Parvalbumin interneuron dysfunction in a thalamus - prefrontal cortex circuit in Disc1 deficiency mice

Two of the most consistent findings across disrupted-in-schizophrenia-1 (DISC1) mouse models are impaired working memory and reduced number or function of parvalbumin interneurons within the prefrontal cortex. While these findings suggest parvalbumin interneuron dysfunction in DISC1-related pathophysiology, to date, cortical inhibitory circuit function has not been investigated in depth in DISC1 deficiency mouse models. Here we assessed the function of a feedforward circuit between the mediodorsal thalamus (MD) and the medial prefrontal cortex (mPFC) in mice harboring a deletion in one allele of the Disc1 gene. We found that the inhibitory drive onto layer 3 pyramidal neurons in the mPFC was significantly reduced in the Disc1 deficient mice. This reduced inhibition was accompanied by decreased GABA release from local parvalbumin, but not somatostatin, inhibitory interneurons, and by impaired feedforward inhibition in the MD-mPFC circuit. Our results reveal a cellular mechanism by which deficiency in DISC1 causes neural circuit dysfunction frequently implicated in psychiatric disorders. Mounting evidence suggests that dysregulation of excitation-inhibition (E-I) balance in neural circuits may be a pathophysiological feature of schizophrenia (Lewis et al., 2011; Lisman, 2012). Data from rodent studies support the role of prefrontal fastspiking parvalbumin (PV) inhibitory interneurons (INs) in cognitive tasks that are impaired in schizophrenia, particularly working memory (Cho et al., 2015; Murray et al., 2015). Cognitive impairment is commonly seen in first-degree relatives of individuals with schizophrenia (Cannon et al., 2000; Myles-Worsley and Park, 2002; Snitz et al., 2006), suggesting that cognitive functions such as working memory, and the brain structures and circuits that subserve them, are highly heritable. Disrupted-in-schizophrenia-1 (DISC1) has emerged as a rare, but penetrant genetic risk factor for psychopathology (Millar et al., 2000), and DISC1 polymorphisms have been reported to correlate with measures of cognitive performance and frontal lobe structure (Cannon et al., 2005; Carless et al., 2011; Hennah et al., 2005; Palo et al., 2007). Work in mouse models has revealed the importance of the Disc1 gene in neurodevelopment (Kamiya et al., 2005; Mao et al., 2009; Niwa et al., 2010), synaptic function (Hayashi-Takagi et al., 2010; Maher and LoTurco, 2012; Sauer et al., 2015; Seshadri et al., ∗We thank members of the B.L. laboratory for discussions. This work was supported by a National Institutes of Health (NIH) training grant (K.D.), and grants from the NIH (B.L. and A.S.), National Alliance for Research on Schizophrenia and Depression (NARSAD) (B.L.), the Wodecroft Foundation (B.L.), the Stanley Family Foundation (B.L.), Simons Foundation Autism Research Initiative (SFARI) (B.L.), and Louis Feil Trust (B.L.). 2015; Wang et al., 2011; Wei et al., 2015), and cognitive processing (Brandon and Sawa, 2011). Notably, working memory impairments are consistently reported across DISC1 mouse models tested (Brandon and Sawa, 2011; Clapcote et al., 2007; Koike et al., 2006; Kvajo et al., 2008; Lee et al., 2013; Li et al., 2007; Lipina et al., 2010; Niwa et al., 2010). Furthermore, a variety of DISC1 mouse models also exhibit reduced prefrontal PV expression (Ayhan et al., 2011; Hikida et al., 2007; Ibi et al., 2010; Lee et al., 2013; Niwa et al., 2010; Shen et al., 2008), suggesting that PV INs may be particularly affected by DISC1 perturbation. To improve our understanding of the role of DISC1 in prefrontal cortical circuit function, we examined local and long-range circuits of the mPFC in mice heterozygous for a deficiency (df) allele of the Disc1 gene (Disc1df/+) (Seshadri et al., 2015; Shahani et al., 2015). We found that Disc1df/+ mice exhibited a specific deficit in inhibitory synaptic transmission. This deficit is expressed as reduced frequency of miniature inhibitory post-synaptic currents (mIPSCs) onto layer 3 (L3) pyramidal neurons (PNs), increased paired-pulse ratio of IPSCs onto these PNs driven by local PV INs, and impaired feedforward inhibition in the mediodorsal thalamus-mPFC circuit that is mediated by PV INs in the mPFC (Delevich et al., 2015). These data support the hypothesis that the genetic risk factor DISC, impacts the function of PV INs, and provide insight into the synaptic and circuit mechanisms of DISC1-related cognitive dysfunction. 1 . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/054759 doi: bioRxiv preprint first posted online May. 21, 2016;