Neuregulin-4 Is Required for the Growth and Elaboration of Striatal Medium Spiny Neuron Dendrites

Abstract Medium spiny neurons (MSNs) comprise the vast majority of neurons in the striatum. Changes in the exuberant dendrites of these widely connected neurons are associated with a multitude of neurological conditions and are caused by a variety of recreational and medicinal drugs. However, we have a poor understanding of the physiological regulators of dendrite growth and elaboration of this clinically important population of neurons. Here, we show that MSN dendrites are markedly smaller and less branched in neonatal mice that possess a homozygous null mutation in the neuregulin-4 gene (Nrg4−/−) compared with wild type (Nrg4+/+) littermates. Nrg4−/− mice also had a highly significant reduction in MSN dendrite spine number in neonates and adults. The striking stunted dendrite arbor phenotype of MSNs observed in Nrg4−/− neonates was replicated in MSNs cultured from Nrg4−/− embryos and was completely rescued by soluble recombinant neuregulin-4. MSNs cultured from wild type mice coexpressed NRG4 and its receptor ErbB4. Our findings show that NRG4 is a major novel regulator of dendritic growth and arborization and spine formation in the striatum and suggest that it exerts its effects by an autocrine/paracrine mechanism.

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Levodopa-Induced Dyskinesia Is Related to Indirect Pathway Medium Spiny Neuron Excitotoxicity: A Hypothesis Based on an Unexpected Finding

Parkinson s Disease ◽

10.1155/2016/6461907 ◽

2016 ◽

Vol 2016 ◽

pp. 1-5 ◽

Cited By ~ 3

Author(s):

Svetlana A. Ivanova ◽

Anton J. M. Loonen

Keyword(s):

Oxidative Stress ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Age Of Onset ◽

Medium Spiny Neuron ◽

Synaptic Membrane ◽

Medium Spiny Neurons ◽

Unexpected Finding ◽

Indirect Pathway ◽

Spiny Neurons

A serendipitous pharmacogenetic finding links the vulnerability to developing levodopa-induced dyskinesia to the age of onset of Huntington’s disease. Huntington’s disease is caused by a polyglutamate expansion of the protein huntingtin. Aberrant huntingtin is less capable of binding to a member of membrane-associated guanylate kinase family (MAGUKs): postsynaptic density- (PSD-) 95. This leaves more PSD-95 available to stabilize NR2B subunit carrying NMDA receptors in the synaptic membrane. This results in increased excitotoxicity for which particularly striatal medium spiny neurons from the indirect extrapyramidal pathway are sensitive. In Parkinson’s disease the sensitivity for excitotoxicity is related to increased oxidative stress due to genetically determined abnormal metabolism of dopamine or related products. This probably also increases the sensitivity of medium spiny neurons for exogenous levodopa. Particularly the combination of increased oxidative stress due to aberrant dopamine metabolism, increased vulnerability to NMDA induced excitotoxicity, and the particular sensitivity of indirect pathway medium spiny neurons for this excitotoxicity may explain the observed increased prevalence of levodopa-induced dyskinesia.

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Pitx3 Deficiency in Mice Affects Cholinergic Modulation of GABAergic Synapses in the Nucleus Accumbens

Journal of Neurophysiology ◽

10.1152/jn.00333.2006 ◽

2006 ◽

Vol 96 (4) ◽

pp. 2034-2041 ◽

Cited By ~ 2

Author(s):

Mischa de Rover ◽

Johannes C. Lodder ◽

Marten P. Smidt ◽

Arjen B. Brussaard

Keyword(s):

Nucleus Accumbens ◽

Medium Spiny Neurons ◽

Wild Type ◽

Cholinergic Modulation ◽

Firing Patterns ◽

Neural Adaptations ◽

Cholinergic Interneurons ◽

Spiny Neurons ◽

Gating Mechanism ◽

Deficient Mice

We investigated to what extent Pitx3 deficiency, causing hyperdopaminergic transmission in the nucleus accumbens microcircuitry, may lead to developmental changes. First, spontaneous firing activity of cholinergic interneurons in the nucleus accumbens was recorded in vitro. Firing patterns in the Pitx3-deficient mice were more variable and intrinsically different from those observed in wild-type mice. Next, to test whether the irregular firing patterns observed in mutant mice affected the endogenous nicotinic modulation of the GABAergic input of medium spiny neurons, we recorded spontaneous GABAergic inputs to these cells before and after the application of the nicotinic receptor blocker mecamylamine. Effects of mecamylamine were found in slices of either genotype, but in a rather inconsistent manner. Possibly this was attributable to heterogeneity in firing of nearby cholinergic interneurons. Thus paired recordings of cholinergic interneurons and medium spiny neurons were performed to more precisely control the experimental conditions of the cholinergic modulation of GABAergic synaptic transmission. We found that controlling action potential firing in cholinergic neurons leads to a conditional increase in GABAergic input frequency in wild-type mice but not in Pitx3-deficient mice. We conclude that Pitx3-deficient mice have neural adaptations at the level of the nucleus accumbens microcircuitry that in turn may have behavioral consequences. It is discussed to what extent dopamine release in the nucleus accumbens may be a long-term gating mechanism leading to alterations in cholinergic transmission in the nucleus accumbens, in line with previously reported neural adaptations found as consequences of repeated drug treatment in rodents.

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Dopaminergic Modulation of Excitatory Postsynaptic Currents in Rat Neostriatal Neurons

Journal of Neurophysiology ◽

10.1152/jn.1997.78.3.1248 ◽

1997 ◽

Vol 78 (3) ◽

pp. 1248-1255 ◽

Cited By ~ 73

Author(s):

Masashi Umemiya ◽

Lynn A. Raymond

Keyword(s):

Dopamine Receptor ◽

Glutamate Receptor ◽

Skf 38393 ◽

Medium Spiny Neuron ◽

Medium Spiny Neurons ◽

Excitatory Postsynaptic Currents ◽

Epsc Amplitude ◽

Postsynaptic Currents ◽

Spiny Neurons ◽

Dopaminergic Modulation

Umemiya, Masashi and Lynn A. Raymond. Dopaminergic modulation of excitatory postsynaptic currents in rat neostriatal neurons. J. Neurophysiol. 78: 1248–1255, 1997. γ-aminobutyric acid (GABA)-containing medium spiny neurons constitute ∼90% of the neuronal population in the neostriatum (caudate and putamen) and play an important role in motor programming. Cortical glutamatergic afferents provide the main excitatory drive for these neurons, whereas nigral dopaminergic neurons play a crucial role in regulating their activity. To further investigate the mechanisms underlying the dopaminergic modulation of medium spiny neuronal activity, we tested the effect of dopamine receptor agonists on excitatory synaptic transmission recorded from these neurons. Excitatory postsynaptic currents (EPSCs) were evoked by local stimulation and recorded from medium spiny neurons in postnatal rat striatal thin brain slices. Recordings were made using the whole cell patch-clamp technique under voltage clamp and conditions that selected for the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate- and kainate-type glutamate receptor-mediated components of the EPSC. Incubation of slices in 10 μM dopamine resulted in a 33 ± 11% (mean ± SE) decrease in the amplitude of evoked EPSCs, an effect that developed during seconds. The relative variability in amplitude of dopamine's effects on medium spiny neuron EPSCs may reflect activation of different receptor subtypes with opposing effects. In contrast to the results with dopamine, incubation of slices in SKF 38393, a D1-type dopamine receptor selective agonist, resulted in dose-dependent potentiation of the medium spiny neuron EPSC that developed during several minutes. At a concentration of 5 μM, SKF 38393 resulted in a 29 ± 4.5% increase in EPSC amplitude, an effect that was blocked by preincubation with the D1-selective antagonist, SCH 23390 (10 μM). On the other hand, 5 μM SKF 38393 had no apparent effect on medium spiny neuron currents activated by exogenous application of glutamate or kainate. However, because of the inherent limitations of rapid agonist perfusion in the brain slice preparation (caused by slow agonist diffusion and rapid glutamate receptor desensitization) and because of anatomic evidence that colocalizes D1 and glutamate receptors to medium spiny neuron dendrites, our results leave open the possibility that the effect of D1 receptor activation on the EPSC is mediated via modulation of postsynaptic glutamate receptor responsiveness. The significant potentiation by D1 receptor agonists of EPSC amplitude at the cortico-striatal medium spiny synapse that we observed, in part, may underlie the role of D1 receptors in facilitating medium spiny neuronal firing, with implications for understanding regulation of movement.

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Populations of striatal medium spiny neurons encode vibrotactile frequency in rats: modulation by slow wave oscillations

Journal of Neurophysiology ◽

10.1152/jn.00489.2012 ◽

2013 ◽

Vol 109 (2) ◽

pp. 315-320 ◽

Cited By ~ 4

Author(s):

Thomas G. Hawking ◽

Todor V. Gerdjikov

Keyword(s):

Slow Wave ◽

Stimulus Frequency ◽

Medium Spiny Neuron ◽

Brain State ◽

Projection Neurons ◽

Medium Spiny Neurons ◽

Population Responses ◽

Spiny Neurons ◽

Striatal Projection Neurons ◽

Slow Wave Oscillations

Dorsolateral striatum (DLS) is implicated in tactile perception and receives strong projections from somatosensory cortex. However, the sensory representations encoded by striatal projection neurons are not well understood. Here we characterized the contribution of DLS to the encoding of vibrotactile information in rats by assessing striatal responses to precise frequency stimuli delivered to a single vibrissa. We applied stimuli in a frequency range (45–90 Hz) that evokes discriminable percepts and carries most of the power of vibrissa vibration elicited by a range of complex fine textures. Both medium spiny neurons and evoked potentials showed tactile responses that were modulated by slow wave oscillations. Furthermore, medium spiny neuron population responses represented stimulus frequency on par with previously reported behavioral benchmarks. Our results suggest that striatum encodes frequency information of vibrotactile stimuli which is dynamically modulated by ongoing brain state.

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Cholinergic interneurons mediate cocaine extinction through similar plasticity across medium spiny neuron subtypes

10.1101/2021.08.29.458113 ◽

2021 ◽

Author(s):

Weston Fleming ◽

Junuk Lee ◽

Brandy A Briones ◽

Scott Bolkan ◽

Ilana B Witten

Keyword(s):

Nucleus Accumbens ◽

Natural Variation ◽

Medium Spiny Neuron ◽

Medium Spiny Neurons ◽

Cholinergic Interneurons ◽

Event Frequency ◽

Mediated Effects ◽

Spiny Neurons ◽

Cholinergic Signaling ◽

Opposing Effects

Cholinergic interneurons (ChINs) in the nucleus accumbens (NAc) have been implicated in the acquisition and extinction of drug associations, as well as related plasticity in medium spiny neurons (MSNs). However, since most previous work has relied on artificial manipulations, if and how endogenous patterns of cholinergic signaling relate to drug associations is unknown. Moreover, despite great interest in the opposing effects of dopamine on MSN subtypes, whether ChIN-mediated effects are similar or different across MSN subtypes is also unknown. Here, we find that endogenous acetylcholine event frequency during extinction negatively correlates with the strength and persistence of cocaine-context associations across individuals, consistent with effects of artificial manipulation of ChIN activity during extinction. Moreover, ChIN activation during extinction produces a reduction in excitatory synaptic strength on both MSN subtypes, similar to the effect of multiple extinction sessions in the absence of ChIN manipulations. Together, our findings indicate that natural variation in NAc acetylcholine may contribute to individual differences in drug-context extinction by modulating glutamatergic presynaptic strength similarly at both D1R and D2R MSN subtypes.

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Pyk2 Stabilizes Striatal Medium Spiny Neuron Structure and Striatal-Dependent Action

Cells ◽

10.3390/cells10123442 ◽

2021 ◽

Vol 10 (12) ◽

pp. 3442

Author(s):

Shannon L. Gourley ◽

Kolluru D. Srikanth ◽

Ellen P. Woon ◽

Hava Gil-Henn

Keyword(s):

Prefrontal Cortex ◽

Tyrosine Kinase ◽

Medial Prefrontal Cortex ◽

Viral Vector ◽

Medium Spiny Neuron ◽

Medium Spiny Neurons ◽

Behavioral Strategies ◽

Spiny Neurons ◽

Tyrosine Kinase 2 ◽

New Strategies

In day-to-day life, we often choose between pursuing familiar behaviors that have been rewarded in the past or adjusting behaviors when new strategies might be more fruitful. The dorsomedial striatum (DMS) is indispensable for flexibly arbitrating between old and new behavioral strategies. The way in which DMS neurons host stable connections necessary for sustained flexibility is still being defined. An entry point to addressing this question may be the structural scaffolds on DMS neurons that house synaptic connections. We find that the non-receptor tyrosine kinase Proline-rich tyrosine kinase 2 (Pyk2) stabilizes both dendrites and spines on striatal medium spiny neurons, such that Pyk2 loss causes dendrite arbor and spine loss. Viral-mediated Pyk2 silencing in the DMS obstructs the ability of mice to arbitrate between rewarded and non-rewarded behaviors. Meanwhile, the overexpression of Pyk2 or the closely related focal adhesion kinase (FAK) enhances this ability. Finally, experiments using combinatorial viral vector strategies suggest that flexible, Pyk2-dependent action involves inputs from the medial prefrontal cortex (mPFC), but not the ventrolateral orbitofrontal cortex (OFC). Thus, Pyk2 stabilizes the striatal medium spiny neuron structure, likely providing substrates for inputs, and supports the capacity of mice to arbitrate between novel and familiar behaviors, including via interactions with the medial-prefrontal cortex.

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