Autism Related Neuroligin-4 Knockout Impairs Intracortical Processing but not Sensory Inputs in Mouse Barrel Cortex

Abstract

Neuroligin-4 (Nlgn4) is a cell adhesion protein that regulates synapse organization and function. Mutations in human NLGN4 are among the causes of autism spectrum disorders. In mouse, Nlgn4 knockout (KO) perturbs GABAergic synaptic transmission and oscillatory activity in hippocampus, and causes social interaction deficits. The complex profile of cellular and circuit changes that are caused by Nlgn4-KO is still only partly understood. Using Nlgn4-KO mice, we found that Nlgn4-KO increases the power in the alpha frequency band of spontaneous network activity in the barrel cortex under urethane anesthesia in vivo. Nlgn4-KO did not affect single-whisker-induced local field potentials, but suppressed the late evoked multiunit activity in vivo. Although Nlgn4-KO did not affect evoked EPSCs in layer 4 (L4) spiny stellate cells in acute thalamocortical slices elicited by electrical stimulation of thalamocortical inputs, it caused a lower frequency of both miniature (m) IPSCs and mEPSCs, and a decrease in the number of readily releasable vesicles at GABAergic and glutamatergic connections, weakening both excitatory and inhibitory transmission. However, Nlgn4 deficit strongly suppresses glutamatergic activity, shifting the excitation-inhibition balance to inhibition. We conclude that Nlgn4-KO does not influence the incoming whisker-mediated sensory information to the barrel cortex, but modifies intracortical information processing.

Oxytocin administration in neonates shapes the hippocampal circuitry and restores social behavior in a mouse model of autism

“…Reductions in synaptic signal-to-noise in cortical and hippocampal pyramidal neurons, driven by a change in the ratio of dendritic excitatory and inhibitory synapses, are widely thought to contribute to reduced efficiency of signal processing in ASD, a mechanism known as the E/I ratio hypothesis (67). We confirm E/I imbalance characterized by increased GABAergic activity and lower glutamatergic activity in CA3 neurons in Magel2 KO mice, consistent with observations made in other ASD models (68)(69)(70)(71). Furthermore, we report that perinatal OT administration restored normal GABAergic activity in Magerl2 KO mice without improving glutamatergic transmission.…”

Microphthalmia, Linear Skin Defects, Callosal Agenesis, and Cleft Palate in a Patient with Deletion at Xp22.3p22.2

“…There is no clear correspondence with the phenotypes from these genes with those of our patient. The NLGN4 gene, for example, has been associated with manifestations within the autism spectrum, [39][40][41][42] which is not observed in our patient. On the other hand, our patient presents short stature but SHOX 42 , a known gene related to short stature, 43,44 that maps to the short arm of the X-chromosome, is not deleted in our patient.…”

Modulation of Neocortical Development by Early Neuronal Activity: Physiology and Pathophysiology

“…The same group demonstrated that expression of an ASD-related mutation of the postsynaptic adhesion molecule neuroligin-3 leads to an enhanced frequency of GDPs in the immature hippocampus (Pizzarelli and Cherubini, 2013 ). Knockout of neuroligin-4, another ASD related member of the neuroligin family, enhances the occurrence and duration of spontaneous spindle bursts in mouse cortex (Unichenko et al, 2017 ). In summary, these studies illustrate that an adequate amount of spontaneous activity may be the prerequisite for proper neurodevelopment, and both enhanced and reduced activity levels may lead to adverse outcomes.…”