Transient inactivation of the ventral hippocampus in neonatal rats impairs the mesolimbic regulation of prefrontal glutamate release in adulthood

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. •We disrupt the development of the ventral hippocampus with TTX infusions at two ages.•Cortical glutamate release was evoked with NMDA infusions into the accumben's shell.•NMDA stimulated glutamate release in controls and rats treated with TTX on PD32.•NMDA failed to stimulate glutamate release in rats treated with TTX on PD7.•TTX PD7 disrupts forebrain development and transmission as seen in schizophrenia.