Evidence for altered trisynaptic circuitry in schizophrenic hippocampus

Recent postmortem studies have demonstrated subtle alterations in the hippo campal formation (HIPP) of patients with schizophrenia (SZ). These changes include a decreased density of nonpyramidal neurons (NPs), an increase of t he GABA(A), but not benzodiazepine receptors and a neuroleptic-dose-related increase of GAD(65)-IR terminals, particularly in sectors CA3 and CA2. Hig h resolution studies of the GABA(A) receptor have further suggested that a decrease of disinhibitory GABAergic activity (i.e., GABA-to-GABA) in stratu m pyramidale of CA3 may coexist with reduced inhibitory modulation (i.e., G ABA-to-excitatory pyramidal neuron) in the stratum oriens of this same sect or. These changes could potentially involve excitotoxic damage to interneur ons in CA2; but, the precise time frame for the induction of such an injury during pre- versus postnatal life cannot as yet be inferred from the avail able data. These findings are consistent with reports of abnormal oscillato ry rhythms and increased basal metabolic activity in the HIPP of patients w ith SZ. The fact that patients with manic depression also show a decrease o f NPs in CA2 suggests that changes in the GABA system may not be related to a susceptibility gene for SZ. Rather, these alterations could be associate d with a nonspecific factor such as stress, experienced either early in lif e or much later during adolescence or adulthood. Presumably, there are also changes associated in other transmitter systems that may play a more speci fic role in establishing the SZ phenotype, Biol Psychiatry 1999;46:589-599 (C) 1999 Society of Biological Psychiatry.