Transient inactivation of the ventral hippocampus in neonatal rats impairs the mesolimbic regulation of prefrontal glutamate release in adulthood
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Transient inactivation of the ventral hippocampus in neonatal rats impairs the mesolimbic regulation of prefrontal glutamate release in adulthood. / Bortz, D M; Jørgensen, Christinna Vangsgaard; Mikkelsen, J D; Bruno, J P.
In: Neuropharmacology, Vol. 84, 09.2014, p. 19-30.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Transient inactivation of the ventral hippocampus in neonatal rats impairs the mesolimbic regulation of prefrontal glutamate release in adulthood
AU - Bortz, D M
AU - Jørgensen, Christinna Vangsgaard
AU - Mikkelsen, J D
AU - Bruno, J P
N1 - Copyright © 2014 Elsevier Ltd. All rights reserved.
PY - 2014/9
Y1 - 2014/9
N2 - Cognitive deficits in schizophrenia (SZ) reflect maturational disruptions within a neural system that includes the ventral hippocampus (VH), nucleus accumbens (NAc), basal forebrain, and prefrontal cortex (PFC). A better understanding of these changes may reveal drug targets for more efficacious cognition enhancers. We have utilized an animal model in which the above distributed system is altered, during a sensitive period of development, by transiently inactivating the VH and its efferent projections. We determined the ability of NAc shell activation to evoke prefrontal glutamate release in adult male Wistar rats that had received saline (Sal) or tetrodotoxin (TTX) as neonates (PD7) or as adolescents (PD32). The nucleus accumbens shell (NAcSh) was activated by NMDA infusions (0.05-0.30 μg/0.5 μL). Basal and evoked glutamate levels were measured amperometrically using a glutamate-sensitive microelectrode. There were no differences in basal glutamate levels among the groups tested (overall 1.41 ± 0.26 uM). However, the dose-related stimulation of prefrontal glutamate levels seen in control rats treated with saline on PD7 (4.31 ± 0.22 μM after 0.15 μg) was markedly attenuated in rats treated with TTX on PD7 (0.45 ± 0.12 μM after 0.15 μg). This effect was age-dependent as infusions of TTX on PD32 did not alter the NMDA-induced increases in glutamate release (4.10 ± 0.37 μM after 0.15 μg). Collectively, these findings reveal that transient inactivation of VH transmission, during a sensitive period of development, leads to a functional mesolimbic-cortical disconnection that produces neurochemical and ultimately cognitive impairments resembling those seen in SZ.
AB - Cognitive deficits in schizophrenia (SZ) reflect maturational disruptions within a neural system that includes the ventral hippocampus (VH), nucleus accumbens (NAc), basal forebrain, and prefrontal cortex (PFC). A better understanding of these changes may reveal drug targets for more efficacious cognition enhancers. We have utilized an animal model in which the above distributed system is altered, during a sensitive period of development, by transiently inactivating the VH and its efferent projections. We determined the ability of NAc shell activation to evoke prefrontal glutamate release in adult male Wistar rats that had received saline (Sal) or tetrodotoxin (TTX) as neonates (PD7) or as adolescents (PD32). The nucleus accumbens shell (NAcSh) was activated by NMDA infusions (0.05-0.30 μg/0.5 μL). Basal and evoked glutamate levels were measured amperometrically using a glutamate-sensitive microelectrode. There were no differences in basal glutamate levels among the groups tested (overall 1.41 ± 0.26 uM). However, the dose-related stimulation of prefrontal glutamate levels seen in control rats treated with saline on PD7 (4.31 ± 0.22 μM after 0.15 μg) was markedly attenuated in rats treated with TTX on PD7 (0.45 ± 0.12 μM after 0.15 μg). This effect was age-dependent as infusions of TTX on PD32 did not alter the NMDA-induced increases in glutamate release (4.10 ± 0.37 μM after 0.15 μg). Collectively, these findings reveal that transient inactivation of VH transmission, during a sensitive period of development, leads to a functional mesolimbic-cortical disconnection that produces neurochemical and ultimately cognitive impairments resembling those seen in SZ.
KW - Animals
KW - Animals, Newborn
KW - Catheters, Indwelling
KW - Disease Models, Animal
KW - Electrodes, Implanted
KW - Glutamic Acid
KW - Hippocampus
KW - Male
KW - Microelectrodes
KW - N-Methylaspartate
KW - Nucleus Accumbens
KW - Prefrontal Cortex
KW - Rats, Wistar
KW - Schizophrenia
KW - Sodium Channel Blockers
KW - Tetrodotoxin
U2 - 10.1016/j.neuropharm.2014.04.005
DO - 10.1016/j.neuropharm.2014.04.005
M3 - Journal article
C2 - 24747179
VL - 84
SP - 19
EP - 30
JO - Neuropharmacology
JF - Neuropharmacology
SN - 0028-3908
ER -
ID: 131787411