Congenital toxoplasmosis induces NMDA receptor hypofunction and neuroinflammation associated with neurobehavioral abnormalities in adult mice

Mohammadreza Youssefi; Seyedeh Mina Masoumi; Ahmad Daryani; Navideh Mirzakhani; Claudia Zizzadoro; Thomas M. Keck; Mohadeseh Abouhosseini Tabari

doi:10.1016/j.expneurol.2026.115911

Congenital toxoplasmosis induces NMDA receptor hypofunction and neuroinflammation associated with neurobehavioral abnormalities in adult mice

Mohammadreza Youssefi
, Seyedeh Mina Masoumi
, Ahmad Daryani
, Navideh Mirzakhani
, Claudia Zizzadoro
, Thomas M. Keck
, Mohadeseh Abouhosseini Tabari

Chemistry

Rowan University

Research output: Contribution to journal › Article › peer-review

Abstract

Maternal infection with Toxoplasma gondii can disrupt fetal brain development, yet the mechanisms underlying the long-term neurobehavioral consequences of congenital toxoplasmosis remain incompletely understood. In this study, we investigated the effects of congenital toxoplasmosis on adult offspring behavior, with particular emphasis on how the gestational timing of maternal infection and offspring sex influence the nature and severity of these alterations. We also evaluated neuroinflammation, neurotrophism, and N-methyl-D-aspartate receptor (NMDAR) subunit expression. Pregnant dams were infected with T. gondii tachyzoites on gestational days (GD) 5, 12, or 17, and offspring of both sexes were assessed in early adulthood (8 weeks) using the open-field, elevated plus maze, Y-maze, and marble burying tests. Brain mRNA expression levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), brain-derived neurotrophic factor (BDNF), and the NMDAR subunits NR1 and NR2A were also quantified. Congenital infection induced hyperactivity, increased anxiety-like behavior, impaired spatial working memory, and enhanced repetitive behaviors. Molecular analyses revealed significantly elevated IL-6 and TNF-α mRNA levels, accompanied by reduced expression of BDNF, NR1, and NR2A. These effects were most pronounced following early- (GD-5) and mid-gestational (GD-12) infection, which were also associated with greater brain cyst burden and more severe neuroinflammation. Male offspring exhibited more pronounced neuroinflammatory and behavioral alterations than females infected at the same gestational stage. Taken together, these findings demonstrate that congenital toxoplasmosis produces behavioral and molecular abnormalities in adult mice and suggest that gestational timing and sex are important determinants of severity and long-term neurodevelopmental outcomes.

Original language	English (US)
Article number	115911
Journal	Experimental Neurology
Volume	405
DOIs	https://doi.org/10.1016/j.expneurol.2026.115911
State	Published - Nov 2026

ASJC Scopus subject areas

Neurology
Developmental Neuroscience

Access to Document

10.1016/j.expneurol.2026.115911

Cite this

@article{bad1dba4153f452aae392c7c4fc05b0b,

title = "Congenital toxoplasmosis induces NMDA receptor hypofunction and neuroinflammation associated with neurobehavioral abnormalities in adult mice",

abstract = "Maternal infection with Toxoplasma gondii can disrupt fetal brain development, yet the mechanisms underlying the long-term neurobehavioral consequences of congenital toxoplasmosis remain incompletely understood. In this study, we investigated the effects of congenital toxoplasmosis on adult offspring behavior, with particular emphasis on how the gestational timing of maternal infection and offspring sex influence the nature and severity of these alterations. We also evaluated neuroinflammation, neurotrophism, and N-methyl-D-aspartate receptor (NMDAR) subunit expression. Pregnant dams were infected with T. gondii tachyzoites on gestational days (GD) 5, 12, or 17, and offspring of both sexes were assessed in early adulthood (8 weeks) using the open-field, elevated plus maze, Y-maze, and marble burying tests. Brain mRNA expression levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), brain-derived neurotrophic factor (BDNF), and the NMDAR subunits NR1 and NR2A were also quantified. Congenital infection induced hyperactivity, increased anxiety-like behavior, impaired spatial working memory, and enhanced repetitive behaviors. Molecular analyses revealed significantly elevated IL-6 and TNF-α mRNA levels, accompanied by reduced expression of BDNF, NR1, and NR2A. These effects were most pronounced following early- (GD-5) and mid-gestational (GD-12) infection, which were also associated with greater brain cyst burden and more severe neuroinflammation. Male offspring exhibited more pronounced neuroinflammatory and behavioral alterations than females infected at the same gestational stage. Taken together, these findings demonstrate that congenital toxoplasmosis produces behavioral and molecular abnormalities in adult mice and suggest that gestational timing and sex are important determinants of severity and long-term neurodevelopmental outcomes.",

author = "Mohammadreza Youssefi and Masoumi, \{Seyedeh Mina\} and Ahmad Daryani and Navideh Mirzakhani and Claudia Zizzadoro and Keck, \{Thomas M.\} and Tabari, \{Mohadeseh Abouhosseini\}",

note = "Publisher Copyright: {\textcopyright} 2026 The Authors",

year = "2026",

month = nov,

doi = "10.1016/j.expneurol.2026.115911",

language = "English (US)",

volume = "405",

journal = "Experimental Neurology",

issn = "0014-4886",

publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - Congenital toxoplasmosis induces NMDA receptor hypofunction and neuroinflammation associated with neurobehavioral abnormalities in adult mice

AU - Youssefi, Mohammadreza

AU - Masoumi, Seyedeh Mina

AU - Daryani, Ahmad

AU - Mirzakhani, Navideh

AU - Zizzadoro, Claudia

AU - Keck, Thomas M.

AU - Tabari, Mohadeseh Abouhosseini

PY - 2026/11

Y1 - 2026/11

N2 - Maternal infection with Toxoplasma gondii can disrupt fetal brain development, yet the mechanisms underlying the long-term neurobehavioral consequences of congenital toxoplasmosis remain incompletely understood. In this study, we investigated the effects of congenital toxoplasmosis on adult offspring behavior, with particular emphasis on how the gestational timing of maternal infection and offspring sex influence the nature and severity of these alterations. We also evaluated neuroinflammation, neurotrophism, and N-methyl-D-aspartate receptor (NMDAR) subunit expression. Pregnant dams were infected with T. gondii tachyzoites on gestational days (GD) 5, 12, or 17, and offspring of both sexes were assessed in early adulthood (8 weeks) using the open-field, elevated plus maze, Y-maze, and marble burying tests. Brain mRNA expression levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), brain-derived neurotrophic factor (BDNF), and the NMDAR subunits NR1 and NR2A were also quantified. Congenital infection induced hyperactivity, increased anxiety-like behavior, impaired spatial working memory, and enhanced repetitive behaviors. Molecular analyses revealed significantly elevated IL-6 and TNF-α mRNA levels, accompanied by reduced expression of BDNF, NR1, and NR2A. These effects were most pronounced following early- (GD-5) and mid-gestational (GD-12) infection, which were also associated with greater brain cyst burden and more severe neuroinflammation. Male offspring exhibited more pronounced neuroinflammatory and behavioral alterations than females infected at the same gestational stage. Taken together, these findings demonstrate that congenital toxoplasmosis produces behavioral and molecular abnormalities in adult mice and suggest that gestational timing and sex are important determinants of severity and long-term neurodevelopmental outcomes.

AB - Maternal infection with Toxoplasma gondii can disrupt fetal brain development, yet the mechanisms underlying the long-term neurobehavioral consequences of congenital toxoplasmosis remain incompletely understood. In this study, we investigated the effects of congenital toxoplasmosis on adult offspring behavior, with particular emphasis on how the gestational timing of maternal infection and offspring sex influence the nature and severity of these alterations. We also evaluated neuroinflammation, neurotrophism, and N-methyl-D-aspartate receptor (NMDAR) subunit expression. Pregnant dams were infected with T. gondii tachyzoites on gestational days (GD) 5, 12, or 17, and offspring of both sexes were assessed in early adulthood (8 weeks) using the open-field, elevated plus maze, Y-maze, and marble burying tests. Brain mRNA expression levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), brain-derived neurotrophic factor (BDNF), and the NMDAR subunits NR1 and NR2A were also quantified. Congenital infection induced hyperactivity, increased anxiety-like behavior, impaired spatial working memory, and enhanced repetitive behaviors. Molecular analyses revealed significantly elevated IL-6 and TNF-α mRNA levels, accompanied by reduced expression of BDNF, NR1, and NR2A. These effects were most pronounced following early- (GD-5) and mid-gestational (GD-12) infection, which were also associated with greater brain cyst burden and more severe neuroinflammation. Male offspring exhibited more pronounced neuroinflammatory and behavioral alterations than females infected at the same gestational stage. Taken together, these findings demonstrate that congenital toxoplasmosis produces behavioral and molecular abnormalities in adult mice and suggest that gestational timing and sex are important determinants of severity and long-term neurodevelopmental outcomes.

UR - https://www.scopus.com/pages/publications/105044989883

UR - https://www.scopus.com/pages/publications/105044989883#tab=citedBy

U2 - 10.1016/j.expneurol.2026.115911

DO - 10.1016/j.expneurol.2026.115911

M3 - Article

C2 - 42431346

SN - 0014-4886

VL - 405

JO - Experimental Neurology

JF - Experimental Neurology

M1 - 115911

ER -

Congenital toxoplasmosis induces NMDA receptor hypofunction and neuroinflammation associated with neurobehavioral abnormalities in adult mice

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Cite this