Phenotypical Screening on Neuronal Plasticity in Hippocampal-Prefrontal Cortex Connectivity Reveals an Antipsychotic with a Novel Profile

Michael Spedding; Claude Sebban; Thérèse M. Jay; Cyril Rocher; Brigitte Tesolin-Decros; Paul Chazot; Esther Schenker; Gabor Szénási; György I. Lévay; Katalin Megyeri; Jozsef Barkóczy; Laszlo G. Hársing; Ian Thomson; Mark O. Cunningham; Miles A. Whittington; Lori-An Etherington; Jeremy J. Lambert; Ferenc A. Antoni; Istvan Gacsályi

doi:10.3390/cells11071181

Phenotypical Screening on Neuronal Plasticity in Hippocampal-Prefrontal Cortex Connectivity Reveals an Antipsychotic with a Novel Profile

Michael Spedding (Lead / Corresponding author), Claude Sebban, Thérèse M. Jay, Cyril Rocher, Brigitte Tesolin-Decros, Paul Chazot, Esther Schenker, Gabor Szénási, György I. Lévay, Katalin Megyeri, Jozsef Barkóczy, Laszlo G. Hársing, Ian Thomson, Mark O. Cunningham, Miles A. Whittington, Lori-An Etherington, Jeremy J. Lambert, Ferenc A. Antoni, Istvan Gacsályi

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Abstract

Dysfunction in the hippocampus-prefrontal cortex (H-PFC) circuit is a critical determinant of schizophrenia. Screening of pyridazinone-risperidone hybrids on this circuit revealed EGIS 11150 (S 36549). EGIS 11150 induced theta rhythm in hippocampal slice preparations in the stratum lacunosum molecular area of CA1, which was resistant to atropine and prazosin. EGIS 11150 enhanced H-PFC coherence, and increased the 8–9 Hz theta band of the EEG power spectrum (from 0.002 mg/kg i.p, at >30× lower doses than clozapine, and >100× for olanzapine, risperidone, or haloperidol). EGIS 11150 fully blocked the effects of phencyclidine (PCP) or ketamine on EEG. Inhibition of long-term potentiation (LTP) in H-PFC was blocked by platform stress, but was fully restored by EGIS 11150 (0.01 mg/kg i.p.), whereas clozapine (0.3 mg/kg ip) only partially restored LTP. EGIS 11150 has a unique electrophysiological profile, so phenotypical screening on H-PFC connectivity can reveal novel antipsychotics.

Original language	English
Article number	1181
Number of pages	21
Journal	Cells
Volume	11
Issue number	7
DOIs	https://doi.org/10.3390/cells11071181
Publication status	Published - 31 Mar 2022

Keywords

Animals
Antipsychotic Agents/pharmacology
Clozapine/pharmacology
Hippocampus
Neuronal Plasticity
Prefrontal Cortex
Rats
Rats, Wistar
Risperidone/pharmacology
S 36549
schizophrenia
theta rhythm
phencyclidine
ketamine
dysconnectivity
EGIS 11150

ASJC Scopus subject areas

General Medicine

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Spedding, M., Sebban, C., Jay, T. M., Rocher, C., Tesolin-Decros, B., Chazot, P., Schenker, E., Szénási, G., Lévay, G. I., Megyeri, K., Barkóczy, J., Hársing, L. G., Thomson, I., Cunningham, M. O., Whittington, M. A., Etherington, L.-A., Lambert, J. J., Antoni, F. A., & Gacsályi, I. (2022). Phenotypical Screening on Neuronal Plasticity in Hippocampal-Prefrontal Cortex Connectivity Reveals an Antipsychotic with a Novel Profile. Cells, 11(7), Article 1181. https://doi.org/10.3390/cells11071181

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title = "Phenotypical Screening on Neuronal Plasticity in Hippocampal-Prefrontal Cortex Connectivity Reveals an Antipsychotic with a Novel Profile",

abstract = "Dysfunction in the hippocampus-prefrontal cortex (H-PFC) circuit is a critical determinant of schizophrenia. Screening of pyridazinone-risperidone hybrids on this circuit revealed EGIS 11150 (S 36549). EGIS 11150 induced theta rhythm in hippocampal slice preparations in the stratum lacunosum molecular area of CA1, which was resistant to atropine and prazosin. EGIS 11150 enhanced H-PFC coherence, and increased the 8–9 Hz theta band of the EEG power spectrum (from 0.002 mg/kg i.p, at >30× lower doses than clozapine, and >100× for olanzapine, risperidone, or haloperidol). EGIS 11150 fully blocked the effects of phencyclidine (PCP) or ketamine on EEG. Inhibition of long-term potentiation (LTP) in H-PFC was blocked by platform stress, but was fully restored by EGIS 11150 (0.01 mg/kg i.p.), whereas clozapine (0.3 mg/kg ip) only partially restored LTP. EGIS 11150 has a unique electrophysiological profile, so phenotypical screening on H-PFC connectivity can reveal novel antipsychotics.",

keywords = "Animals, Antipsychotic Agents/pharmacology, Clozapine/pharmacology, Hippocampus, Neuronal Plasticity, Prefrontal Cortex, Rats, Rats, Wistar, Risperidone/pharmacology, S 36549, schizophrenia, theta rhythm, phencyclidine, ketamine, dysconnectivity, EGIS 11150",

author = "Michael Spedding and Claude Sebban and Jay, {Th{\'e}r{\`e}se M.} and Cyril Rocher and Brigitte Tesolin-Decros and Paul Chazot and Esther Schenker and Gabor Sz{\'e}n{\'a}si and L{\'e}vay, {Gy{\"o}rgy I.} and Katalin Megyeri and Jozsef Bark{\'o}czy and H{\'a}rsing, {Laszlo G.} and Ian Thomson and Cunningham, {Mark O.} and Whittington, {Miles A.} and Lori-An Etherington and Lambert, {Jeremy J.} and Antoni, {Ferenc A.} and Istvan Gacs{\'a}lyi",

note = "Funding Information: The funding for the discovery and development of EGIS 11150 (S 36549) was from EGIS Pharmaceuticals Ltd., 1106 Budapest, Hungary and Institut de Recherches Internationales Servier, 92284 Suresnes, France; Servier funded the contracted studies. Publisher Copyright: {\textcopyright} 2022 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2022",

month = mar,

day = "31",

doi = "10.3390/cells11071181",

language = "English",

volume = "11",

journal = "Cells",

issn = "2073-4409",

publisher = "MDPI",

number = "7",

}

Spedding, M, Sebban, C, Jay, TM, Rocher, C, Tesolin-Decros, B, Chazot, P, Schenker, E, Szénási, G, Lévay, GI, Megyeri, K, Barkóczy, J, Hársing, LG, Thomson, I, Cunningham, MO, Whittington, MA, Etherington, L-A, Lambert, JJ, Antoni, FA & Gacsályi, I 2022, 'Phenotypical Screening on Neuronal Plasticity in Hippocampal-Prefrontal Cortex Connectivity Reveals an Antipsychotic with a Novel Profile', Cells, vol. 11, no. 7, 1181. https://doi.org/10.3390/cells11071181

TY - JOUR

T1 - Phenotypical Screening on Neuronal Plasticity in Hippocampal-Prefrontal Cortex Connectivity Reveals an Antipsychotic with a Novel Profile

AU - Spedding, Michael

AU - Sebban, Claude

AU - Jay, Thérèse M.

AU - Rocher, Cyril

AU - Tesolin-Decros, Brigitte

AU - Chazot, Paul

AU - Schenker, Esther

AU - Szénási, Gabor

AU - Lévay, György I.

AU - Megyeri, Katalin

AU - Barkóczy, Jozsef

AU - Hársing, Laszlo G.

AU - Thomson, Ian

AU - Cunningham, Mark O.

AU - Whittington, Miles A.

AU - Etherington, Lori-An

AU - Lambert, Jeremy J.

AU - Antoni, Ferenc A.

AU - Gacsályi, Istvan

N1 - Funding Information: The funding for the discovery and development of EGIS 11150 (S 36549) was from EGIS Pharmaceuticals Ltd., 1106 Budapest, Hungary and Institut de Recherches Internationales Servier, 92284 Suresnes, France; Servier funded the contracted studies. Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2022/3/31

Y1 - 2022/3/31

N2 - Dysfunction in the hippocampus-prefrontal cortex (H-PFC) circuit is a critical determinant of schizophrenia. Screening of pyridazinone-risperidone hybrids on this circuit revealed EGIS 11150 (S 36549). EGIS 11150 induced theta rhythm in hippocampal slice preparations in the stratum lacunosum molecular area of CA1, which was resistant to atropine and prazosin. EGIS 11150 enhanced H-PFC coherence, and increased the 8–9 Hz theta band of the EEG power spectrum (from 0.002 mg/kg i.p, at >30× lower doses than clozapine, and >100× for olanzapine, risperidone, or haloperidol). EGIS 11150 fully blocked the effects of phencyclidine (PCP) or ketamine on EEG. Inhibition of long-term potentiation (LTP) in H-PFC was blocked by platform stress, but was fully restored by EGIS 11150 (0.01 mg/kg i.p.), whereas clozapine (0.3 mg/kg ip) only partially restored LTP. EGIS 11150 has a unique electrophysiological profile, so phenotypical screening on H-PFC connectivity can reveal novel antipsychotics.

AB - Dysfunction in the hippocampus-prefrontal cortex (H-PFC) circuit is a critical determinant of schizophrenia. Screening of pyridazinone-risperidone hybrids on this circuit revealed EGIS 11150 (S 36549). EGIS 11150 induced theta rhythm in hippocampal slice preparations in the stratum lacunosum molecular area of CA1, which was resistant to atropine and prazosin. EGIS 11150 enhanced H-PFC coherence, and increased the 8–9 Hz theta band of the EEG power spectrum (from 0.002 mg/kg i.p, at >30× lower doses than clozapine, and >100× for olanzapine, risperidone, or haloperidol). EGIS 11150 fully blocked the effects of phencyclidine (PCP) or ketamine on EEG. Inhibition of long-term potentiation (LTP) in H-PFC was blocked by platform stress, but was fully restored by EGIS 11150 (0.01 mg/kg i.p.), whereas clozapine (0.3 mg/kg ip) only partially restored LTP. EGIS 11150 has a unique electrophysiological profile, so phenotypical screening on H-PFC connectivity can reveal novel antipsychotics.

KW - Animals

KW - Antipsychotic Agents/pharmacology

KW - Clozapine/pharmacology

KW - Hippocampus

KW - Neuronal Plasticity

KW - Prefrontal Cortex

KW - Rats

KW - Rats, Wistar

KW - Risperidone/pharmacology

KW - S 36549

KW - schizophrenia

KW - theta rhythm

KW - phencyclidine

KW - ketamine

KW - dysconnectivity

KW - EGIS 11150

UR - http://www.scopus.com/inward/record.url?scp=85127427690&partnerID=8YFLogxK

U2 - 10.3390/cells11071181

DO - 10.3390/cells11071181

M3 - Article

C2 - 35406745

SN - 2073-4409

VL - 11

JO - Cells

JF - Cells

IS - 7

M1 - 1181

ER -

Phenotypical Screening on Neuronal Plasticity in Hippocampal-Prefrontal Cortex Connectivity Reveals an Antipsychotic with a Novel Profile

Abstract

Keywords

ASJC Scopus subject areas

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