PMID- 34279736
OWN - NLM
STAT- MEDLINE
DCOM- 20220203
LR  - 20220203
IS  - 1432-2013 (Electronic)
IS  - 0031-6768 (Print)
IS  - 0031-6768 (Linking)
VI  - 473
IP  - 8
DP  - 2021 Aug
TI  - Presynaptic GABA(B) receptor-mediated network excitation in the medial prefrontal 
      cortex of Tsc2(+/-) mice.
PG  - 1261-1271
LID - 10.1007/s00424-021-02576-5 [doi]
AB  - The TSC1 and TSC2 tumor suppressor genes control the activity of mechanistic 
      target of rapamycin (mTOR) pathway. Elevated activity of this pathway in 
      Tsc2(+/-) mouse model leads to reduction of postsynaptic GABA(B) 
      receptor-mediated inhibition and hyperexcitability in the medial prefrontal 
      cortex (mPFC). In this study, we asked whether presynaptic GABA(B) receptors 
      (GABA(B)Rs) can compensate this shift of hyperexcitability. Experiments were 
      performed in brain slices from adolescent wild-type (WT) and Tsc2(+/-) mice. 
      Miniature and spontaneous postsynaptic currents (m/sPSCs) were recorded from 
      layer 2/3 pyramidal neurons in mPFC using patch-clamp technique using a 
      Cs(+)-based intrapipette solution. Presynaptic GABA(B)Rs were activated by 
      baclofen (10 microM) or blocked by CGP55845 (1 microM). Independent on genotype, GABA(B)R 
      modulators bidirectionally change miniature excitatory postsynaptic current 
      (mEPSC) frequency by about 10%, indicating presynaptic GABA(B)R-mediated effects 
      on glutamatergic transmission are comparable in both genotypes. In contrast, 
      frequencies of both mIPSCs and sIPCSs were suppressed by baclofen stronger in 
      Tsc2(+/-) neurons than in WT ones, whereas CGP55845 significantly increased 
      (m/s)IPSC frequencies only in WT cells. Effects of baclofen and CGP55845 on the 
      amplitudes of evoked (e)IPSCs confirmed these observations. These data indicate 
      (1) that GABAergic synapses are inhibited by ambient GABA in WT but not in 
      Tsc2(+/-) slices, and (2) that baclofen shifts the E/I ratio, determined as the 
      ratio of (m/s)EPSC frequency to (m/s)IPSC frequency, towards excitation only in 
      Tsc2(+/-) cells. This excitatory presynaptic GABA(B)R-mediated action has to be 
      taken into account for a possible medication of mental disorders using baclofen.
CI  - (c) 2021. The Author(s).
FAU - Bassetti, Davide
AU  - Bassetti D
AUID- ORCID: 0000-0003-1350-4390
AD  - Institute of Physiology, University Medical Center of the Johannes Gutenberg 
      University Mainz, Duesbergweg 6, 55128, Mainz, Germany. dbassett@uni-mainz.de.
FAU - Luhmann, Heiko J
AU  - Luhmann HJ
AD  - Institute of Physiology, University Medical Center of the Johannes Gutenberg 
      University Mainz, Duesbergweg 6, 55128, Mainz, Germany.
FAU - Kirischuk, Sergei
AU  - Kirischuk S
AD  - Institute of Physiology, University Medical Center of the Johannes Gutenberg 
      University Mainz, Duesbergweg 6, 55128, Mainz, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210719
PL  - Germany
TA  - Pflugers Arch
JT  - Pflugers Archiv : European journal of physiology
JID - 0154720
RN  - 0 (Receptors, GABA-B)
RN  - 0 (Tsc2 protein, mouse)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
SB  - IM
MH  - Animals
MH  - GABAergic Neurons/*metabolism
MH  - Mice
MH  - Patch-Clamp Techniques
MH  - Prefrontal Cortex/*metabolism
MH  - Presynaptic Terminals/*metabolism
MH  - Receptors, GABA-B/*metabolism
MH  - Tuberous Sclerosis Complex 2 Protein/genetics
PMC - PMC8302497
OTO - NOTNLM
OT  - Autistic spectrum disorder
OT  - E/I ratio
OT  - Hyperexcitability
OT  - MTOR
OT  - Presynaptic tonic inhibition
COIS- The authors declare no competing interests.
EDAT- 2021/07/20 06:00
MHDA- 2022/02/04 06:00
PMCR- 2021/07/19
CRDT- 2021/07/19 13:02
PHST- 2021/03/03 00:00 [received]
PHST- 2021/05/05 00:00 [accepted]
PHST- 2021/04/21 00:00 [revised]
PHST- 2021/07/20 06:00 [pubmed]
PHST- 2022/02/04 06:00 [medline]
PHST- 2021/07/19 13:02 [entrez]
PHST- 2021/07/19 00:00 [pmc-release]
AID - 10.1007/s00424-021-02576-5 [pii]
AID - 2576 [pii]
AID - 10.1007/s00424-021-02576-5 [doi]
PST - ppublish
SO  - Pflugers Arch. 2021 Aug;473(8):1261-1271. doi: 10.1007/s00424-021-02576-5. Epub 
      2021 Jul 19.