Disruption of Nrxn1a Within Excitatory Forebrain Circuits Drives Value-Based Dysfunction

Alabi, Opeyemi O.; Robinson, Mara; Fortunato, Michael; Kable, Joe; Fuccillo, Marc V.

doi:10.1016/j.biopsych.2020.02.190

Cited by 1 publication

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“…Nevertheless, this selective decrease in cortical-iSPN excitatory drive is expected to promote disinhibition of thalamic structures projecting back to the cortex. It is an interesting future question as to whether this thalamic disinhibition can explain both simple motor phenotypes (e.g., hyperactivity, aggression) (Etherton et al, 2009;Grayton et al, 2013) and more complex reward-processing deficits observed in mice with Nrxn1a mutations (Alabi et al, 2020). It is worth noting a recent study of the Tsc1 deletion ASD mouse model, which exhibited increased corticostriatal connectivity selectively onto dSPNs, with synaptic strength unperturbed at thalamostriatal synapses (Benthall et al, 2018).…”

Section: Nrxn1a Maintains Nmdar Function At Pfas-dms Synapses Onto Both Dms Spn Subtypesmentioning

confidence: 99%

Neurexin1⍺ differentially regulates synaptic efficacy within striatal circuits

Davatolhagh

Fuccillo

2021

Cell Reports

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SUMMARY Mutations in genes essential for synaptic function, such as the presynaptic adhesion molecule Neurexin1α (Nrxn1α), are strongly implicated in neuropsychiatric pathophysiology. As the input nucleus of the basal ganglia, the striatum integrates diverse excitatory projections governing cognitive and motor control, and its impairment may represent a recurrent pathway to disease. Here, we test the functional relevance of Nrxn1α in striatal circuits by employing optogenetic-mediated afferent recruitment of dorsal prefrontal cortical (dPFC) and parafascicular thalamic connections onto dorsomedial striatal (DMS) spiny projection neurons (SPNs). For dPFC-DMS circuits, we find decreased synaptic strength specifically onto indirect pathway SPNs in both Nrxn1α +/− and Nrxn1α −/− mice, driven by reductions in neurotransmitter release. In contrast, thalamic excitatory inputs to DMS exhibit relatively normal excitatory synaptic strength despite changes in synaptic N -methyl-D-aspartate receptor (NMDAR) content. These findings suggest that dysregulation of Nrxn1α modulates striatal function in an input- and target-specific manner.

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