Circuitry-based gene expression profiles in GABA cells of the trisynaptic pathway in schizophrenics versus bipolars

Abstract

Significant reductions in GABAergic cell numbers and/or activity have been demonstrated in the hippocampus of subjects with schizophrenia and bipolar disorder. To understand how different subpopulations of interneurons are regulated, laser microdissection and gene expression profiling have been used to "deconstruct" the trisynaptic pathway, so that subtypes of GABA cells could be defined by their location in various layers of CA3/2 and CA1. The results suggest that the cellular endophenotypes for SZ and BD may be determined by multiple factors that include unique susceptibility genes for the respective disorders and altered integration among hippocampal GABA cells with extrinsic and intrinsic afferent fiber systems. The extensive and intricate data that has come from this study has provided insights into how a complex circuit, like the trisynaptic pathway, may be regulated in human hippocampus in both health and disease.

Fig. 1.

Schematic diagrams of the trisynaptic pathway showing pyramidal neurons (triangular) and GABA cells (square) in stratum oriens (SO), stratum pyramidal (SP), and stratum radiatum (SR) of sectors CA3/2 and CA1. The perforant path projection from the entorhinal cortex project to the granule cells and these in turn send mossy fiber projections that synapse on the apical dendrites of pyramidal neurons in sector CA3/2. The latter cell sends projects axons into the SO where they travel as Schaffer collaterals that eventually form excitatory synapse with the apical dendrites of pyramidal neurons in sector CA1. Collateral branches of pyramidal neurons in CA3/2 and CA1 form synapses with GABAergic interneurons on the SO. The arrows at the bottom of each diagram show the direction of feed-forward excitation along the trisynaptic pathway and suggest that this may be increased in schizophrenics because of diminished GABAergic tone in both CA3/2 and CA1. In BDs, however, feed-forward excitation may be attenuated at the level of CA1 because of the heightened activity of GABA cells with in SO at this locus.