Neuron type-specific expression of a mutant KRAS impairs hippocampal-dependent learning and memory

Hyun-Hee Ryu,Yong-Seok Lee,Han Byul Jang,Sang Jeong Kim,Minkyung Kang,Kyoung-Doo Hwang

doi:10.1038/s41598-020-74610-y

Abstract

KRAS mutations are associated with rare cases of neurodevelopmental disorders that can cause intellectual disabilities. Previous studies showed that mice expressing a mutant KRAS have impaired the development and function of GABAergic inhibitory neurons, which may contribute to behavioural deficits in the mutant mice. However, the underlying cellular mechanisms and the role of excitatory neurons in these behavioural deficits in adults are not fully understood. Herein, we report that neuron type-specific expression of a constitutively active mutant KRASG12V in either excitatory or inhibitory neurons resulted in spatial memory deficits in adult mice. In inhibitory neurons, KRASG12V induced ERK activation and enhanced GABAergic synaptic transmission. Expressing KRASG12V in inhibitory neurons also impaired long-term potentiation in the hippocampal Shaffer-collateral pathway, which could be rescued by picrotoxin treatment. In contrast, KRASG12V induced ERK activation and neuronal cell death in excitatory neurons, which might have contributed to the severe behavioural deficits. Our results showed that both excitatory and inhibitory neurons are involved in mutant KRAS-associated learning deficits in adults via distinct cellular mechanisms.

Highlights

KRAS mutations are associated with rare cases of neurodevelopmental disorders that can cause intellectual disabilities
To examine the effects of inhibitory neuron-specific expression of KRASG12V on hippocampal-dependent spatial learning and memory, we performed the hidden-platform version of the Morris water maze (MWM) test
Open field analyses revealed that KRASG12V expression in vGAT+inhibitory neurons increased total distance traveled, while anxiety-like behaviours assessed by the time spent in the center zone remained unchanged (Supplementary Fig. S1e and f)

Summary

Introduction

KRAS mutations are associated with rare cases of neurodevelopmental disorders that can cause intellectual disabilities. We report that neuron type-specific expression of a constitutively active mutant KRASG12V in either excitatory or inhibitory neurons resulted in spatial memory deficits in adult mice. Our results showed that both excitatory and inhibitory neurons are involved in mutant KRAS-associated learning deficits in adults via distinct cellular mechanisms. Mutations in genes encoding the RAS-ERK signalling pathway proteins are associated with multiple genetic disorders, collectively termed RASopathies. These include Noonan syndrome (NS), neurofibromatosis, Costello syndrome, cardiofaciocutaneous syndrome (CFCS), LEOPARD syndrome, and o thers[3,4,5,6]. We investigated the cell type-dependent roles of KRAS by expressing the mutant KRASG12V either in excitatory or in inhibitory neurons in adult mice.

Methods

Results

Conclusion