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

  1. Stephanie C Gantz  Is a corresponding author
  2. Maria M Ortiz
  3. Andrew J Belilos
  4. Khaled Moussawi  Is a corresponding author
  1. Department of Molecular Physiology and Biophysics, University of Iowa, United States
  2. Biological and Biomedical Neuroscience Program, University of North Carolina, United States
  3. National Institute on Drug Abuse, United States
  4. Department of Psychiatry, School of Medicine, University of Pittsburgh, United States
6 figures and 1 additional file

Figures

In vivo activation of PSAM4-GlyR enhances c-fos expression in D1-MSNs.

(A) Left, cartoon of viral injection site in the ventral striatum. Right, representative confocal images of Cre-dependent PSAM4-GlyR expression (eGFP) in Cre-expressing D1-MSNs (tdTomato). (B) …

Figure 1—source data 1

PSAM4-GlyR enhances c-fos expression in D1-MSNs in-vivo (source data).

https://cdn.elifesciences.org/articles/64241/elife-64241-fig1-data1-v1.xlsx
Activation of PSAM4-GlyR in D1-MSNs produces an inward current.

(A) Representative traces of whole-cell voltage-clamp recordings (Vhold −88 mV) demonstrate no effect of uPSEM792 (10 or 50 nM) in control neurons. In PSAM4-GlyR+ neurons, 10 or 50 nM uPSEM792

Figure 2—source data 1

of PSAM4-GlyR depolarizes D1-MSNs (source data).

https://cdn.elifesciences.org/articles/64241/elife-64241-fig2-data1-v1.xlsx
Activation of PSAM4-GlyR depolarizes D1-MSNs and does not inhibit firing.

(A) In PSAM4-GlyR+ neurons, activation of PSAM4-GlyR with uPSEM792 (10 and 50 nM) significantly depolarized the membrane potential (Vm) compared to control (non-PSAM4-GlyR) neurons, measured in …

Figure 3—source data 1

PSAM4-GlyR does not inhibit firing of D1-MSNs (source data).

https://cdn.elifesciences.org/articles/64241/elife-64241-fig3-data1-v1.xlsx
In cell-attached configuration, activation of PSAM4-GlyR triggers firing of D1-MSNs when the membrane is depolarized to subthreshold potentials.

(A) Representative traces of cell-attached recordings from a control (gray) or PSAM4-GlyR+ neuron in standard aCSF (4.5 mM [K+]). Action currents were evoked following uPSEM792 by applying a high …

Figure 4—source data 1

PSAM4-GlyR induces D1-MSN firing in cell-attached recordings (source data).

https://cdn.elifesciences.org/articles/64241/elife-64241-fig4-data1-v1.xlsx
Current–voltage relationship of PSAM4-GlyR current shows rightward shift in reversal potential and transient or small outward currents at depolarized potentials.

(A) Current was recorded in response to voltage steps (1 s, −118 to −28 mV, 10 mV) from Vhold −88 mV in aCSF and after application of uPSEM792 (50 or 100 nM). uPSEM792-induced current was isolated …

Figure 5—source data 1

Current-voltage relationship of PSAM4-GlyR current (source data).

https://cdn.elifesciences.org/articles/64241/elife-64241-fig5-data1-v1.xlsx
PSAM4-GlyR activation in D1-MSNs reduces GABAergic synaptic inhibition.

(A) Representative traces of GABA-A receptor-mediated synaptic currents in a PSAM4-GlyR+ neuron in aCSF, evoked during voltage steps from Vhold −88 mV (voltage steps: 1 s, −118 to −28 mV, 10 mV; …

Figure 6—source data 1

Reduced GABAergic synaptic inhibition (source data).

https://cdn.elifesciences.org/articles/64241/elife-64241-fig6-data1-v1.xlsx

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