Inhibitory control of sensory gating in a computer model of the CA3 region of the hippocampus

Abstract

A model of the CA3 region of the hippocampus was used to simulate the P50 auditory-evoked potential response to repeated stimuli in order to study the neuronal circuits involved in a sensoryprocessing deficit associated with schizophrenia. Normal subjects have a reduced P50 auditoryevoked potential amplitude in response to the second of two paired auditory click stimuli spaced 0.5 s apart. However, schizophrenic patients do not gate or reduce their response to the second click. They have equal auditory-evoked response amplitudes to both clicks. When schizophrenic patients were medicated with traditional neuroleptics, the evoked potential amplitude to both clicks increased, but gating of the second response was not restored or improved. Animal studies suggest a role for septohippocampal cholinergic activity in sensory gating. We used a computational model of this system in order to study the relative contributions of local processing and afferent activity in sensory gating. We first compared the effect of information representation as average firing rate to information representation as cell assemblies in order to evaluate the best method to represent the response of hippocampal neurons to the auditory click. We then studied the effects of nicotinic cholinergic input on the response of the network and the effect of GABA B receptor activation on the ability of the local network to suppress the test response. The results of our model showed that nicotinic cholinergic input from the septum to the hippocampus can control the flow of sensory information from the cortex into the hippocampus. In addition, postsynaptic GABA B receptor activation was not sufficient to suppress the test response when the interstimulus interval was 500 ms. However, presynaptic GABA B receptor activity may be responsible for the suppression of the test response at this interstimulus interval.

The role of cannabinoids in the neurobiology of sensory gating: A firing rate model study

“…Previous modelling studies have explored the local processing and afferent activity in-3 volvement in sensory gating [9,15,14]. Moxon et al [15,14] have explained the nicotinic cholinergic input role in sensory gating and the dopaminergic modulation of the P50 (N40).…”

“…Moxon et al [15,14] have explained the nicotinic cholinergic input role in sensory gating and the dopaminergic modulation of the P50 (N40). In addition they have suggested that GABA B synapses are involved in suppressing the second (test) tone, by suppressing cortical input and recurrent excitation.…”

Effects of the Novel α7 Nicotinic Acetylcholine Receptor Agonist ABT-107 on Sensory Gating in DBA/2 Mice: Pharmacodynamic Characterization

“…Desensitization of receptors with the 1.0 mol/kg dose of ABT-107 may be one explanation for a lack of in vivo efficacy in the DBA/2 sensory gating model. Activation of ␣7 nAChRs on GABA-containing hippocampal interneurons is thought to be a neuronal substrate for sensory gating (Miller and Freedman, 1995;Moxon et al, 2003), and desensitizing this inhibitory system would result in reduced control over excitatory pyramidal neuron firing. Populations of nAChRs may exist between the activated and desensitized states at the same time (Picciotto et al, 2008), and perhaps a net activation is being produced by ABT-107 at plasma concentrations of ϳ1 to 2 ng/ml.…”

GABAB receptor blockade in the hippocampus affects sensory and sensorimotor gating in Long-Evans rats

“…One neural circuit that mediates both sensory and sensorimotor gating connects the medial septum (Ma and Leung 2007;Ma et al , 2009Miller and Freedman 1993) to the hippocampus (Bast and Feldon 2003;Miller and Freedman 1995), nucleus accumbens, and then ventral pallidum (Arai et al 2008;de Bruin et al 2001;Kretschmer and Koch 1998;Swerdlow and Geyer 1990). Within this neural circuit, dopamine in the nucleus accumbens (de Bruin et al 2001;Swerdlow and Geyer 1990), glutamate, and GABA in the medial septum Leung 2000, 2007;Ma et al , 2009, hippocampus (Moxon et al 2003;Hershman et al 1995), and ventral pallidum (Arai et al 2008;Swerdlow and Geyer 1990) participate in mediation of the gating phenomena.…”