Parvalbumin-containing GABA cells and schizophrenia: experimental model based on targeted gene delivery through adeno-associated viruses.

Abstract

Understanding the contribution of transmitter systems in behavioural pharmacology has a long tradition. Multiple techniques such as transmitter-specific lesions, and also localized administration of pharmacological toxins including agonists and antagonists of selected receptors have been applied. More recently, modern genetic tools have permitted cell-type selective interferences, for example by expression of light-sensitive channels followed by optogenetic stimulation in behaviourally meaningful settings or by engineered channels termed DREADDS that respond to peripherally administered drugs. We here took a similar approach and employed a Cre recombinase-dependent viral delivery system (adeno-associated virus) to express tetanus toxin light chain (TeLc) and thus, block neural transmission specifically in parvalbumin-positive (PV+) neurons of the limbic and infralimbic prefrontal circuitry. PV-TeLc cohorts presented with normal circadian activity as recorded in PhenoTyper home cages, but a reproducible increase in anxiety was extracted in both the open field and light-dark box. Interestingly, working memory assessed in a spontaneous alternation Y-maze task was impaired in PV-TeLc mice. We also recorded local field potentials from a separate cohort and found no global changes in brain activity, but found a behaviourally relevant lack of modulation in the gamma spectral band. These anomalies are reminiscent of endophenotypes of schizophrenia and appear to be critically dependent on GABAergic signalling through PV neurones. At the same time, these observations validate the use of viral vector delivery and its expression in Cre-lines as a useful tool for understanding the role of selective components of the brain in behaviour and the underpinning physiology.