Disrupted Activity in the Hippocampal–Accumbens Circuit of Type III Neuregulin 1 Mutant Mice

Abstract

Neuregulin 1 (Nrg1), a schizophrenia susceptibility gene, is involved in fundamental aspects of neurodevelopment. Mice lacking any one of several isoforms of Nrg1 have a variety of schizophrenia-related phenotypes, including deficits in working memory and sensorimotor gating, loss of spines in pyramidal neurons in the ventral subiculum, loss of dendrites in cortical pyramidal cells, loss of parvalbumin-positive interneurons in the prefrontal cortex, and altered plasticity in cortico-limbic synapses (Chen et al., 2008; Zhong et al., 2008; Chen et al., 2010);. Mice heterozygous for a disruption in exon 7 of the Nrg1 genelack Type-III (cysteine-rich domain-containing) isoforms and have sensorimotor gating deficits that may involve changes in the activity of a circuit involving projections from the ventral hippocampus (vHPC) to medium spiny neurons in the nucleus accumbens (nACC). To explore the neural basis of these deficits, we examined electrophysiological activity in the nACC and vHPC of these mice. Under urethane anesthesia, bursts of spontaneous activity propagated from the vHPC to the nACC in both wild-type and mutant mice. However, these bursts were weaker in mutant nACC, with reduced local field potential amplitude and spiking activity. Single units in mutant nACC fired less frequently within the bursts, and more frequently outside of the bursts. Moreover, within-burst nACC spiking was less modulated by vHPC activity, as determined by phase-locking to the low-frequency oscillatory components of the bursts. These data suggest that the efficacy of vHPC input to the nACC is reduced in the Type III Nrg1 heterozygotes, supporting a role for Nrg1 in the functional profile of hippocampal-accumbens synapses.

Brain Rhythms Connect Impaired Inhibition to Altered Cognition in Schizophrenia

“…In the ventral striatum, schizophrenia-associated abnormalities may decrease hippocampal θ modulation [113, 114]. In rat dorsal striatum, dopamine agonism changes low-frequency phase modulation of high frequency power from the δ to the θ band [115], suggesting coordination with hippocampus rather than PFC [109].…”

Sensory encoding in Neuregulin 1 mutants

“…Similarly, other studies reported that NRG1 treatment of hippocampal slices had no effects on basal synaptic transmission (Bjarnadottir et al 2007; Huang et al 2000; Kwon et al 2005), although one study reported increased firing rates of inhibitory cells in hippocampal and cortical slices after NRG1 treatment (Li et al 2011). Moreover, acute extracellular recordings of single cells and LFPs in hippocampus and nucleus accumbens in urethane anesthetized NRG1 type III knockouts revealed no difference in mean firing rates between mutant and WT neurons (Nason et al 2011). The contradiction with our results may be explained by differences in recording methodology (in vitro versus in vivo), anesthesia type and depth, or differences in the brain region and NRG1 isoform/mutation under investigation.…”

“…The contradiction with our results may be explained by differences in recording methodology (in vitro versus in vivo), anesthesia type and depth, or differences in the brain region and NRG1 isoform/mutation under investigation. With regard to anesthesia, baseline firing rates are generally decreased under deep anesthesia such as under urethane, which may occlude potential NRG1-related changes in firing rate in the nucleus accumbens (Nason et al 2011). More generally, it is conceivable that NRG1-related effects on baseline firing rates are dependent on the precise excitatory–inhibitory tuning of the network, which might differ according to the type of NRG1 mutation or isoform, the connectivity in the brain region being studied, and the brain state (awake versus anesthetized).…”

“…Previous research has investigated changes in phase relationships between oscillatory brain activity (i.e., LFPs) in various schizophrenia models, revealing alterations in phase locking between brain areas (phase coherence; Del Pino et al 2013; Nason et al 2011; Nicolás et al 2011; Sigurdsson et al 2010; Zhang et al 2012) and between trials (intertrial coherence; Carlson et al 2011; Featherstone et al 2013; Vohs et al 2012). To the best of our knowledge, only two studies have examined the timing of action potentials in rodent models of schizophrenia.…”

“…Describing the baseline activity in freely moving or anesthetized animals, studies found enhancements in oscillatory 30–80 Hz power (Carlen et al 2012; Del Pino et al 2013; Gandal et al 2012b; Hakami et al 2009; Kittelberger et al 2012; Kocsis 2012; Kulikova et al 2012; Ma and Leung 2007; Marquis et al 1989; Molina et al 2014; Pinault 2008) and in spiking activity (Belforte et al 2010; Carlen et al 2012; Jackson et al 2004; Molina et al 2014; Wood et al 2012; Zhang et al 2012) in different cortical and subcortical regions. In addition, reduced temporal precision of spiking and oscillatory activity has been reported in these models, in particular in the hippocampus and prefrontal cortex (Carlson et al 2011; Del Pino et al 2013; Featherstone et al 2013; Molina et al 2014; Nason et al 2011; Sigurdsson et al 2010; Zhang et al 2012). …”