Dysfunctional GABAergic inhibition in the prefrontal cortex leading to "psychotic" hyperactivation

Abstract

Background: The GABAergic system in the brain seems to be dysfunctional in various psychiatric disorders. Many studies have suggested so far that, in schizophrenia patients, GABAergic inhibition is selectively but consistently reduced in the prefrontal cortex (PFC).

Results: This study used a computational model of the PFC to investigate the dynamics of the PFC circuit with and without chandelier cells and other GABAergic interneurons. The inhibition by GABAergic interneurons other than chandelier cells effectively regulated the PFC activity with rather low or modest levels of dopaminergic neurotransmission. This activity of the PFC is associated with normal cognitive functions and has an inverted-U shaped profile of dopaminergic modulation. In contrast, the chandelier cell-type inhibition affected only the PFC circuit dynamics in hyperdopaminergic conditions. Reduction of chandelier cell-type inhibition resulted in bistable dynamics of the PFC circuit, in which the upper stable state is associated with a hyperactive mode. When both types of inhibition were reduced, this hyperactive mode and the conventional inverted-U mode merged.

Conclusion: The results of our simulation suggest that, in schizophrenia, a reduction of GABAergic inhibition increases vulnerability to psychosis by (i) producing the hyperactive mode of the PFC with hyperdopaminergic neurotransmission by dysfunctional chandelier cells and (ii) increasing the probability of the transition to the hyperactive mode from the conventional inverted-U mode by dysfunctional GABAergic interneurons.

Figure 1

The mode diagram of the PFC with respect to dopaminergic modulation via D1 receptors. The vertical axis is the population activity of the pyramidal neurons in the PFC, and the horizontal axis is the D1 receptor activation level (which is denoted by z in the text). Only the curves numbered 0 correspond to the equilibrium state of the PFC circuit. See the text for the method of drawing of this diagram.

Figure 2

Nullclines of the state variables of the pyramidal neurons and the GABAergic interneurons other than chandelier cells for three different levels of D1 receptor activation. A: z = 3.0; B: z = 5.0; C: z = 7.0. The nullcline for the pyramidal neurons (dx_p/dt = 0) is depicted in blue and the nullcline for the GABAergic interneurons (dx_n/dt = 0) is depicted in green. The inset (A1) is an enlargement view of A. The circles indicate stable fixed points and the crosses indicate unstable fixed points. The arrows show the direction of state transition toward one of the stable fixed points.

Figure 3

Mode diagrams. A: Control. B: With chandelier cells. C: Weaker GABAergic interneurons other than chandelier cells. D: Stronger GABAergic interneurons other than chandelier cells. The chandelier cells are dysfunctional in A, C and D.

Figure 4

Three-dimensional representations of DA modulatory landscapes with (B) and without (A, C, and D) chandelier cells. The strength of the inhibition by other GABAergic interneurons are also varied (A: 1.0, B: 1.0, C: 0.95, and D: 1.06). Note that the onset of the H mode is very quick (less than 100 ms), whereas the inverted-U mode profiles are very slow to evolve. Even at t = 1000 ms, the profiles of the inverted-U mode have not reached the equilibrium states. The profiles at equilibrium are shown in Figure 3.

Figure 5

Mode diagrams and state transition. A: When the chandelier cells are dysfunctional but the GABAergic inhibition by the other interneurons is normal, the transition from the inverted-U mode to the H mode hardly occurs because of a gap between the two modes. The gap becomes wider in the existence of chandelier cells. B: When the chandelier cells are dysfunctional and the GABAergic inhibition by the other interneurons is reduced, the two modes are connected, so that the transition to the H mode would occur readily.

Figure 6

A schematic diagram of the model. The PFC contains pyramidal neurons and GABAergic interneurons (chandelier cells (C) and others (N)), which are connected reciprocally and have also self-innervations. All populations of neurons are under dopaminergic modulation via D1 receptors. The transient input to the pyramidal neurons triggers the dynamics of the circuit.

Figure 7

The profiles of the activation functions of the chandelier cells (C) and the other GABAergic interneurons (N) in the model.