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Age- and Sex-Related Characteristics of Tonic Gaba Currents in the Rat Substantia Nigra Pars Reticulata

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Abstract

Previous studies have shown that the pharmacologic effects of GABAergic drugs and the postsynaptic phasic GABAAergic inhibitory responses in the anterior part of the rat substantia nigra pars reticulata (SNRA) are age- and sex-specific. Here, we investigate whether there are age- and sex-related differences in the expression of the δ GABAA receptor (GABAAR) subunit and GABAAR mediated tonic currents. We have used δ-specific immunochemistry and whole cell patch clamp to study GABAAR mediated tonic currents in the SNRA of male and female postnatal day (PN) PN5-9, PN11-16, and PN25-32 rats. We observed age-related decline, but no sex-specific changes, in bicuculline (BIM) sensitive GABAAR tonic current density, which correlated with the decline in δ subunit in the SNRA between PN15 and 30. Furthermore, we show that the GABAAR tonic currents can be modified by muscimol (GABAAR agonist; partial GABACR agonist), THIP (4,5,6,7-tetrahydroisoxazolo (5,4-c)pyridin-3-ol: α4β3δ GABAARs agonist and GABACR antagonist), and zolpidem (α1-subunit selective GABAAR agonist) in age- and sex-dependent manner specific for each drug. We propose that the emergence of the GABAAR-sensitive anticonvulsant effects of the rat SNRA during development may depend upon the developmental decline in tonic GABAergic inhibition of the activity of rat SNRA neurons, although other sex-specific factors are also involved.

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Abbreviations

SNR:

Substantia nigra pars reticulata

SNRA :

Anterior part of the substantia nigra pars reticulata

sIPSCs:

Spontaneous inhibitory postsynaptic currents

PN:

Postnatal days

-ir:

Immunoreactivity

GABAARs:

GABAA receptors

GABACRs:

GABAC receptors

aCSF:

Artificial cerebrospinal fluid

D-AP5:

d-(-)-2-Amino-5-phosphonopentanoic acid

CNQX:

6-Cyano-2,3-dihydroxy-7-nitro-quinoxaline

BIM:

Bicuculline methobromide

DMSO:

Dimethyl sulfoxide

TBS:

Tris based saline

THIP:

4,5,6,7-Tetrahydroisoxazolo (5,4-c)pyridin-3-ol

TTX:

Tetrodotoxin

gabazine:

SR 95531 hydrobromide

RT:

Room temperature

NGS:

Normal goat serum

SE:

Standard error

Rs:

Series resistance

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Acknowledgments

The authors acknowledge the Grant support by NIH NINDS Grants NS020253, NS045243, NS058303, NS062947, NS078333, grants from the International Rett Syndrome Foundation, PACE, Heffer Family Foundation, Autism Speaks, Citizens United for Research in Epilepsy (CURE), Department of Defense, and GAČR 309/08/H079. SLM is the Charles Frost Chair in Neurosurgery and Neurology.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Saul R. Korey Department of Neurology, Laboratory of Developmental Epilepsy Bronx, Albert Einstein College of Medicine, 1410 Pelham Pkwy South, Kennedy Rm 306, Bronx, NY, 10461, USA

    O. Chudomel, H. Hasson, S. L. Moshé & A. S. Galanopoulou

  2. Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, 1410 Pelham Pkwy South, Kennedy Rm 306, Bronx, NY, 10461, USA

    S. L. Moshé & A. S. Galanopoulou

  3. Department of Pediatrics, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Kennedy Center, New York City, NY, USA

    S. L. Moshé

  4. Department of Neurology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, The Czech Republic

    O. Chudomel & M. Bojar

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  1. O. Chudomel
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  2. H. Hasson
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  3. M. Bojar
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  4. S. L. Moshé
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  5. A. S. Galanopoulou
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Correspondence to O. Chudomel.

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Chudomel, O., Hasson, H., Bojar, M. et al. Age- and Sex-Related Characteristics of Tonic Gaba Currents in the Rat Substantia Nigra Pars Reticulata. Neurochem Res 40, 747–757 (2015). https://doi.org/10.1007/s11064-015-1523-3

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