Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

Abstract

Many risk genes interact synergistically to produce schizophrenia and many neurotransmitter interactions have been implicated. We have developed a circuit-based framework for understanding gene and neurotransmitter interactions. NMDAR hypofunction has been implicated in schizophrenia because NMDAR antagonists reproduce symptoms of the disease. One action of antagonists is to reduce the excitation of fast-spiking interneurons, resulting in disinhibition of pyramidal cells. Overactive pyramidal cells, notably those in the hippocampus, can drive a hyperdopaminergic state that produces psychosis. Additional aspects of interneuron function can be understood in this framework, as follows. (i) In animal models, NMDAR antagonists reduce parvalbumin and GAD67, as found in schizophrenia. These changes produce further disinhibition and can be viewed as the aberrant response of a homeostatic system having a faulty activity sensor (the NMDAR). (ii) Disinhibition decreases the power of gamma oscillation and might thereby produce negative and cognitive symptoms. (iii) Nicotine enhances the output of interneurons, and might thereby contribute to its therapeutic effect in schizophrenia.

Figure 1

Simplified circuitry that provides a framework for understanding the actions of neurotransmitters and risk genes in schizophrenia. Two loops are shown: (i) the reciprocal interactions between pyramidal cells and fast-spiking interneurons and (ii) the hippocampal ventral tegmental area (VTA) loop (note that the connection between the hippocampus and VTA is shown as monosynaptic for simplicity, but is actually polysynaptic through the striatum and ventral pallidum). The effect of dopamine on the hippocampus is probably excitatory [109], raising the possibility that the hippocampal-VTA loop could go into positive feedback, thereby generating the sudden onset of psychosis. The reciprocal relationship of pyramidal cells and fast-spiking interneurons is ubiquitous in the hippocampus and cortex. This loop is responsible for homeostasis of firing of pyramidal cells and for the generation of gamma frequency oscillations. Abnormalities in these oscillations might underlie cognitive and negative symptoms. Cholinergic input to fast-spiking (FS) interneurons is from the medial septal region (MS). ACh = acetylcholine.