Parvalbumin and GAD65 Interneuron Inhibition in the Ventral Hippocampus Induces Distinct Behavioral Deficits Relevant to Schizophrenia

Abstract

Hyperactivity within the ventral hippocampus (vHPC) has been linked to both psychosis in humans and behavioral deficits in animal models of schizophrenia. A local decrease in GABA-mediated inhibition, particularly involving parvalbumin (PV)-expressing GABA neurons, has been proposed as a key mechanism underlying this hyperactive state. However, direct evidence is lacking for a causal role of vHPC GABA neurons in behaviors associated with schizophrenia. Here, we probed the behavioral function of two different but overlapping populations of vHPC GABA neurons that express either PV or GAD65 by selectively inhibiting these neurons with the pharmacogenetic neuromodulator hM4D. We show that acute inhibition of vHPC GABA neurons in adult mice results in behavioral changes relevant to schizophrenia. Inhibiting either PV or GAD65 neurons produced distinct behavioral deficits. Inhibition of PV neurons, affecting ϳ80% of the PV neuron population, robustly impaired prepulse inhibition of the acoustic startle reflex (PPI), startle reactivity, and spontaneous alternation, but did not affect locomotor activity. In contrast, inhibiting a heterogeneous population of GAD65 neurons, affecting ϳ40% of PV neurons and 65% of cholecystokinin neurons, increased spontaneous and amphetamine-induced locomotor activity and reduced spontaneous alternation, but did not alter PPI. Inhibition of PV or GAD65 neurons also produced distinct changes in network oscillatory activity in the vHPC in vivo. Together, these findings establish a causal role for vHPC GABA neurons in controlling behaviors relevant to schizophrenia and suggest a functional dissociation between the GABAergic mechanisms involved in hippocampal modulation of sensorimotor processes.

Animal Models of Deficient Sensorimotor Gating in Schizophrenia: Are They Still Relevant?

“…Swerdlow et al 2008). A number of creative strategies have been used to understand this complex genetic landscape and its overlap with brain circuitry, via assessing the PPI-altering effects of gene knockouts, humanized gene insertions (e.g., Risbrough et al 2014), strain differences in regional gene expression (e.g., Shilling et al 2008), drug-induced changes in regional expression of genes identified in postmortem schizophrenia brain tissue (e.g., Dietz et al 2014), and pharmacogenetic manipulations of neural activity in targeted neuron populations via the use of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) (e.g., Nguyen et al 2014), among other techniques. These strategies are not without potential pitfalls, including the importance of assessing hearing loss in mutant animals as a potential basis for reduced inhibitory effects of auditory prepulses.…”

Enhanced Neuronal Activity in the Medial Prefrontal Cortex during Social Approach Behavior

“…It could be the target animal's movement, odor, or sound, or some combination of these factors. A previous study has shown that olfactory cues are sufficient to elicit social approach behaviors in mice (Ryan et al, 2008). However, it is possible that other sensory cues, or their combinations with olfactory cues, contribute to social approach behaviors.…”

“…Mouse models of social dysfunction are widely used to investigate neural mechanisms underlying various neuropsychiatric diseases, such as autism spectrum disorders (ASDs), depression, and schizophrenia (Bey and Jiang, 2001;Yang et al, 2011;Ting et al, 2012;Kleijer et al, 2014;Lombardi et al, 2015;Kazdoba et al, 2016). Previous studies have found that the medial prefrontal cortex (mPFC) plays a crucial role in mouse social behavior.…”

“…We addressed this issue in the present study by examining the activity of mPFC neurons in mice during a three-chamber test (Crawley, 2004), which is widely used to measure social dysfunction in animal models of ASDs (Won et al, 2012;Huang et al, 2014;Chung et al, 2015), schizophrenia (Del Pino et al, 2013;Nguyen et al, 2014), and other neurodevelopmental disorders (Grayton et al, 2013;Barnes et al, 2015). In the three-chamber test, a subject mouse is allowed to explore two opposing chambers containing another mouse (social stimulus) or an inanimate object (nonsocial stimulus), and the relative amount of time spent exploring the social versus nonsocial target is used as an index of social preference.…”

Functional G-protein-coupled receptor 35 is expressed by neurons in the CA1 field of the hippocampus

“…Considering that: (i) KYNA is a known GPR35 agonist [2], (ii) cognitive impairments in patients with schizophrenia and in preclinical rodent models of the disease appear to be linked to decreased interneuron function [34,35], and (iii) GPR35 activation, as shown here, leads to a reduction of SRI firing, it is tempting to hypothesize that KYNA-induced activation of GPR35 in SRIs may be one of the molecular mechanisms underlying the pathophysiology of this catastrophic disorder. If this hypothesis holds true, then centrally acting GPR35 antagonists would emerge as promising therapeutic measures to mitigate signs and symptoms resulting from KYNA-induced disruption of the functionality of hippocampal networks in schizophrenia.…”