K. KRETSCHMANNOVA1 J. S. PADILLA1, S. GELMAN1, J. PALMA1, H. FERNANDES1, G. TOMBAUGH1, M. KWAN1, J. BELTRAN1, A. GHAVAMI1, E. LEAHY1
1PsychoGenics, Inc., Paramus, NJ, USA
Autism-spectrum disorder (ASD) is characterized by profound social deficits including difficulties with communication and social interaction, and by the presence of restricted and repetitive behaviors and interests (RRBI). A growing body of evidence points to the involvement of basal ganglia in ASD-related pathophysiology with striatal dysfunction underlying RRBI. Here we compared the excitatory synaptic transmission in the striatum and nucleus accumbens in four genetic models of ASD: Shank3 KO (Feng), Cntnap2 KO (Pele), Fmr1 KO and Mecp2 KO (Bird).
We used extracellular field potential recordings and whole-cell patch clamp recordings from medium spiny neurons to assess corticostriatal synaptic transmission in dorsal striatum and extracellular field potential recordings to examine intra-nucleus accumbens synaptic transmission in these mouse models. In an attempt to correlate potential impairment in synaptic transmission with gene changes, we also evaluated mRNA expression levels of PSD95, synaptophysin, AMPA and NMDA receptor subunits in the striatum and BDNF isoforms in the cortex.
Examination of synaptically-driven population spikes revealed functional deficits in dorsal striatum and nucleus accumbens of Shank3 KO mice. Both, evoked AMPA- and NMDA-receptor mediated currents from medium spiny neurons in dorsal striatum were reduced in this ASD mouse model. These findings were paralleled by the changes in the expression of synaptic proteins. We found significantly reduced levels of transcripts for PSD95, synaptophysin, GluA1, GluA2, GluN2A and GluN2B in the striatum and BDNF isoforms I, IV, VI and IX in the cortex.
Despite the importance of the striatum for the control of RRBI and the role of nucleus accumbens in social reward, other examined ASD mouse models did not show any deficits in either corticostriatal or intra-nucleus accumbens synaptic transmission. Further analysis is needed to understand specific changes in basal ganglia circuits and sub-circuits and how their dysfunction contributes to ASD symptomatology.