Synaptic alterations in the striatum and the cortex of a new mouse model of autism spectrum disorders: JAKMIP1 knock-out mouse

Autism spectrum disorders (ASD) are developmental conditions characterized by alterations in social interaction, communication and behavior. Major effect mutations such as the inherited duplication of 15q11-q13 (dup(15q)) or FMR1 gene (Fragile X mental retardation), are associated with ASD. Mutations in the FMR1 gene lead to the loss of FMR protein, a translational repressor. Its absence disturbs synaptic plasticity and neuronal development. Animal models of Fragile X syndrome do not display a robust behavioral phenotype. Interestingly, previous studies analyzing the transcriptome of lymphoblastoid cells from autistic males diagnosed with ASD and Fragile X syndrome, ASD and dup(15q), and idiopathic ASD revealed that all patient groups had altered levels of janus kinase and microtubule-interacting protein 1 (JAKMIP1). The present study examined electrophysiological alterations in a recently generated JAKMIP1 knockout (KO) mouse. These animals displayed a striking stereotypical behavioral phenotype consisting of "jumping." This motor stereotypy suggested a potential involvement of basal ganglia circuits. We investigated whether the striatum could contribute to the development of the phenotype in these animals. We recorded medium-sized spiny neurons (MSNs) in the dorsal striatum of male juvenile (P14) and male adult (2-3 months) JAKMIP1 KO and wildtype (WT) littermate mice using whole-cell patch clamp recordings in voltage clamp mode. Cortical pyramidal neurons (CPNs) in layer II/III also were recorded in adult KO and WT mice. In the striatum, adult JAKMIP1 KO mice displayed a significant increase in frequency of spontaneous inhibitory (IPSCs) and excitatory postsynaptic currents (EPSCs) suggesting up-regulation of GABA and glutamate neurotransmission in MSNs. In the cortex, adult JAKMIP1 KO mice also showed an increase in spontaneous EPSC frequency but did not display changes in IPSCs. To examineglutamate receptor-mediated responses in MSNs we used electrical stimulation toevoke AMPA receptor (AMPAR)- and NMDA receptor (NMDAR)-mediatedcurrents. The amplitude of the AMPAR response was not altered at both ages. Incontrast, the charge and the decay time of the NMDAR response weresignificantly increased in the P14 but not in the 2-3 month KO mice. Interestingly,a proportion of KO MSNs showing an AMPAR response failed to display aNMDAR response at both ages. These results demonstrate that there aresignificant alterations in synaptic activity in the cortex and striatum of JAKMIP1KO mice. Future studies will be aimed an uncovering the cellular mechanisms forthese changes in neuronal communication.