Neuroligins in neurodevelopmental conditions: how mouse models ofde novomutations can help us link synaptic function to social behavior

Abstract

Neurodevelopmental conditions (or neurodevelopmental disorders, NDDs) are highly heterogeneous with overlapping characteristics and shared genetic etiology. The large symptom variability and etiological heterogeneity have made it challenging to understand the biological mechanisms underpinning NDDs. To accommodate this individual variability, one approach is to move away from diagnostic criteria and focus on distinct dimensions with relevance to multiple NDDs. This domain approach is well suited to preclinical research, where genetically modified animal models can be used to link genetic variability to neurobiological mechanisms and behavioral traits. Genetic factors associated with NDDs can be grouped functionally into common biological pathways, with one prominent functional group being genes associated with the synapse. These include the neuroligins, a family of postsynaptic transmembrane proteins that are key modulators of synaptic function. Here, we review how research using neuroligin mouse models has provided insight into how synaptic proteins contribute to behavioral traits associated with NDDs. We focus on how mutations in different neuroligins affect social behaviors, as differences in social interaction and communication are a common feature of most NDDs. Importantly, mice carrying distinct mutations in neuroligins share some neurobiological and behavioral phenotypes with other synaptic gene mutations. Comparing the functional implications of mutations in multiple synaptic proteins is a first step toward identifying convergent neurobiological pathways in multiple brain regions and circuits.

Designer molecules of the synaptic organizer MDGA1 reveal 3D conformational control of biological function

“…Genetic abnormalities of MDGAs, NLGNs, and NRXNs are implicated in the pathogenesis of neuropsychiatric disorders, such as autism spectrum disorder, schizophrenia (SZ), and bipolar disorder (1,(15)(16)(17)(18)(19). Furthermore, dysfunction of MDGAs, NLGNs, and NRXNs appears to alter excitation/ ‡ Co-first authors.…”

Inhibitory Synaptic Influences on Developmental Motor Disorders

“…Altered synaptic stabilization molecules are noted for their influence on development. At GABAergic synapses, Neuroligin-2 is predominantly associated with neurobehavioural disorders, including autism and attention deficit hyperactivity disorder and reduced GABAergic inhibitory neurotransmission [ 142 , 143 , 144 ]. By contrast, the gephyrin mutant, which lacks the glycine receptor binding and destabilization has a phenotype at birth, with marked startle responses and death from respiratory muscle dysfunction [ 145 , 146 ].…”

Designer molecules of the synaptic organizer MDGA1 reveal 3D conformational control of biological function

“…Genetic abnormalities of MDGAs, NLGNs, and NRXNs are implicated in the pathogenesis of neuropsychiatric disorders, such as autism spectrum disorders, schizophrenia (SZ), and bipolar disorder ( 1 , 15 , 16 , 17 , 18 , 19 ). Furthermore, dysfunction of MDGAs, NLGNs, and NRXNs appears to alter excitation/inhibition balances in brain circuits, disrupting—for instance—neural circuits critical for cognition and behavior ( 1 , 3 , 4 , 7 , 9 , 20 ).…”