Cntn4, a risk gene for neuropsychiatric disorders, modulates hippocampal synaptic plasticity and behavior

Abstract

Neurodevelopmental and neuropsychiatric disorders, such as autism spectrum disorders (ASD), anorexia nervosa (AN), Alzheimer’s disease (AD), and schizophrenia (SZ), are heterogeneous brain disorders with unknown etiology. Genome wide studies have revealed a wide variety of risk genes for these disorders, indicating a biological link between genetic signaling pathways and brain pathology. A unique risk gene is Contactin 4 (Cntn4), an Ig cell adhesion molecule (IgCAM) gene, which has been associated with several neuropsychiatric disorders including ASD, AN, AD, and SZ. Here, we investigated the Cntn4 gene knockout (KO) mouse model to determine whether memory dysfunction and altered brain plasticity, common neuropsychiatric symptoms, are affected by Cntn4 genetic disruption. For that purpose, we tested if Cntn4 genetic disruption affects CA1 synaptic transmission and the ability to induce LTP in hippocampal slices. Stimulation in CA1 striatum radiatum significantly decreased synaptic potentiation in slices of Cntn4 KO mice. Neuroanatomical analyses showed abnormal dendritic arborization and spines of hippocampal CA1 neurons. Short- and long-term recognition memory, spatial memory, and fear conditioning responses were also assessed. These behavioral studies showed increased contextual fear conditioning in heterozygous and homozygous KO mice, quantified by a gene-dose dependent increase in freezing response. In comparison to wild-type mice, Cntn4-deficient animals froze significantly longer and groomed more, indicative of increased stress responsiveness under these test conditions. Our electrophysiological, neuro-anatomical, and behavioral results in Cntn4 KO mice suggest that Cntn4 has important functions related to fear memory possibly in association with the neuronal morphological and synaptic plasticity changes in hippocampus CA1 neurons.

Pcdh11x controls target specification of mossy fiber sprouting

“…We shortlisted these molecules for further analysis. Although Cntn4 was significantly enriched only in 14-day KA GCs after MF sprouting has developed, we also shortlisted this gene, because it has been linked to circuit formation ( Oguro-Ando et al, 2017 ), target specification ( Osterhout et al, 2015 ), synaptic plasticity ( Oguro-Ando et al, 2021 ), neurodevelopmental disorders ( Baig et al, 2017 ; Oguro-Ando et al, 2017 ), and Alzheimer’s disease ( Carrasquillo et al, 2009 ). In addition, we looked for CAMs, whose abundance change has been reported in different temporal lobe epilepsy models or in MF sprouting (see section “Discussion,” Figure 1C ).…”

Contribution of copy number variations to the risk of severe eating disorders

“…28 CNTN4 has an important function related to synaptic plasticity and associative learning. 29 Cntn4-deficient mice show increased fear conditioning, which is a potential underlying mechanism of AN. 30 In gene set analysis, we observed a nominally significant enrichment of rare exonic CNVs in synaptic signaling in ED patients.…”

“…RBFOX1 plays a critical role in shaping excitatory and inhibitory synaptic function and neuronal connectivity 28 . CNTN4 has an important function related to synaptic plasticity and associative learning 29 . Cntn4 ‐deficient mice show increased fear conditioning, which is a potential underlying mechanism of AN 30 …”

Connecting the Neurobiology of Developmental Brain Injury: Neuronal Arborisation as a Regulator of Dysfunction and Potential Therapeutic Target

“…Dystroglycan, an extracellular matrix protein, has been shown to stimulate the growth of dendritic arbours in mouse hippocampal neurons in vitro in a manner dependent on cell division control protein 42 (Cdc42) GTPase [ 70 ]. CNTN4, a protein associated with schizophrenia and most commonly found to alter synaptic function, has also been shown to regulate arborisation of hippocampal neurons in the mouse [ 101 ]. However, in this case, the effect was relatively small, possibly reflecting the primary role of CNTN4 in synapse organisation and, therefore, the late stage at which it acts in development.…”