Neurexin1⍺ differentially regulates synaptic efficacy within striatal circuits

Abstract

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.

Schizophrenia-associatedNRXN1deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids

“…First, the NMDAR subunit GRIN2B was differentially expressed in GABAergic neurons across genetic backgrounds. This finding was significant as it confirms previous results showing that Nrxn1 signals through NMDARs 9,10 and NRXN1 haploinsufficient human induced neurons carry upregulated levels of the endogenous NMDAR antagonist KYAT3 35 . Moreover, genetic variants in the NMDAR subunits, GRIN2B and GRIN2A , are both observed in SCZ populations 63,66,67 .…”

“…Neurexin-1 (NRXN1), the single gene present in this locus, encodes a type I membrane cell adhesion molecule that functions as a synaptic organizer at central synapses 7 . NRXN1, as a presynaptic molecule, associates with multiple soluble and transmembrane molecules, thereby endowing specific synapses with unique synaptic signaling and transmission properties [8][9][10][11][12][13] . NRXN1 also undergoes extensive alternative splicing, further enriching the diversity of these interactions [14][15][16][17] .…”

Neurexin1α knockout rats display oscillatory abnormalities and sensory processing deficits back-translating key endophenotypes of psychiatric disorders

“…From a mechanistic perspective, we suggest N-Methyl-d-aspartate receptor (NMDAR) hypofunction to be involved in the oscillatory abnormalities and sensory processing deficits we identified in Nrxn1α −/− rats for two reasons. First, Nrxn1 has been shown to be important for postsynaptic NMDAR recruitment and function [ 3 , 25 ] and second, core endophenotypes found in our study, such as increased spontaneous gamma power and deficits in MMN-like responses can be induced by pharmacological blockade of NMDAR in rat [ 35 , 84 – 86 ], non-human primate [ 87 – 89 ] and human [ 90 – 92 ]. In this regard, our results line up with the NMDAR hypofunction hypothesis for SZ and ASD [ 93 , 94 ] by linking characteristic NMDAR-dependent translational endophenotypes to disease-relevant Nrxn1α deletions with construct validity.…”

“…However, a recent patch-clamp study demonstrated hyperexcitability of patient-derived stem cells with deletion specifically in Nrxn1α [ 20 ], which may manifest as epilepsy on the network level [ 21 – 23 ]. Rodent models with deletion of Nrxn1α display synaptic deficits as well, including decreased excitatory postsynaptic currents in CA1 pyramidal cells [ 4 ], reduced inhibition from a subpopulation of hippocampal interneurons [ 24 ], reduction of thalamic and cortical excitatory drive to striatal spiny projection neurons [ 25 ], disruption of synaptic transmission from the prefrontal cortex to the amygdala, as well as impaired feedforward inhibition within the amygdala [ 26 ]. On the behavioral level, Nrxn1 KO mice and rats elicit autistic-like traits [ 27 – 29 ], including learning deficits, increased grooming, deficits in sensorimotor gating and altered social behavior.…”

Spatial and Temporal Gene Function Studies in Rodents: Towards Gene-Based Therapies for Autism Spectrum Disorder

“…A conditional deletion of Nrxn1α in excitatory telencephalic forebrain circuits leads to reward processing dysfunctions in mice, underscoring the importance of Nrxn1 in those brain regions for certain forms of reward-processing [ 49 ]. More recently, Davatolhagh and Fuccillo demonstrated that a loss of Nrxn1α leads to divergent synaptic transmission within the dorsal medial striatum for inputs from the dorsal prefrontal cortex and parafascicular thalamic nucleus [ 67 , 68 ]. Taken together, these findings suggest that the loss of Nrxn1 leads to alterations in cortico-striatal–thalamic circuits where expression of Nrxn1a is high during a specific developmental window, namely mid-prenatally and during early childhood.…”