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

Abstract

To reveal the neuronal underpinnings of sensory processing deficits in patients with schizophrenia, previous studies have investigated brain activity in response to sustained sensory stimulation at various frequencies. This paradigm evoked neural activity at the stimulation frequency and harmonics thereof. During visual and auditory stimulation that elicited enhanced or ‘resonant’ responses in healthy controls, patients with schizophrenia displayed reduced activity. The present study sought to elucidate the cellular basis of disease-related deficits in sensory resonance properties using mice heterozygous for the schizophrenia susceptibility gene Neuregulin 1 (NRG1). We applied repetitive whisker stimulation at 1–15 Hz, a range relevant to whisking behavior in mice, and measured cellular activity in the primary somatosensory cortex. At frequencies where control mice displayed enhancements in measures of response magnitude and precision, NRG1 (+/−) mutants showed reductions. Our results demonstrate for the first time a link between a mutation of a schizophrenia risk gene and altered neuronal resonance properties in sensory cortex.

GABAergic Abnormalities Associated with Sensorimotor Cortico-striatal Community Structural Deficits in ErbB4 Knockout Mice and First-Episode Treatment-Naïve Patients with Schizophrenia

“…Our data confirmed that the NRG1 and PLCG1 mRNA levels were significantly decreased in the right somatosensory cortex and striatum in ErbB4-KO mice, suggesting changes in ErbB4-NRG1 signaling in this schizophrenia-like mouse model. In line with this result, previous studies have also reported decreased ErbB4 protein and NRG1-related cellular activity in the somatosensory cortex in schizophrenic patients [17,44].…”

Neurovascular unit alteration in somatosensory cortex and enhancement of thermal nociception induced by amphetamine involves central AT1 receptor activation

“…Psychostimulants, such as amphetamine (Amph) and its derivatives, increase catecholaminergic neurotransmission and elicit neuroinflammatory effects that lead to neurodegeneration processes along with glial and vascular alterations (Moratalla et al ., ). Moreover, repeated Amph exposure has been associated with altered perception, similar to the sensory dysfunctions described for brain disorders that involve dopaminergic neurotransmission imbalance and neuroinflammation, such as Parkinson and schizophrenia (Govindaiah et al ., ; Jukkola et al ., ; Barz et al ., ). The primary somatosensory cortex (S1) is the main responsible area for sensory afferent inputs processing and its integration with motor responses, two essential processes for proper organism‐environment interaction (Borich et al ., ; Berman et al ., ).…”

Developmental Dysfunction of VIP Interneurons Impairs Cortical Circuits

“…ErbB4 expression is restricted to GABAergic neurons in the cortex (Yau et al, 2003; Flames et al, 2004; Neddens et al, 2011), and this pathway plays a role in regulating GABAergic synaptic development (Fazzari et al, 2010; Del Pino et al, 2013). ErbB4 signaling is necessary for normal interneuron migration and synapse formation during development (Fazzari et al, 2010; Shamir et al, 2012), and global disruptions of the Nrg-1/ErbB4 pathway lead to decreased GABA release in the mature cerebral cortex (Woo et al, 2007; Mei and Xiong, 2008; Neddens and Buonanno, 2010; Ting et al, 2011) and impaired circuit function in mature animals (Barz et al, 2015, 2016). Disruption of the Nrg1-ErbB4 pathway specifically in PV interneurons reduces excitatory synaptic input to these cells and appears to contribute to the behavioral and neural phenotypes observed in the total ErbB4 deletion model (Chen et al, 2010; Wen et al, 2010; Shamir et al, 2012; Del Pino et al, 2013).…”