Neuroligin-1 deficient mice exhibit pathway-specific alterations in striatal NMDA receptor-mediated currents
Wednesday, Nov 13, 2013, 8:00 AM - 9:00 AM
++C.07.a. Autism: Genetic and animal models
, J. M. REIMERS, C. F. OCHOA, C. M. DEWEY, C. M. POWELL;
Neurol. and Neurotherapeutics, U.T. Southwestern Med. Ctr., Dallas, TX
Mutations in the transynaptic cell adhesion proteins neuroligin-1 (NL1) and Neurexin-1 (Nxn1) have been found in individuals affected with autistic spectrum disorders (ASD) and other neuropsychiatric disorders. Knockout of these proteins in mouse models results in altered neurotransmission as well as in autistic-like behaviors, including repetitive/perseverative behaviors. Our laboratory has implicated alterations in glutamatergic synaptic transmission in the basal ganglia in repetitive behaviors in NL1 knockout (KO) mice. Specifically, we have demonstrated decreased striatal NMDA/AMPA ratio in correlation with increased grooming in NL1 KO mice. Furthermore, systemic injection of D-cycloserine, a partial NMDA receptor co-agonist, reverses increased grooming in this model, further supporting the involvement of NMDAR alterations in this phenotype (Blundell et al., J. Neruoscience 2010). Glutamatergic projections to the basal ganglia can terminate in either of two biochemically distinct medium spiny neurons (MSNs) of the striatum. MSNs express either dopamine 1-type receptors (D1) or dopamine 2-type receptors (D2) to the direct and indirect pathways, respectively. We hypothesized that differential effects on these two pathways may give rise to the exacerbated repetitive grooming phenotype in NL1 KO mice. We find a decrease in NMDA/AMPA ratio specifically in the direct (D1) pathway but not in the indirect (D2) pathway synapses. In addition, given the distinct impact of different NMDAR subunits to the function of this receptor, we also investigated the contribution of GluN2A and GluN2B (the main GluN2 subunits expressed by MSNs) to NMDAR currents. Our preliminary data also suggest that the reduction in NMDA currents in the direct pathway is due to a specific decrease in currents driven by the GluN2B subunit-containing type of NMDAR. Ongoing experiments are aimed at identifying potential mechanisms for this pathway specificity.
NIH Grant 1R01MH093697 to CMP
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