Abnormalities of synaptic transmission and plasticity in the hippocampus represent an integral part of the altered programming triggered by early life stress. Prenatally restraint stressed (PRS) rats develop long-lasting biochemical and behavioral changes, which are the expression of an anxious/depressive-like phenotype. We report here that PRS rats showed a selective impairment of depolarization- or
kainate-stimulated
glutamate and [(3)H]
d-aspartate release in the ventral hippocampus, a region encoding memories related to stress and emotions.
GABA release was unaffected in PRS rats. As a consequence of reduced
glutamate release, PRS rats were also highly resistant to
kainate-induced
seizures. Abnormalities of
glutamate release were associated with large reductions in the levels of synaptic vesicle-related
proteins, such as VAMP (
synaptobrevin), syntaxin-1,
synaptophysin,
synapsin Ia/b and IIa, munc-18, and Rab3A in the ventral hippocampus of PRS rats. Anxiety-like behavior in male PRS (and control) rats was inversely related to the extent of depolarization-evoked
glutamate release in the ventral hippocampus. A causal relationship between anxiety-like behavior and reduction in
glutamate release was demonstrated using a mixture of the mGlu2/3 receptor antagonist,
LY341495, and the
GABA(B) receptor antagonist, CGP52432, which was shown to amplify depolarization-evoked [(3)H]
d-aspartate release in the ventral hippocampus. Bilateral microinfusion of CGP52432 plus
LY341495 in the ventral hippocampus abolished anxiety-like behavior in PRS rats. These findings indicate that an impairment of
glutamate release in the ventral hippocampus is a key component of the neuroplastic program induced by PRS, and that strategies aimed at enhancing
glutamate release in the ventral hippocampus correct the "anxious phenotype" caused by early life stress.