Sensory encoding in Neuregulin 1 mutants

Abstract

Schizophrenic patients show altered sensory perception as well as changes in electrical and magnetic brain responses to sustained, frequency-modulated sensory stimulation. Both the amplitude and temporal precision of the neural responses differ in patients as compared to control subjects, and these changes are most pronounced for stimulation at gamma frequencies (20–40 Hz). In addition, patients display enhanced spontaneous gamma oscillations, which has been interpreted as ‘neural noise’ that may interfere with normal stimulus processing. To investigate electrophysiological markers of aberrant sensory processing in a model of schizophrenia, we recorded neuronal activity in primary somatosensory cortex of mice heterozygous for the schizophrenia susceptibility gene Neuregulin 1. Sensory responses to sustained 20–70 Hz whisker stimulation were analyzed with respect to firing rates, spike precision (phase locking) and gamma oscillations, and compared to baseline conditions. The mutants displayed elevated spontaneous firing rates, a reduced gain in sensory-evoked spiking and gamma activity, and reduced spike precision of 20–40 Hz responses. These findings present the first in vivo evidence of the linkage between a genetic marker and altered stimulus encoding, thus suggesting a novel electrophysiological endophenotype of schizophrenia.

Neuregulin-1 and schizophrenia in the genome-wide association study era

“…One study also suggests that excess Nrg1 may lead to similar impairments, as peak frequency, but not amplitude, of gamma oscillations were reduced in type I Nrg1 over-expressing mice (Deakin et al 2012), which also supports the inverted "U" model of Nrg1 function (Agarwal et al 2014;Law 2014;Talmage 2008). Gamma oscillations are linked to cognitive performance in humans (Engel et al 2015;Heermann et al 2011;Jensen et al 2007) and mice with abnormal Nrg1 expression which have the aforementioned deficits in evoked gamma oscillations, also have cognitive deficits (Agarwal et al 2014;Barz et al 2014;Chen et al 2008;Chesworth et al 2012;Duffy et al 2010;Yin et al 2013). Therefore, maladaptive gamma oscillations, putatively stemming from Nrg1-induced GABAergic dysfunction, may be a key downstream neurobiological consequence of abnormal Nrg1 expression, mediating risk for schizophrenia.…”

“…Similarly, baseline synaptic firing of somatosensory neurons in EGF-like domain "knockout" mice is significantly above control levels. In contrast, these same Nrg1 models show deficits in evoked gamma oscillations induced by whisker stimulation (Barz et al 2014), auditory cues -albeit all Nrg1 mutant mice are known to have auditory abnormalities (Jin et al 2011;Kato et al 2015;Stankovic et al 2004;Tang et al 2015) -and the psychotomimetic, ketamine (Long et al 2015) whilst addition of Nrg1 in wild-type mice has been shown to enhance kainic-acid evoked gamma oscillations in prefrontal cortex (Hou et al 2014) and hippocampus (Fisahn et al 2009), the former in vivo and the latter in vitro. One study also suggests that excess Nrg1 may lead to similar impairments, as peak frequency, but not amplitude, of gamma oscillations were reduced in type I Nrg1 over-expressing mice (Deakin et al 2012), which also supports the inverted "U" model of Nrg1 function (Agarwal et al 2014;Law 2014;Talmage 2008).…”

Altered resonance properties of somatosensory responses in mice deficient for the schizophrenia risk gene Neuregulin 1

“…The experimental procedures have been previously described in detail (Barz et al 2014). Briefly, 5 adult (4–6 months old) heterozygous NRG1 male mice ( NRG1 +/−) and 5 adult male wildtype (WT) littermates ( NRG1 +/+) were used for the experiments.…”

“…These include deficits in auditory novelty detection, contextual fear conditioning and social interaction (Ehrlichman et al 2009), as well as hyperlocomotion and deficient sensory gating after pharmacological challenge (Duffy et al 2008). In addition, recent research indicates that the temporal precision of neuronal responses during 20–40 Hz whisker stimulation is reduced in the somatosensory cortex of NRG1 (+/−) mutants (Barz et al 2014). Moreover, baseline activity was significantly elevated in the mutants.…”

“…Moreover, baseline activity was significantly elevated in the mutants. When stimulus-evoked spike rates were normalized by baseline spike levels, mutant mice displayed significant reductions in their spike signal-to-noise level across the tested frequencies (20–70 Hz; Barz et al 2014). However, responses in the low-frequency (1–15 Hz) range have not been characterized so far.…”