Neurofibromin Regulation of ERK Signaling Modulates GABA Release and Learning

Abstract

Summary We uncovered a new role for ERK signaling in GABA release, long-term potentiation (LTP) and learning, and show that disruption of this mechanism accounts for the learning deficits in a mouse model for Neurofibromatosis type I (NF1), a common genetic cause for learning disabilities. Genetic, pharmacological, electrophysiological and behavioral data demonstrate that neurofibromin modulates ERK/synapsin I dependent GABA release, which in turn modulate hippocampal LTP and learning. An Nf1 heterozygous null mutation, which results in enhanced ERK and synapsin I phosphorylation, increased pre-synaptic GABA release in the hippocampus which was reversed by pharmacologically down-regulating ERK signaling. Importantly, the learning deficits associated with the Nf1 mutation were rescued by a sub-threshold dose of a GABAA antagonist. Accordingly, Cre-deletions of the Nf1 gene showed that only those deletions involving inhibitory neurons caused hippocampal inhibition, LTP and learning abnormalities. Importantly, our results also revealed lasting increases in GABA release triggered by learning, indicating that the mechanisms uncovered here are of general importance for learning and memory.

P4‐253: Hilar GABAergic interneuron activity controls spatial learning and memory retrieval

“…In line with this conclusion, learning triggers a rapid increase in inhibitory synaptogenesis and the GABA content of inhibitory synapses [20], accompanied by long-lasting enhancement of synaptic inhibition onto excitatory neurons in mice [21]. Learning also triggers a lasting increase in GABA release from hippocampal GABAergic interneurons in mice [6,22], and learning-related feed-forward inhibitory connectivity growth in the hippocampus is required for memory precision [23]. Conversely, decreasing GABA levels in the hippocampus by overexpressing GABA transport 1 (GAT1), which is responsible for GABA reuptake after its synaptic release, impairs learning and memory in mice [24].…”

“…Hilar interneurons prevent overexcitation of granule neurons and participate in the formation and regulation of brain oscillations [4,5]. The balance of excitatory and inhibitory neuronal activity in the hippocampus, including the dentate gyrus, is thought to be required for normal learning and memory [6], while an imbalance has been implicated in the pathogenesis of amnesia in Alzheimer's disease (AD) and schizophrenia [7,8,9,10]. Although extensive research has demonstrated the importance of excitatory granule neurons in learning and memory [8], the role of hilar GABAergic interneurons remains unclear.…”

Genotype and cognitive phenotype of patients with tuberous sclerosis complex

“…[7][8][9][10][11][12][13] A bimodal intellectual quotient (IQ) distribution in the total TSC population has been suggested 7 and was recently refined as being observed only in the TSC2 population. 10 TSC patients with germline TSC1 and TSC2 mutations have only one fully functional TSC2 allele in all their cells, and this condition could lead to neurocognitive dysfunction through the mechanism of haplo-insufficiency, [14][15][16] similar to Fragile-X syndrome and Neurofibromatosis type 1. [14][15][16] However, in TSC there are additional factors which may contribute to cognitive impairment, including loss of heterozygosity, which may contribute to tuber development, 17,18 and effects of early onset and refractory epilepsy.…”

“…10 TSC patients with germline TSC1 and TSC2 mutations have only one fully functional TSC2 allele in all their cells, and this condition could lead to neurocognitive dysfunction through the mechanism of haplo-insufficiency, [14][15][16] similar to Fragile-X syndrome and Neurofibromatosis type 1. [14][15][16] However, in TSC there are additional factors which may contribute to cognitive impairment, including loss of heterozygosity, which may contribute to tuber development, 17,18 and effects of early onset and refractory epilepsy. Thus far, no associations have been found between specific TSC mutation types and cognitive outcomes, 10,19 although there are reports on associations with epilepsy and psychiatric features.…”

Neurofibromin regulates corticostriatal inhibitory networks during working memory performance

“…Specific deficits in the domains of visuospatial and executive functions are among the most common cognitive deficits associated with this syndrome (1,4,5). Previous mechanistic studies in a mouse model of NF1 (Nf1 heterozygous null mutants or Nf1 +/− ) demonstrated that neurofibromin modulates Rasdependent GABA release in the hippocampus, which in turn modulates long-term potentiation (LTP) and hippocampaldependent learning (6,7). However, the mechanisms underlying frontal executive dysfunction in NF1, including prominent working memory deficits (5), are unknown.…”