The distribution of neuroligin4, an autism-related postsynaptic molecule, in the human brain

Abstract

NLGN4X was identified as a single causative gene of rare familial nonsyndromic autism for the first time. It encodes the postsynaptic membrane protein Neuroligin4 (NLGN4), the functions and roles of which, however, are not fully understood due to the lack of a closely homologous gene in rodents. It has been confirmed only recently that human NLGN4 is abundantly expressed in the cerebral cortex and is localized mainly to excitatory synapses. However, the detailed histological distribution of NLGN4, which may have important implications regarding the relationships between NLGN4 and autistic phenotypes, has not been clarified. In this study, we raised specific monoclonal and polyclonal antibodies against NLGN4 and examined the distribution of NLGN4 in developing and developed human brains by immunohistochemistry. We found that, in the brain, NLGN4 is expressed almost exclusively in neurons, in which it has a widespread cytoplasmic pattern of distribution. Among various types of neurons with NLGN4 expression, we identified consistently high expression of NLGN4 in hypothalamic oxytocin (OXT)/vasopressin (AVP)-producing cells. Quantitative analyses revealed that the majority of OXT/AVP-producing neurons expressed NLGN4. NLGN4 signals in other large neurons, such as pyramidal cells in the cerebral cortex and hippocampus as well as neurons in the locus coeruleus and the raphe nucleus, were also remarkable, clearly contrasting with no or scarce signals in Purkinje cells. These data suggest that NLGN4 functions in systems involved in intellectual abilities, social abilities, and sleep and wakefulness, impairments of which are commonly seen in autism.

Neuroplasticity of children in autism spectrum disorder

“…One study found that mice prenatally exposed to valproic acid (VPA) exhibited cognitive and motor deficits in Y-maze learning, which may be due to reduced levels of proteins involved in excitatory synapse formation, such as Nlgn1 and PSD-95 ( 80 ). Among the subtypes of Nlgn, the Nlgn2 gene is often reduced in expression in severe neuropsychiatric disorders ( 81 ), Nlgn3 primarily mediates enteric neuron-neuroglial ( 82 ), and Nlgn4 is primarily involved in functioning in intelligence, social skills, sleep, and arousal ( 83 ) and impairments of all of these subtypes are associated with ASD. Additionally, GPR85, an ASD risk factor, associates with NLGN-associated postsynaptic density protein PSD-95 in brain, interfering with dendritic formation via the NLGN-PSD-95 receptor complex and causing neural excitation-inhibition imbalance, affecting learning and memory ( 84 ).…”

Micro-Scale Control of Oligodendrocyte Morphology and Myelination by the Intellectual Disability-Linked Protein Acyltransferase ZDHHC9

“…Given that many XLID genes are neuronally enriched (4)(5)(6)(7)(8)(9)(10), an a priori hypothesis is that ZDHHC9 acts in neurons. However, patients with ZDHHC9 mutations have grossly normal gray matter (GM) but reduced brain white matter (WM) volume, especially in the corpus callosum (CC)…”