Long-Term Memory Deficits are Associated with Elevated Synaptic ERK1/2 Activation and Reversed by mGluR5 Antagonism in an Animal Model of Autism

Abstract

A significant proportion of patients with autism exhibit some degree of intellectual disability. The BTBR T þ Itpr3 tf /J mouse strain exhibits behaviors that align with the major diagnostic criteria of autism. To further evaluate the BTBR strain's cognitive impairments, we quantified hippocampus-dependent object location memory (OLM) and found that one-third of the BTBR mice exhibited robust memory, whereas the remainder did not. Fluorescence deconvolution tomography was used to test whether synaptic levels of activated extracellular signal-regulated kinase 1/2 (ERK1/2), a protein that contributes importantly to plasticity, correlate with OLM scores in individual mice. In hippocampal field CA1, the BTBRs had fewer post-synaptic densities associated with high levels of phosphorylated (p-) ERK1/2 as compared with C57BL/6 mice. Although counts of p-ERK1/2 immunoreactive synapses did not correlate with OLM performance, the intensity of synaptic p-ERK1/2 immunolabeling was negatively correlated with OLM scores across BTBRs. Metabotropic glutamate receptor (mGluR) 5 signaling activates ERK1/2. Therefore, we tested whether treatment with the mGluR5 antagonist MPEP normalizes synaptic and learning measures in BTBR mice: MPEP facilitated OLM and decreased synaptic p-ERK1/2 immunolabeling intensity without affecting numbers of p-ERK1/2 þ synapses. In contrast, semi-chronic ampakine treatment, which facilitates memory in other models of cognitive impairment, had no effect on OLM in BTBRs. These results suggest that intellectual disabilities associated with different neurodevelopmental disorders on the autism spectrum require distinct therapeutic strategies based on underlying synaptic pathology.

Spaced training rescues memory and ERK1/2 signaling in fragile X syndrome model mice

“…Our results support the former hypothesis: (i) KOs have more densely p-ERK1/2+ synapses than WTs, (ii) their memory impairment following a single massed trial was associated with an absence of training-induced synaptic ERK1/2 activation, (iii) spaced training, which fully restores OLM in the KOs, induced robust synaptic ERK1/2 activation, and (iv) realization of the spacing effect on learning in KO mice required ERK1/2 activation. These findings build on a rapidly expanding literature implicating ERK1/2 signaling in neurodevelopmental disabilities, including FXS (5,32). How might abnormal regulation of synaptic ERK1/2 signaling affect long-term encoding events?…”

“…Such a behavioral approach might complement pharmacological treatments shown to facilitate learning in Fmr1 KOs or other models of congenital intellectual disability (6,31,32,38). The likelihood for successful outcome is increased by the dramatic potency of spaced training.…”

Pharmacology of Basimglurant (RO4917523, RG7090), a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression

“…In a disease context outside of MDD, however, in FXS and autism procognitive effects of mGlu5 inhibition have been reported (Michalon et al, 2014;Seese et al, 2014).…”

Regulation of ERK Kinase by MEK1 Kinase Inhibition in the Brain

“…ERK inhibitors impair contextual fear conditioning memory formation (7)(8)(9). Furthermore, dysregulation of ERK signaling has been implicated in both neuropsychiatric and neurological disorders, including schizophrenia (10 -12), depression (13)(14)(15)(16)(17)(18)(19), addiction (20 -23), autism (24,25), mental retardation (26) and Alzheimer disease (27). Although ERK signaling mediates the actions of many CNS drug therapies, more direct pharmacological interventions that target ERK signaling have been limited chiefly to the field of oncology and may be accompanied by unwanted side effects.…”