A short duration GABAergic inhibition in identified neostriatal medium spiny neurons: In vitro slice study

Radnikow, Gabriele, Jutta Rohrbacher, and Ulrich Misgeld. Heterogeneity in use-dependent depression of inhibitory postsynaptic potentials in the rat neostriatum in vitro. J. Neurophysiol. 77: 427–434, 1997. “Minimal stimulation” was applied to evoke responses in an “all-or-none” fashion in presumed medium spiny neurons of rat neostriatal slices in the presence of antagonists for glutamatergic excitation. For comparison, responses were evoked in the same cells by compound stimulation. Bicuculline (30 μM) blocked responses evoked by minimal stimulation, indicating that they were γ-aminobutyric acid-A (GABAA)-receptor-mediated inhibitory postsynaptic potentials (IPSPs), whereas responses evoked by compound stimulation were only reduced in amplitude. Likewise, R(−)baclofen (1–20 μM) blocked IPSPs evoked by minimal stimulation in all but one cell. On the contrary, responses evoked by compound stimulation were always reduced in amplitude but never blocked. Paired-pulse depression (PPD) of averaged responses to minimal and compound stimulation was observed at a stimulus interval of 300 ms. The GABAB receptor antagonist CGP55845A (0.5 μM) had no effect on PPD evoked by compound stimulation but abolished PPD evoked by minimal stimulation. In a second set of experiments, the two stimulation paradigms were used to evoke responses in neostriatal slices continuously bathed in R(−)baclofen (10–20 μM). In R(−)baclofen a strong PPD was evoked by minimal and by compound stimulation. The amplitude of the response to compound stimulation increased on application of CGP55845A (0.5 μM). At the same time, PPD evoked by compound stimulation decreased. On the contrary, IPSP amplitude and PPD evoked by minimal stimulation remained unchanged. We conclude that two types of GABAergic terminals exist in the rat neostriatum, only one of which is regulated by GABAB receptors. However, the other class of terminals, not regulated by GABAB receptors, displays a much more pronounced PPD.

Download Full-text

Brain-derived neurotrophic factor regulates maturation of the DARPP-32 phenotype in striatal medium spiny neurons: studies in vivo and in vitro

Neuroscience ◽

10.1016/s0306-4522(96)00684-7 ◽

1997 ◽

Vol 79 (2) ◽

pp. 509-516 ◽

Cited By ~ 54

Author(s):

S Ivkovic ◽

O Polonskaia ◽

I Fariñas ◽

M.E Ehrlich

Keyword(s):

Neurotrophic Factor ◽

Brain Derived Neurotrophic Factor ◽

Medium Spiny Neurons ◽

Spiny Neurons

Download Full-text

The difficulty to model Huntington’s disease in vitro using striatal medium spiny neurons differentiated from human induced pluripotent stem cells

Scientific Reports ◽

10.1038/s41598-021-85656-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kim Le Cann ◽

Alec Foerster ◽

Corinna Rösseler ◽

Andelain Erickson ◽

Petra Hautvast ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Neurodegenerative Disorder ◽

Induced Pluripotent Stem Cell ◽

Medium Spiny Neurons ◽

Striatal Neurons ◽

Large Variability ◽

Spiny Neurons ◽

Induced Pluripotent

AbstractHuntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded polyglutamine repeat in the huntingtin gene. The neuropathology of HD is characterized by the decline of a specific neuronal population within the brain, the striatal medium spiny neurons (MSNs). The origins of this extreme vulnerability remain unknown. Human induced pluripotent stem cell (hiPS cell)-derived MSNs represent a powerful tool to study this genetic disease. However, the differentiation protocols published so far show a high heterogeneity of neuronal populations in vitro. Here, we compared two previously published protocols to obtain hiPS cell-derived striatal neurons from both healthy donors and HD patients. Patch-clamp experiments, immunostaining and RT-qPCR were performed to characterize the neurons in culture. While the neurons were mature enough to fire action potentials, a majority failed to express markers typical for MSNs. Voltage-clamp experiments on voltage-gated sodium (Nav) channels revealed a large variability between the two differentiation protocols. Action potential analysis did not reveal changes induced by the HD mutation. This study attempts to demonstrate the current challenges in reproducing data of previously published differentiation protocols and in generating hiPS cell-derived striatal MSNs to model a genetic neurodegenerative disorder in vitro.

Download Full-text

B02 A new in vivo and in vitro single-cell atlas of developing medium spiny neurons to guide future improvements for huntington disease cell-replacement therapies and disease modelling

10.1136/jnnp-2021-ehdn.22 ◽

2021 ◽

Author(s):

Vittoria Bocchi ◽

Paola Conforti ◽

Ilaria Campus ◽

Dario Besusso ◽

Elena Cattaneo

Keyword(s):

Single Cell ◽

Huntington Disease ◽

Disease Modelling ◽

Medium Spiny Neurons ◽

Cell Replacement ◽

Spiny Neurons ◽

Disease Cell

Download Full-text

Excitation of medium spiny neurons by ‘inhibitory’ ultrapotent chemogenetics via shifts in chloride reversal potential

eLife ◽

10.7554/elife.64241 ◽

2021 ◽

Vol 10 ◽

Author(s):

Stephanie C Gantz ◽

Maria M Ortiz ◽

Andrew J Belilos ◽

Khaled Moussawi

Keyword(s):

Brain Slices ◽

Reversal Potential ◽

Cell Types ◽

Receptor Activation ◽

D1 Receptor ◽

Medium Spiny Neurons ◽

Inhibitory Function ◽

Spiny Neurons

Ultrapotent chemogenetics, including the chloride-permeable inhibitory PSAM4-GlyR receptor, were recently proposed as a powerful strategy to selectively control neuronal activity in awake, behaving animals. We aimed to validate the inhibitory function of PSAM4-GlyR in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) in the ventral striatum. Activation of PSAM4-GlyR with the uPSEM792 ligand enhanced rather than suppressed the activity of D1-MSNs in vivo as indicated by increased c-fos expression in D1-MSNs and in vitro as indicated by cell-attached recordings from D1-MSNs in mouse brain slices. Whole-cell recordings showed that activation of PSAM4-GlyR depolarized D1-MSNs, attenuated GABAergic inhibition, and shifted the reversal potential of PSAM4-GlyR current to more depolarized potentials, perpetuating the depolarizing effect of receptor activation. These data show that ‘inhibitory’ PSAM4-GlyR chemogenetics may activate certain cell types and highlight the pitfalls of utilizing chloride conductances to inhibit neurons.

Download Full-text