (red fluorescent protein) reporter. A 3D projection of the same neurons can be viewed here.

1 Appearance and location
2 Function
3 Direct pathway – motor neurons
4 Indirect pathway – motor neurons
5 References '
6 External links "    

    I have put these references into a single, chronological, list.  It was originally composed of two lists and a couple of fragments.  They were not chronologically integrated, and this made searching it difficult.  Some references were identified in more than one search.  I've eliminated the duplicates.  I've also titled the two complete searches "SEARCH # 1:" and "SEARCH # 2:" , in order to highlight the fact that not all the searches used the same criteria.   The other searches are incomplete. 
The search which located a particular reference can be deduced from the locator number which follows the year.  Thus, XXX<YYY is reference XXX from search YYY.  Unfortunately,  these numbers are not constant.  They change as new references are added to the search terms.  However, they do provide some guidance as to where in a search a particular reference might be found.   

    Searching PubMed for "Medium spiny neuron" found 1,741 references:
    I decided that this was just too many references to wade through, so I added additional search criteria to create several smaller searches. 

    Searching PubMed for "Medium spiny neuron efferent gaba" identified 13 references:

    Searching PubMed for "Medium spiny neuron connections" identified 77 references.   


    Searching PubMed for "Medium spiny neuron gaba" identified 276 references:   

    Searching PubMed for "Medium spiny neuron afferent" identified 93 references.   

    Searching PubMed for "Medium spiny neuron gaba diagrams" identified zero references. 

1979 1735<1741
Projection of neostriatal spiny neurons to the substantia nigra. Application of a combined Golgi-staining and horseradish peroxidase transport proc...      

1980 276<276
Recurrent inhibition in the rat neostriatum.  
     "During intracellular recording, in the neostriatum of rats anesthetized with urethane, the triggering of an action potential in the recorded neuron by a depolarizing pulse of current resulted in inhibition in that same neuron. This inhibition was evident through its ability to reduce the amplitude of EPSPs evoked from stimulation of substantia nigra. The shunting of SN EPSPs was shown not to be due to action potential currents. The inhibition is antagonized by the GABA blocking agent bicuculline. Intracellular labeling of recorded neurons revealed them as medium spiny neurons.   
    It is concluded that the extensive axon collaterals of spiny projection neurons mediate recurrent inhibition, a portion of which involves autoptic synapses of a neuron back onto itself."  
    155 Related citations:  

1981  13<13 
Anatomy and physiology of the neostriatum.   
    "Striatal neurons receive convergent excitatory inputs from the cerebral cortex, the intralaminar thalamus, the substantia nigra (pars compacta) and the dorsal raphe nucleus.  
    The striatal projection neurons are numerous and medium spiny neurons are at least one type of projection neurons which receive direct convergent excitation from extrinsic afferents. The resultant influence of this excitation is directed, in turn, not only to extra-striatal target neurons, but also extensively to cells within the neostriatum.  
    The action of the medium spiny projection neurons is inhibitory and most likely GABA-ergic."  
    145 Related citations:   
    2 Cited by's.   

1988 10<13
Synaptic organization of the striatum   
    "The striatum, the main component of the basal ganglia, is composed of mainly one type of neuron, the so-called medium spiny neuron. This neuron cell type, which constitutes over 90% of striatal neurons, is the major output neuron of the striatum.  Combined ultrastructural neuroanatomical methods have elucidated the organization of afferent connectivity to these neurons.  
    The major physiologic function of striatal efferent activity appears to be inhibition of tonically active GABAergic neurons in the globus pallidus and substantia nigra pars reticulata.  
    Thus, the excitatory input from the cerebral cortex, whose afferents make asymmetric synapses with the spines of medium spiny neurons, appears to drive the efferent activity of the striatum. Other extrinsic and intrinsic afferent synapses are situated in a position to regulate the effect of the corticostriatal excitatory input to the medium spiny neurons. For example,  
    dopaminergic afferents from the midbrain make mainly symmetric synapses with the spine necks and dendritic shafts of the medium spiny neurons.  
    Medium spiny neurons themselves have local axon collaterals, in addition to their efferent axon that exits the striatum, which serve to link together local clusters of medium spiny neurons. These local axon collaterals, which contain either GABA, substance P, or enkephalin, also make mainly symmetric synapses with the necks of spines or dendritic shafts of medium spiny neurons. Other afferents with similar synaptic connections to these neurons arise from cholinergic or somatostatinergic striatal intrinsic neurons.  
    Additionally, the patterns of extrinsic and intrinsic afferents to medium spiny neurons and their extrinsic projections are related to the organization of medium spiny neurons into two mosaically organized macroscopic compartments, the striatal patches and matrix."   
    160 Related citations:   
    26 Cited by's:     
    Major point: 
"The major physiologic function of striatal efferent activity appears to be inhibition of tonically active GABAergic neurons in the globus pallidus and substantia nigra pars reticulata."   

1988    67<77 
Synaptic organization of the globus pallidus.  
    "The synaptic organization of the globus pallidus is reviewed with respect to present knowledge about neurons, fibers, axon terminals, and their intrinsic synaptic relationships. Information derived from studies employing Nissl stains, Golgi impregnations, lesion degeneration techniques, immunohistochemistry, and anterograde axonal labeling in various species are presented along with ultrastructural data.  
    Studies indicate that the globus pallidus contains a principal efferent neuron with smooth or spiny dendrites and simple or complex terminal dendritic arborizations. This cell type receives convergent inputs from intrinsic and extrinsic sources and uses gamma-aminobutyric acid as a transmitter.  
    A smaller and separate population of pallidal projection neurons contains acetylcholine. Two other less frequent neuronal types, of small and medium size, have also been recognized. Three to six types of axonal boutons forming synaptic contacts with pallidal neurons have been recognized in various studies. Among these, three types (types I, II, and III) are the most prevalent. Studies indicate that the most frequent category (type I) originates from neostriatal neurons via radial fiber projections and contains immunoreactive GABA and enkephalins. The synaptic architecture of the globus pallidus is dominated by a mosaic-like arrangement of long dendrites that are ensheathed by longitudinally oriented axons making synapses en passant. Triadic synapses involving dendrites that are pre- and postsynaptic are encountered infrequently.  
    Because both striatopallidal and pallidothalamic connections are inhibitory, pallidal target neurons in the thalamus may be "disinhibited" when the neostriatum is activated."       
    111 Related citations:   
    2 Cited by's. 
    Key Point:   
    Because both striatopallidal and pallidothalamic connections are inhibitory, pallidal target neurons in the thalamus may be "disinhibited" when the neostriatum is activated."       

1993    63<77   
Dendritic domains of medium spiny neurons in the primate striatum: relationships to striosomal borders  
    "Medium spiny neurons are the projection neurons of the striatum. They receive the majority of striatal afferents, and they make up the vast majority of all neurons in the striatum. These densely spiny cells thus constitute a major substrate for input-output processing in the striatum.
    In the experiments described here we analyzed the dendritic fields of spiny neurons in the squirrel monkey striatum and plotted their orientations with respect to the borders between striosomes and matrix. Medium-sized spiny neurons in the caudate nucleus were filled intracellularly in a fixed-slice preparation with the fluorescent dye Lucifer Yellow. Dendritic arbors were reconstructed following immunostaining of the injected neurons with antiserum to Lucifer Yellow and counterstaining for striosome/matrix compartments. A majority of the medium spiny neurons studied had dendritic arborizations that remained within their compartment of origin. Thus the striosome/matrix subdivision not only partitions neurotransmitter molecules and extrinsic striatal connections into two domains in the primate caudate nucleus, but also constrains the dendritic arbors of many projection neurons there. Other medium spiny neurons, however, in both striosomes and matrix, had dendrites that crossed from one compartment into the other. About a quarter of the spiny neurons reconstructed had at least one such crossing dendrite. These results suggest that compartmentalization of afferent and efferent processing by projection neurons in the primate striatum is not absolute. For a subpopulation of spiny neurons in striosomes and matrix, inputs to one compartment could have a direct influence on output cells of the other."     
    139 Related citations:   
    7 Cited by's.   

Striosome (Wiki)
    "The striosomes (also referred to as the striatal patches) are one of two complementary chemical compartments within the striatum (the other compartment is known as the matrix) that can be visualized by staining for immunocytochemical markers such as acetylcholinesterase,[1] enkephalin, substance P, limbic system-associated membrane protein (LAMP),[2] AMPA receptor subunit 1 (GluR1),[3] dopamine receptor subunits, and calcium binding proteins.[4] Striosomal abnormalities have been associated with neurological disorders, such as mood dysfunction in Huntington's disease,[5] though their precise function remains unknown. Striosomes were discovered by Ann Graybiel in 1978 using acetylcholinesterase histochemistry."   

2003    50<77 
Individual nucleus accumbens-projection neurons receive both basolateral amygdala and ventral subicular afferents in rats.  
    See: Amygdaloid Hippocampal Convergence  for full Abstract, Related citations and Cited by's. 

2009    32<77 
From real-world events to psychosis: the emerging neuropharmacology of delusions.              
    See:  Personality Disorders  for full Abstract, Related citations, Cited by's and a   Free PMC Article  .   

2010 30<77
Reconstructing the three-dimensional GABAergic microcircuit of the striatum   
    "A system's wiring constrains its dynamics, yet modelling of neural structures often overlooks the specific networks formed by their neurons. We developed an approach for constructing anatomically realistic networks and reconstructed the GABAergic microcircuit formed by the medium spiny neurons (MSNs) and fast-spiking interneurons (FSIs) of the adult rat striatum. We grew dendrite and axon models for these neurons and extracted probabilities for the presence of these neurites as a function of distance from the soma. From these, we found the probabilities of intersection between the neurites of two neurons given their inter-somatic distance, and used these to construct three-dimensional striatal networks. The MSN dendrite models predicted that half of all dendritic spines are within 100µm of the soma. The constructed networks predict distributions of gap junctions between FSI dendrites, synaptic contacts between MSNs, and synaptic inputs from FSIs to MSNs that are consistent with current estimates. The models predict that to achieve this, FSIs should be at most 1% of the striatal population. They also show that the striatum is sparsely connected: FSI-MSN and MSN-MSN contacts respectively form 7% and 1.7% of all possible connections. The models predict two striking network properties: the dominant GABAergic input to a MSN arises from neurons with somas at the edge of its dendritic field; and FSIs are inter-connected on two different spatial scales: locally by gap junctions and distally by synapses. We show that both properties influence striatal dynamics: the most potent inhibition of a MSN arises from a region of striatum at the edge of its dendritic field; and the combination of local gap junction and distal synaptic networks between FSIs sets a robust input-output regime for the MSN population. Our models thus intimately link striatal micro-anatomy to its dynamics, providing a biologically grounded platform for further study."    
    129 Related citations:   
    10  Cited by's:     
    and a Free PMC Article   
New terms: 
    "fast-spiking interneurons (FSIs)"  
    "gap junctions between FSI dendrites"  

2011 2<13
Targeting neuronal populations of the striatum.    
    "The striatum is critically involved in motor and motivational functions. The dorsal striatum, caudate-putamen, is primarily implicated in motor control and the learning of habits and skills, whereas the ventral striatum, the nucleus accumbens, is essential for motivation and drug reinforcement.  
    The GABA medium-sized spiny neurons (MSNs, about 95% of striatal neurons), which are targets of the cerebral cortex and the midbrain dopaminergic neurons, form two pathways. The dopamine D(1) receptor-positive (D(1)R) striatonigral MSNs project to the medial globus pallidus and substantia nigra pars reticulata (direct pathway) and co-express D(1)R and substance P, whereas dopamine D(2) receptor-positive (D(2)R) striatopallidal MSNs project to the lateral globus pallidus (indirect pathway) and co-express D(2)R, adenosine A(2A) receptor (A(2A)R) and enkephalin (Enk).  
    The specific role of the two efferent pathways in motor and motivational control remained poorly understood until recently. Indeed, D(1)R striatonigral and D(2)R striatopallidal neurons, are intermingled and morphologically indistinguishable, and, hence, cannot be functionally dissociated with techniques such as chemical lesions or surgery.  
    In view of the still debated respective functions of projection D(2)R striatopallidal and D(1)R striatonigral neurons and striatal interneurons, both in motor control and learning but also in more cognitive processes such as motivation, the present review sum up the development of new models and techniques (bacterial artificial chromosome transgenesis, optogenetic, viral transgenesis) allowing the selective targeting of these striatal neuronal populations in adult animal brain to understand their specific roles."   
    106 Related citations:    
    10 Cited by's:   
    and a  
Free PMC Article   
    Major points:  ** 
    "The dorsal striatum, caudate-putamen, is primarily implicated in motor control and the learning of habits and skills, whereas the ventral striatum, the nucleus accumbens, is essential for motivation and drug reinforcement."  
    "dopamine D(1) receptor-positive (D(1)R) striatonigral MSNs project to the medial globus pallidus and substantia nigra pars reticulata (direct pathway)"  
    "dopamine D(2) receptor-positive (D(2)R) striatopallidal MSNs project to the lateral globus pallidus (indirect pathway)"  
    My comment: 
Doesn't specify which pathway supplies dopamine to the nucleus accumbens.  Probably the D(2)R.   

2011  1<13
Differential DAergic Control of D1 and D2 Receptor Agonist Over Locomotor Activity and GABA Level in the Striatum.
    "The basal ganglia, a group of nuclei, are associated with a variety of functions, including motor control. The striatum, which is the major input station of the basal ganglia in the brain, is regulated in part by dopaminergic input from the substantia nigra. The striatum is made up 96% of medium spiny neurons which are GABAergic cells.  
    GABAergic cells are known to contain DA receptors which divide into two main branches- the D1 receptor (D1R)-expressing direct pathway and the D2 receptor (D2R)-expressing indirect pathway. The role of these two efferent pathways has not been clear in control of motor behaviors. To establish the influence of the different DA subtypes on GABAergic systems in the striatum, D1 selective receptor agonist (SKF 38393) and D2 selective receptor agonist (Quinpirole) were administered to mice. SKF 38393 and quinpirole were administered intraperitoneally in a volume of 0, 1, 5, 10 (mg/kg) and motor activity was assessed for 60 min immediately after the injection of DA agonists. Mice were sacrificed after behavioral test and the striatum in the brain were dissected for analysis of GABA level with HPLC. Both SKF 38393 and quinpirole dose-dependently increased locomotor activity but, GABA level in the striatum was clearly different in two agonists. These findings provide insight into the selective contributions of the direct and indirect pathways to striatal GABAergic motor behaviors."
    104 Related citations:  
    and a Free PMC Article       
    Major point: 
"The striatum is made up 96% of medium spiny neurons which are GABAergic cells.  GABAergic cells are known to contain DA receptors which divide into two main branches-
    the D1 receptor (D1R)-expressing direct pathway and the  
    D2 receptor (D2R)-expressing indirect pathway. "  

2011   28<77
Functional connectome of the striatal medium spiny neuron.
    "Dopamine system disorders ranging from movement disorders to addiction and schizophrenia involve striatal medium spiny neurons (MSNs), yet their functional connectivity has been difficult to determine comprehensively. We generated a mouse with conditional channelrhodopsin-2 expression restricted to medium spiny neurons and assessed the specificity and strength of their intrinsic connections in the striatum and their projections to the globus pallidus and the substantia nigra.  
    In the striatum, medium spiny neurons connected with other MSNs and tonically active cholinergic interneurons, but not with fast-spiking GABA interneurons.  
    In the globus pallidus, medium spiny neurons connected strongly with one class of electrophysiologically identified neurons, but weakly with the other.  
    In the substantia nigra, medium spiny neurons connected strongly with GABA, but not with dopamine neurons.  
    Projections to the globus pallidus showed solely D2-mediated presynaptic inhibition, whereas projections to the substantia nigra showed solely D1-mediated presynaptic facilitation. This optogenetic approach defines the functional connectome of the striatal medium spiny neuron."
    124 Related citations:          
    55  Cited by's:        and a Free PMC Article   
    More re: two pathways: 
" Projections to the globus pallidus showed solely D2-mediated presynaptic inhibition, whereas projections to the substantia nigra showed solely D1-mediated presynaptic facilitation."  

2014 13<77
Synchronized firing of fast-spiking interneurons is critical to maintain balanced firing between direct and indirect pathway neurons of the striatum 
    "The inhibitory circuits of the striatum are known to be critical for motor function, yet their contributions to Parkinsonian motor deficits are not clear.  
    Altered firing in the globus pallidus suggests that striatal medium spiny neurons (MSN) of the direct (D1 MSN) and indirect pathway (D2 MSN) are imbalanced during dopamine depletion. Both MSN classes receive inhibitory input from each other and from inhibitory interneurons within the striatum, specifically the fast-spiking interneurons (FSI).  
    To investigate the role of inhibition in maintaining striatal balance, we developed a biologically-realistic striatal network model consisting of multicompartmental neuron models: 500 D1 MSNs, 500 D2 MSNs and 49 FSIs. The D1 and D2 MSN models are differentiated based on published experiments of individual channel modulations by dopamine, with D2 MSNs being more excitable than D1 MSNs. Despite this difference in response to current injection, in the network D1 and D2 MSNs fire at similar frequencies in response to excitatory synaptic input. Simulations further reveal that inhibition from FSIs connected by gap junctions is critical to produce balanced firing. Although gap junctions produce only a small increase in synchronization between FSIs, removing these connections resulted in significant firing differences between D1 and D2 MSNs, and balanced firing was restored by providing synchronized cortical input to the FSIs.  
    Together these findings suggest that desynchronization of FSI firing is sufficient to alter balanced firing between D1 and D2 MSNs. " 
    No Related citations or Cited by's, but a  Free PMC Article .   

2014    8<77
Direct and indirect pathways of basal ganglia: a critical reappraisal.  
    "The basal ganglia are subcortical nuclei controlling voluntary actions and have been implicated in Parkinson's disease (PD). The prevailing model of basal ganglia function states that two circuits, the direct and indirect pathways, originate from distinct populations of striatal medium spiny neurons (MSNs) and project to different output structures. These circuits are believed to have opposite effects on movement. Specifically,  
    the activity of direct pathway MSNs is postulated to promote movement, whereas  
    the activation of indirect pathway MSNs is hypothesized to inhibit it.  
    Recent findings have revealed that this model might not fully account for the concurrent activation of both pathways during movement. Accordingly, we propose a model in which intrastriatal connections are critical and the two pathways are structurally and functionally intertwined. Thus, all MSNs might either facilitate or inhibit movement depending on the form of synaptic plasticity expressed at a certain moment. In PD, alterations of dopamine-dependent synaptic plasticity could alter this coordinated activity. "  
    No Related citations, but 
    17 Cited by's:   

2015    1<77
Multiple actions of a D3 dopamine receptor agonist, PD128907, on GABAergic inhibitory transmission between medium spiny neurons in mouse nucleus accumbens ...   
    "The nucleus accumbens (NAc) plays a crucial role in pathophysiological responses, such as reward-related behaviors, addiction, depression and schizophrenia, through activation of dopaminergic system in the midbrain area.  
    Principal cells in the NAc are medium spiny neurons (MSNs), which constitute the majority (90-95%) of NAc neuron populations in rodents. MSNs are mutually connected to form networks of lateral inhibition. Our previous study showed that activation of D2-like receptors presynaptically inhibited GABAergic transmission between MSN-MSN connections in the NAc. D2-like receptors in MSNs have been reported to consist of D2 and D3 receptors, but their functional roles remain to be elucidated. This study, therefore, aimed at examining the effects of D3 receptor activation on MSN-MSN connections using PD128907, a preferential D3 dopamine receptor agonist, and whole cell recordings from MSNs in acute slices including the NAc. In more than half of cells tested, PD128907 reduced the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in a concentration-dependent manner. However, the agonist caused multiple actions, namely, decrease, increase and no significant changes, in the amplitude as well as the frequency of sIPSCs in individual cells.  
    Our data, together with the results from previous studies, show that dopamine could suppress GABAergic transmission, i.e., lateral inhibition between some of MSNs, via activation of both D2 and D3 receptors. "  
    No Related citations, Cited by's. 

SubC    Medium Spiny Neurons   
160313 - 1123