GABAergic Medium Spiny Neurons Research Articles

Dopamine D1–D2 Receptor Heteromer in Dual Phenotype GABA/Glutamate-Coexpressing Striatal Medium Spiny Neurons: Regulation of BDNF, GAD67 and VGLUT1/2

In basal ganglia a significant subset of GABAergic medium spiny neurons (MSNs) coexpress D1 and D2 receptors (D1R and D2R) along with the neuropeptides dynorphin (DYN) and enkephalin (ENK). These coexpressing neurons have been recently shown to have a region-specific distribution throughout the mesolimbic and basal ganglia circuits. While the functional relevance of these MSNs remains relatively unexplored, they have been shown to exhibit the unique property of expressing the dopamine D1–D2 receptor heteromer, a novel receptor complex with distinct pharmacology and cell signaling properties. Here we showed that MSNs coexpressing the D1R and D2R also exhibited a dual GABA/glutamate phenotype. Activation of the D1R–D2R heteromer in these neurons resulted in the simultaneous, but differential regulation of proteins involved in GABA and glutamate production or vesicular uptake in the nucleus accumbens (NAc), ventral tegmental area (VTA), caudate putamen and substantia nigra (SN). Additionally, activation of the D1R–D2R heteromer in NAc shell, but not NAc core, differentially altered protein expression in VTA and SN, regions rich in dopamine cell bodies. The identification of a MSN with dual inhibitory and excitatory intrinsic functions provides new insights into the neuroanatomy of the basal ganglia and demonstrates a novel source of glutamate in this circuit. Furthermore, the demonstration of a dopamine receptor complex with the potential to differentially regulate the expression of proteins directly involved in GABAergic inhibitory or glutamatergic excitatory activation in VTA and SN may potentially provide new insights into the regulation of dopamine neuron activity. This could have broad implications in understanding how dysregulation of neurotransmission within basal ganglia contributes to dopamine neuronal dysfunction.

Palmitoylation and trafficking of GAD65 are impaired in a cellular model of Huntington's disease

HD (Huntington's disease) is caused by an expanded polyQ (polyglutamine) repeat in the htt (huntingtin protein). GABAergic medium spiny neurons in the striatum are mostly affected in HD. However, mhtt (mutant huntingtin)-induced molecular changes in these neurons remain largely unknown. The present study focuses on the effect of mhtt on the subcellular localization of GAD (glutamic acid decarboxylase), the enzyme responsible for synthesizing GABA (γ-aminobutyric acid). We report that the subcellular distribution of GAD is significantly altered in two neuronal cell lines that express either the N-terminus of mhtt or full-length mhtt. GAD65 is predominantly associated with the Golgi membrane in cells expressing normal htt; however, it diffuses in the cytosol of cells expressing mhtt. As a result, vesicle-associated GAD65 trafficking is impaired. Since palmitoylation of GAD65 is required for GAD65 trafficking, we then demonstrate that palmitoylation of GAD65 is reduced in the HD model. Furthermore, overexpression of HIP14 (huntingtin-interacting protein 14), the enzyme responsible for palmitoylating GAD65 in vivo, could rescue GAD65 palmitoylation and vesicle-associated GAD65 trafficking. Taken together, our data support the idea that GAD65 palmitoylation is important for the delivery of GAD65 to inhibitory synapses and suggest that impairment of GAD65 palmitoylation by mhtt may lead to altered inhibitory neurotransmission in HD.

Dystonia as a Presenting Feature of Alcohol Withdrawal

Dystonia as a Presenting Feature of Alcohol Withdrawal

Immunohistochemical localization of enkephalin in the human striatum: A postmortem ultrastructural study

Within the basal ganglia, the functionally defined region referred to as the striatum contains a subset of GABAergic medium spiny neurons expressing the neuropeptide enkephalin. Although the major features of ultrastructural enkephalin localization in striatum have been characterized among various species, its ultrastructural organization has never been studied in the human brain. Human striatal tissue was obtained from the Maryland and Alabama Brain Collections from eight normal controls. The brains were received and fixed within 8 h of death allowing for excellent preservation suitable for electron microscopy. Tissue from the dorsal striatum was processed for enkephalin immunoreactivity and prepared for electron microscopy. General morphology of the dorsal striatum was consistent with light microscopy in human. The majority of neurons labeled with enkephalin was medium-sized and had a large nonindented nucleus with a moderate amount of cytoplasm, characteristic of medium spiny neurons. Of the spines receiving synapses in dorsal striatum, 39% were labeled for enkephalin and were of varied morphologies. Small percentages (2%) of synapses were formed by labeled axon terminals. Most (82%) labeled terminals formed symmetric synapses. Enkephalin-labeled terminals showed no preference toward spines or dendrites for postsynaptic targets, whereas in rat and monkey, the vast majority of synapses in the neuropil are formed with dendritic shafts. Thus, there is an increase in the prevalence of axospinous synapses formed by enkephalin-labeled axon terminals in human compared with other species. Quantitative differences in synaptic features were also seen between the caudate nucleus and the putamen in the human tissue.

Circuit Specific Functions of Cannabinoid CB1 Receptor in the Balance of Investigatory Drive and Exploration

Well balanced novelty seeking and exploration are fundamental behaviours for survival and are found to be dysfunctional in several psychiatric disorders. Recent studies suggest that the endocannabinoid (eCB) system is an important control system for investigatory drive. Pharmacological treatment of rodents with cannabinergic drugs results in altered social and object investigation. Interestingly, contradictory results have been obtained, depending on the treatment, drug concentration and experimental conditions. The cannabinoid type 1 (CB1) receptor, a central component of the eCB system, is predominantly found at the synapses of two opposing neuronal populations, i.e. on inhibitory GABAergic and excitatory glutamatergic neurons. In the present study, using different transgenic mouse lines, we aimed at investigating the impact of CB1 receptor inactivation in glutamatergic or GABAergic neurons on investigatory behaviour. We evaluated animate (interaction partner) and inanimate (object) exploratory behaviour in three different paradigms. We show that exploration was increased when CB1 receptor was deleted from cortical and striatal GABAergic neurons. No effect was observed when CB1 receptor was deleted specifically from dopamine receptor D1-expressing striatal GABAergic medium spiny neurons. In contrast, deletion of CB1 receptor from cortical glutamatergic neurons resulted in a decreased exploration. Thus, our results indicate that exploratory behaviour is accurately balanced in both, the social and non-social context, by the eCB system via CB1 receptor activation on cortical glutamatergic and GABAergic neurons. In addition, the results could explain the contradictory findings of previous pharmacological studies and could further suggest a possibility to readjust an imbalance in exploratory behaviour observed in psychiatric disorders.

Morphological characterization of large intercalated neurons provides novel insight on intrinsic networks of the amygdala

Background Although extinction-based therapies are effective treatments for anxiety disorders, the neural bases of fear extinction remain still largely unclear. Recent evidence suggests that the intercalated cell masses of the amygdala (ITCs) are critical structures for fear expression and extinction. They consist of clusters of densely packed medium spiny GABAergic neurons surrounding the basolateral amygdaloid complex (BLA). Five percent of ITC neurons are large cells mostly present near the cluster borders. So far, no information is available regarding the neurochemical features, afferents and efferents of large ITC cells, preventing any elucidation of their functional role. Only recently we discovered that large ITC neurons display immunoreactivity for either neurokinin 1 or metabotropic glutamate 1a (mGlu1a) receptors. We also found that dendrites of these neurons receive inhibitory inputs from medial capsular projecting ITC cells [1]. The aim of our study consists in the characterization of the morphological features, as well as the afferent and efferent connectivity, of large ITC neurons in order to further clarify their potential participation in the neuronal processes underlying fear extinction.

Enhanced GABAergic tone in the ventral pallidum: memory of unpleasant experiences?

The nucleus accumbens (NAc) has emerged as an important part of the neural circuitry regulating depressive-like behaviors. Given that the NAc GABAergic medium spiny neurons project to the ventral pallidum (VP), it is reasonable to suggest that the VP may also be involved in these behaviors. Consequently, we explored the role of the VP GABAergic terminals during depressive-like behaviors in rats using the forced swim test (FST) and the sucrose preference test (SPT). Microdialysis coupled with micellar electrokinetic chromatography was used to monitor in vivo changes of GABA in the VP during the FST. GABA levels significantly increased during day-1 and day-2 during swimming, returning to the pre-swimming levels after the test. Basal concentrations of GABA on day-2 of the FST significantly increased with respect to day-1. In another set of experiments, intra-VP injections of vigabatrin (a GABA transaminase inhibitor) increased extracellular GABA and immobility behaviors in the FST while the direct GABAA receptor antagonist bicuculline reduced immobility behaviors. In the SPT, intra-VP vigabatrin injection significantly reduced preference for sucrose while bicuculline did not produce any change. At the postsynaptic side, we used semiquantitative RT-PCR to measure mRNA expression of 17 GABAA receptor subunits (α1-α6, β1-β3, γ2, δ, ε, θ, π, and ρ1-ρ3) in rats subjected to the FST. We found a significant reduction of α3 and γ2 subunit expression and an increase of δ subunit expression after day-2 in rats subject to the FST which might enhance tonic inhibition of the VP. Furthermore, immunoblot experiments revealed that protein expression of γ2 and δ subunits changed 6 days after FST in a way similar to mRNA expression. These results suggest that the enhanced VP-GABAergic tone might trigger a low motivational state, anhedonia and a possible memory mechanism for unpleasant experiences.

Functional changes in postsynaptic adenosine A 2A receptors during early stages of a rat model of Huntington disease

Huntington disease (HD) is a neurodegenerative disorder involving preferential loss of striatal GABAergic medium spiny neurons. Adenosine A 2A receptors (A 2ARs) are present in the striatum at both presynaptic and post-synaptic levels. Blocking pre-synaptic A 2ARs, localized in glutamatergic terminals that contact striatal GABAergic dynorphinergic neurons, reduces glutamate release, which could be beneficial in HD. On the other hand, blockade of post-synaptic A 2ARs, localized in striatal GABAergic enkephalinergic neurons, could exacerbate the motor dysfunction. To evaluate the function of pre- or post-synaptic A 2ARs in HD we used selective antagonists for these receptors in a transgenic rat model of HD. Locomotor activity after systemic administration of the postsynaptic A 2AR antagonist KW-6002 was used to investigate the function of post-synaptic A 2ARs. The role of pre-synaptic A 2ARs was instead evaluated by measuring the reduction of the electromyographic response of mastication muscles during electrical stimulation of the orofacial motor cortex after the systemic administration of the presynaptic A 2AR antagonist SCH-442416. The ability of KW-6002 to produce locomotor activation was lost at 6 and 12 month-old of age in heterozygous and homozygous transgenic rats, but not in wild-type littermates. Nevertheless, no significant changes were observed up to 12 months of age in the potency of SCH-442416 to decrease the electromyographic response after cortical electrical stimulation. These results agree with a selective impairment of the striatal GABAergic enkephalinergic neuronal function during pre-symptomatic stages in HD. Since presynaptic A 2AR function is not impaired, this receptor could probably be used as a target for the symptomatic treatment of the disease.

GABAergic Neurons from Mouse Embryonic Stem Cells Possess Functional Properties of Striatal Neurons In Vitro, and Develop into Striatal Neurons In Vivo in a Mouse Model of Huntington’s Disease

Huntington's disease (HD) is a neurodegenerative disease where GABAergic medium spiny neurons (MSNs) in the striatum degenerate. Embryonic stem cell-derived neural transplantation may provide an appropriate therapy for HD. Here we aimed to develop a suitable protocol to obtain a high percentage of functional GABAergic neurons from mouse embryonic stem cells (mESCs), and then tested their differentiation potential in vivo. The monolayer method was compared with the embryoid body and five stage method for its efficiency in generating GABAergic neurons from mESCs. All three methods yielded a similar percentage of GABAergic neurons from mESCs. Monolayer method-derived GABAergic neurons expressed the MSN marker dopamine- and cyclic AMP-regulated phosphoprotein (DARPP32). The pluripotent stem cell population could be eliminated in vitro by treating cells with puromycin and retinoic acid. Using patch-clamp recordings, the functional properties of GABAergic neurons derived from mESCs were compared to GABAergic neurons derived from primary lateral ganglionic eminence. Both types of neurons showed active membrane properties (voltage-gated Na(+) and K(+) currents, Na(+)-dependent action potentials, and spontaneous postsynaptic currents) and possessed functional glutamatergic receptors and transporters. mESC-derived neural progenitors were transplanted into a mouse model of HD. Grafted cells differentiated to mature neurons expressing glutamate decarboxylase, dopamine type 1 receptors, and DARPP32. Also, neural precursors and dividing populations were found in the grafts. In summary, mESCs are able to differentiate efficiently into functional GABAergic neurons using defined in vitro conditions, and these survive and differentiate following grafting to a mouse model of HD.

Striatal cellular properties conserved from lampreys to mammals

The striatum of the lamprey, the first vertebrate group to appear in evolution, shows striking similarities to that of mammals with respect to histochemical markers, afferent and efferent projections and the effect of dopamine depletion, which leads to hypokinetic motor symptoms. The cellular properties of lamprey striatal neurons were studied here using patch-clamp recordings in acute striatal slices. Sixty-five per cent of recorded neurons were characterised by a prominent inward rectification due to a K+ conductance of the Kir type. They had a ramping response with a long delay to the first action potential due to activation of a low-voltage-activated A-type K+ current. Many such inwardly rectifying neurons (IRNs) had a hyperpolarised resting membrane potential and some had spiny dendrites. The remaining 35% of the neurons (non-IRNs) represent a heterogeneous group, including some with characteristics similar to the fast-spiking interneuron of the mammalian striatum. They showed short-lasting, large after hyperpolarisations (AHPs) and discharged action potentials at high frequency. None of the recorded neurons were spontaneously active but they received GABAergic and glutamatergic synaptic input. The fact that most lamprey striatal neurons display inward rectification indicates that this is a conserved characteristic of striatal neurons throughout vertebrate phylogeny. This is a cellular property of critical importance for the operations of the striatum in mammals.

Effects of Dopamine and Glutamate on Synaptic Plasticity: A Computational Modeling Approach for Drug Abuse as Comorbidity in Mood Disorders

Major depressive disorder (MDD) affects about 16% of the general population and is a leading cause of death in the United States and around the world. Aggravating the situation is the fact that "drug use disorders" are highly comorbid in MDD patients, and VICE VERSA. Drug use and MDD share a common component, the dopamine system, which is critical in many motivation and reward processes, as well as in the regulation of stress responses in MDD. A potentiating mechanism in drug use disorders appears to be synaptic plasticity, which is regulated by dopamine transmission. In this article, we describe a computational model of the synaptic plasticity of GABAergic medium spiny neurons in the nucleus accumbens, which is critical in the reward system. The model accounts for effects of both dopamine and glutamate transmission. Model simulations show that GABAergic medium spiny neurons tend to respond to dopamine stimuli with synaptic potentiation and to glutamate signals with synaptic depression. Concurrent dopamine and glutamate signals cause various types of synaptic plasticity, depending on input scenarios. Interestingly, the model shows that a single 0.5 mg/kg dose of amphetamine can cause synaptic potentiation for over 2 h, a phenomenon that makes synaptic plasticity of medium spiny neurons behave quasi as a bistable system. The model also identifies mechanisms that could potentially be critical to correcting modifications of synaptic plasticity caused by drugs in MDD patients. An example is the feedback loop between protein kinase A, phosphodiesterase, and the second messenger cAMP in the postsynapse. Since reward mechanisms activated by psychostimulants could be crucial in establishing addiction comorbidity in patients with MDD, this model might become an aid for identifying and targeting specific modules within the reward system and lead to a better understanding and potential treatment of comorbid drug use disorders in MDD.

Dissecting Inhibitory Control of Striatal Projection Neurons

Event Abstract Back to Event Dissecting Inhibitory Control of Striatal Projection Neurons Damodaran Sriraman1* and Kim Blackwell1 1 George Mason University, United States The striatum is the main input nucleus of the basal ganglia and is involved in processing inputs from the cortex and thalamus. This processing is carried out by GABAergic medium spiny projection neurons (MSPN) that comprise 90-95% of the neuronal population in the rodent striatum (Bolam and Bennett, 1993). These neurons project to the basal ganglia output structures, the globus pallidus and substantia nigra; therefore understanding striatal processing will help elucidate further the factors affecting basal ganglia function. GABAergic inhibition plays a very important role in the modulation of the MSPN network (Tepper et al., 2008). Among the different GABAergic interneurons in the striatum, the fast-spiking interneurons (FSIs) provide strong feedforward inhibition of the MSPNs (Koos & Tepper, 1999; Tepper et al., 2008), whereas MSPNs provide widespsread but weak feedback inhibition of each other. The FSIs are interconnected through electrical synapses/gap junctions (Galarreta and Hestrin, 2001) and GABAergic synapses (Gittis et al., 2010). It has been hypothesized that gap junctions are involved in coordinating synchronous activity in populations of the MSPN network (Berke et al., 2004, Galarreta and Hestrin, 2002). However, recent experiments (Berke, 2008) suggest that FSIs do not fire synchronously, and recent simulations (Hjorth et al., 2009) have shown that gap junctions alone are not sufficient to synchronize FSI network activity in the striatum, except transiently in response to synchronous cortical activity. The function of the widespread but weak feedback loop of the MSPNs is also not clear (Plenz, 2002). The present study constructs a network of the realistic multi-compartmental model MSPNs receiving both realistic synaptic input from a model FSI network and simulated input trains from the cortex. The FSI network, which also receives cortical input trains, is connected by both gap junctions (Hjorth et al., 2009) and chemical synapses (Gittis et al., 2010). The simulations address the role of chemical synapses and gap junctions in the FSI network in controlling activity in the MSPN network of the striatum. The simulations also parse out the contributions of the feedforward and feedback connections on the MSN output thus addressing the functional contribution of each type of connection to the network activity. Keywords: computational neuroscience Conference: 4th INCF Congress of Neuroinformatics, Boston, United States, 4 Sep - 6 Sep, 2011. Presentation Type: Poster Presentation Topic: Computational neuroscience Citation: Sriraman D and Blackwell K (2011). Dissecting Inhibitory Control of Striatal Projection Neurons. Front. Neuroinform. Conference Abstract: 4th INCF Congress of Neuroinformatics. doi: 10.3389/conf.fninf.2011.08.00031 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 17 Oct 2011; Published Online: 19 Oct 2011. * Correspondence: Dr. Damodaran Sriraman, George Mason University, Fairfax, United States, dsriraman@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Damodaran Sriraman Kim Blackwell Google Damodaran Sriraman Kim Blackwell Google Scholar Damodaran Sriraman Kim Blackwell PubMed Damodaran Sriraman Kim Blackwell Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Huntington's Disease: Effect of Memantine on FDG-PET Brain Metabolism?

In this open-label pilot study, the authors evaluated the effect of memantine on the distribution of brain glucose metabolism in four Huntington's disease (HD) patients as determined by serial 18-fluoro-deoxyglucose [F(18)]FDG-PET scans over a period of 3-4 months (90-129 days, with one patient choosing to continue treatment over the 18-month follow-up period). The treatment regimen was well tolerated. No significant differences on neuropsychological parameters before and after treatment were detected; but the patient who continued treatment did not deteriorate at 18 months' reevaluation, whereas the three patients who had stopped treatment after 3 to 4 months had minor progression in all cognitive domains on re-evaluation 12 months after the end of treatment.

Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease

Caused by a polyglutamine expansion in the huntingtin protein, Huntington's disease leads to striatal degeneration via the transcriptional dysregulation of a number of genes, including those involved in mitochondrial biogenesis. Here we show that transglutaminase 2, which is upregulated in HD, exacerbates transcriptional dysregulation by acting as a selective corepressor of nuclear genes; transglutaminase 2 interacts directly with histone H3 in the nucleus. In a cellular model of HD, transglutaminase inhibition de-repressed two established regulators of mitochondrial function, PGC-1α and cytochrome c and reversed susceptibility of human HD cells to the mitochondrial toxin, 3-nitroproprionic acid; however, protection mediated by transglutaminase inhibition was not associated with improved mitochondrial bioenergetics. A gene microarray analysis indicated that transglutaminase inhibition normalized expression of not only mitochondrial genes but also 40% of genes that are dysregulated in HD striatal neurons, including chaperone and histone genes. Moreover, transglutaminase inhibition attenuated degeneration in a Drosophila model of HD and protected mouse HD striatal neurons from excitotoxicity. Altogether these findings demonstrate that selective TG inhibition broadly corrects transcriptional dysregulation in HD and defines a novel HDAC-independent epigenetic strategy for treating neurodegeneration.

Selective Activation of Striatal Fast-Spiking Interneurons during Choice Execution

Basal ganglia circuits are essential for the organization and execution of voluntary actions. Within the striatum, fast-spiking interneurons (FSIs) are thought to tightly regulate the activity of medium-spiny projection neurons (MSNs) through feed-forward inhibition, yet few studies have investigated the functional contributions of FSIs in behaving animals. We recorded presumed MSNs and FSIs together with motor cortex and globus pallidus (GP) neurons, in rats performing a simple choice task. MSN activity was widely distributed across the task sequence, especially near reward receipt. By contrast, FSIs showed a coordinated pulse of increased activity as chosen actions were initiated, in conjunction with a sharp decrease in GP activity. Both MSNs and FSIs were direction selective, but neighboring MSNs and FSIs showed opposite selectivity. Our findings suggest that individual FSIs participate in local striatal information processing, but more global disinhibition of FSIs by GP is important for initiating chosen actions while suppressing unwanted alternatives.

Sequentially Switching Cell Assemblies in Random Inhibitory Networks of Spiking Neurons in the Striatum

The striatum is composed of GABAergic medium spiny neurons with inhibitory collaterals forming a sparse random asymmetric network and receiving an excitatory glutamatergic cortical projection. Because the inhibitory collaterals are sparse and weak, their role in striatal network dynamics is puzzling. However, here we show by simulation of a striatal inhibitory network model composed of spiking neurons that cells form assemblies that fire in sequential coherent episodes and display complex identity-temporal spiking patterns even when cortical excitation is simply constant or fluctuating noisily. Strongly correlated large-scale firing rate fluctuations on slow behaviorally relevant timescales of hundreds of milliseconds are shown by members of the same assembly whereas members of different assemblies show strong negative correlation, and we show how randomly connected spiking networks can generate this activity. Cells display highly irregular spiking with high coefficients of variation, broadly distributed low firing rates, and interspike interval distributions that are consistent with exponentially tailed power laws. Although firing rates vary coherently on slow timescales, precise spiking synchronization is absent in general. Our model only requires the minimal but striatally realistic assumptions of sparse to intermediate random connectivity, weak inhibitory synapses, and sufficient cortical excitation so that some cells are depolarized above the firing threshold during up states. Our results are in good qualitative agreement with experimental studies, consistent with recently determined striatal anatomy and physiology, and support a new view of endogenously generated metastable state switching dynamics of the striatal network underlying its information processing operations.

Input dependent population dynamics in a model of the inhibitory spiking network of medium spiny neurons in the striatum.

Event Abstract Back to Event Input dependent population dynamics in a model of the inhibitory spiking network of medium spiny neurons in the striatum. A. Ponzi1* and J. Wickens1 1 OIST, Japan We investigate a model of an inhibitory spiking network of striatal GABAergic medium spiny neurons (MSN) by computer simulation. We show that the network exhibits complex spatial temporal population dynamics produced by the occurrence of episodically firing cell assemblies even when the inputs from the excitatory cortical cells are composed of many independent Poisson spiking processes, providing the excitatory inputs obey certain conditions. We also show that cell assembly dynamics can occur for several different choices of MSN cell model and is thus a network generated property, while details of MSN cell spiking statistics do depend on the cell model. When cell input firing rates are dynamically variable we show the network can display input dependent population dynamics and investigate how this depends on excitatory input parameters and also on inhibitory network parameters such as connectivity. We discuss how our results may relate to striatal cognitive functions in behavioural tasks. Conference: EMBO workshop: Gaba Signalling and Brain Networks , Amsterdam, Netherlands, 30 Jun - 2 Jul, 2010. Presentation Type: Poster Presentation Topic: Posters Citation: Ponzi A and Wickens J (2010). Input dependent population dynamics in a model of the inhibitory spiking network of medium spiny neurons in the striatum.. Conference Abstract: EMBO workshop: Gaba Signalling and Brain Networks . doi: 10.3389/conf.fnins.2010.15.00018 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 24 Jun 2010; Published Online: 24 Jun 2010. * Correspondence: A. Ponzi, OIST, Okinawa, Japan, aponz1@oist.jp Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers A. Ponzi J. Wickens Google A. Ponzi J. Wickens Google Scholar A. Ponzi J. Wickens PubMed A. Ponzi J. Wickens Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Substance P selectively modulates GABAA receptor-mediated synaptic transmission in striatal cholinergic interneurons

Substance P (SP) is co-localized and co-released with gamma-amino butyric acid (GABA) from approximately 50% of GABAergic medium spiny neurons (MSNs) in the striatum. MSNs innervate several cellular targets including neighboring MSNs and cholinergic interneurons via collaterals. However, the functional role of SP release onto striatal interneurons is unknown. Here we examined SP-mediated actions on inhibitory synaptic transmission in cholinergic interneurons using whole-cell recordings in mouse corticostriatal slices. We found that SP selectively suppressed GABA(A) receptor-mediated inhibitory post-synaptic currents (IPSCs), but not excitatory post-synaptic currents (EPSCs) in cholinergic interneurons. In contrast, SP did not alter IPSCs in fast-spiking interneurons and MSNs. SP suppressed IPSC amplitude in a concentration-dependent and reversible manner, and the NK1 receptor antagonist RP67580 attenuated the SP-mediated suppression. In addition, RP67580 alone enhanced the evoked IPSC amplitude in cholinergic interneurons, suggesting an endogenous action of SP on regulation of inhibitory synaptic transmission. SP did not alter the paired-pulse ratio, but reduced the amplitudes of GABA(A) agonist muscimol-induced outward currents and miniature IPSCs in cholinergic interneurons, suggesting SP exerts its effects primarily at the post-synaptic site. Our results indicate that the physiological effects of SP are to enhance the activity of striatal cholinergic interneurons and provide a rationale for designing potential new antiparkinsonian agents.

Homeostatic plasticity in a reward processing region: accumbens neurons scale too! (Commentary on Sun & Wolf)

There is an expanding literature that supports the idea that several aspects of addiction to drugs of abuse are behavioral expressions of pathological forms of learning and memory coded in brain circuits involved in reward processing. At a cellular level, it has now been well demonstrated that several drugs of abuse interfere with synaptic plasticity mechanisms in reward regions and thereby influence their function (Wolf et al., 2004; Kauer & Malenka, 2007). In this context, it is relevant to emphasize that whereas LTP and LTD, the two most studied forms of synaptic plasticity, are widely viewed as cellular models of learning and memory, it is also well appreciated that their implementation in neuronal network models carries an inherent stability problem (Turrigiano, 2008). The phenomenon of homeostatic synaptic scaling (O’Brien et al., 1998; Turrigiano et al., 1998) satisfactorily solves many of the issues related to this problem and has thus triggered considerable interest. This plasticity refers to the bi-directional ability of the overall synaptic strength of a neuron to actively compensate for changes in overall excitability levels, presumably to maintain firing rates within an optimal range (Davis, 2006; Turrigiano, 2008). Although homeostatic scaling can intuitively be expected to be found in all circuits where LTP and LTD are operative, including reward processing circuits, we still have an incomplete understanding of the degree of universality of this mechanism in the brain. Also, if such a mechanism were operant in brain reward circuits, would drugs of abuse affect it? If so, by what mechanisms? The study of Sun & Wolf (2009) published in this issue of EJN provides interesting progress along these lines. To begin addressing these questions, the authors sought to determine whether neurons of the nucleus accumbens in an in vitro culture preparation exhibit the core features of homeostatic synaptic scaling. This nucleus, an intricate part of the brain reward pathway implicated in addiction, is overwhelmingly composed of GABAergic medium spiny projection neurons and receives a strong dopaminergic input from the ventral tegmentum area. Experimentally, this network architecture brings an inherent complication for in vitro culture preparation as this structure does not provide an intrinsic glutamatergic drive required for the establishment of functional networks. To circumvent this issue, the authors used a clever co-culture system where accumbens neurons were co-cultured with prefrontal cortex pyramidal neurons (which provide strong excitatory input to accumbens neurons in situ). Using this system, the authors blocked synaptic activity for prolonged periods of time using pharmacological tools and observed a robust compensatory upregulation of surface expression of AMPA receptors (AMPARs), the hallmark of synaptic scaling. Importantly, this synaptic scaling in accumbens neurons was bi-directional, as increases in network activity lead to a reduction of surface expression of AMPARs. As such, these findings show that accumbens neurons, like cortical and spinal neurons, exhibit robust homeostatic synaptic scaling. The authors further worked out some interesting molecular details of this phenomenon. In an attempt to broadly recapitulate in a culture system the conditions of chronic cocaine use, the authors administered repeated dopamine treatments over several days (which is known to enhance surface expression of AMPARs; Wolf et al., 2004) before the scaling challenge. Intriguingly, the dopamine-induced increase in AMPAR expression occluded that induced by scaling challenge. The presence of an occlusion between two phenomena is usually interpreted as indicating some level of commonality between their expression mechanisms. It is possible that there might be fixed upper and lower limits of synaptic strength that cannot be surpassed by the scaling process, and that would be maximized by the dopamine treatment. The outcome of this interplay on overall network function at this point is unclear, so is its pathological role. Extrapolating a little, would cocaine essentially hijack the scaling process? Would it, in effect, modulate its dynamic range? Its gain? Regardless of these mechanistic minutiae that await clarification, this study of Sun & Wolf (2009) firmly establishes the presence of synaptic scaling in a brain region involved in reward and hints that drugs of abuse, like cocaine, may adversely affect its function. Altogether, just as we are trying to understand the computational features of the interaction between homeostatic synaptic scaling and classic synaptic plasticity that are relevant for information storage, this study shows that this challenge likely equally applies to our quest to understand the neural basis of addiction.

Cannabinoid (CB 1), GABA A and GABA B receptor subunit changes in the globus pallidus in Huntington's disease

Huntington's disease (HD) is a disease of the basal ganglia which results in a major loss of the striatal GABAergic medium spiny neurons containing enkephalin and substance P. These neurons project principally to the globus pallidus (GP) and substantia nigra pars reticulata (SNr). Both GABA A and GABA B receptors are localised postsynaptically on neurons in the GP and SNr, and cannabinoid (CB 1) receptors are localised presynaptically on the axon terminals of the medium spiny projection neurons in the GP and SNr. The aims of this project were to investigate the changes in the distribution of CB 1, GABA A, and GABA B receptor subunits, as well as enkephalin and substance P in the GP in the HD brain compared to the normal brain. The results of this study have shown firstly, that in the HD brain there is a dramatic loss of enkephalin and CB 1 receptor immunoreactivity (IR) in the external segment of the globus pallidus (GPe) and a major loss of substance P and CB 1 receptor-IR from the internal segment of the globus pallidus (GPi). Secondly, the degeneration of these striatal efferent neurons results in the upregulation of the various subunits of both GABA A (α 1, β 2,3 and γ 2) and GABA B (R 1) receptors in the GP in HD. Detailed double labelling confocal microscopy studies show that in HD the increased GABA A and GABA B receptor-IR is distributed not just in punctate “synaptic” regions, but throughout all dendritic and somal membranes of pallidal neurons. These results provide the first comprehensive description of the changes of CB 1, GABA A and GABA B receptor subunits in the HD basal ganglia. The upregulation of both GABA A and GABA B receptors may serve to increase the sensitivity of pallidal neurons to the decreased levels of GABA that occurs in the GP in HD. The loss of CB 1 receptors in HD is also thought to be a compensatory mechanism due to evidence that endocannabinoids modulate the reuptake of GABA in the GP. These findings show the high degree of plasticity of CB 1, GABA A and GABA B receptors and provide a better understanding of the GABAergic modulation of basal ganglia neurons in the normal and diseased human brain.