The calmodulin-binding transcription activator CAMTA1 is required for long-term memory formation in mice

Abstract

The formation of long-term memory requires signaling from the synapse to the nucleus to mediate neuronal activitydependent gene transcription. Synapse-to-nucleus communication is initiated by influx of calcium ions through synaptic NMDA receptors and/or L-type voltage-gated calcium channels and involves the activation of transcription factors by calcium/calmodulin signaling in the nucleus. Recent studies have drawn attention to a new family of transcriptional regulators, the so-called calmodulin-binding transcription activator (CAMTA) proteins. CAMTAs are expressed at particularly high levels in the mouse and human brain, and we reasoned that, as calmodulin-binding transcription factors, CAMTAs may regulate the formation of long-term memory by coupling synaptic activity and calcium/calmodulin signaling to memory-related transcriptional responses. This hypothesis is supported by genetic studies that reported a correlation between Camta gene polymorphisms or mutations and cognitive capability in humans. Here, we show that acute knockdown of CAMTA1, but not CAMTA2, in the hippocampus of adult mice results in impaired performance in two memory tests, contextual fear conditioning and object -place recognition test. Short-term memory and neuronal morphology were not affected by CAMTA knockdown. Gene expression profiling in the hippocampus of control and CAMTA knockdown mice revealed a number of putative CAMTA1 target genes related to synaptic transmission and neuronal excitability. Patch clamp recordings in organotypic hippocampal slice cultures provided further evidence for CAMTA1-dependent changes in electrophysiological properties. In summary, our study provides experimental evidence that confirms previous human genetic studies and establishes CAMTA1 as a regulator of long-term memory formation.

Mutations in Vps15 perturb neuronal migration in mice and are associated with neurodevelopmental disease in humans

“…Spines located on tertiary apical dendritic branches in a single focal plane located at least 120 μm from the soma were quantitated ( n = 4–6 neurons per animal (n = 3 animals per genotype). Neuron morphology was analyzed as previously reported 70 . Golgi-Cox impregnated 120-μm adult mouse brain sections were imaged in 1-μm z-intervals using a Axioplan bright-field microscope, and CA1 pyramidal neurons were traced in 3D using ImageJ’s Simple Neurite Tracer plugin ( n = 3 animals per genotype, 3 neurons each).…”

Networks of Cultured iPSC-Derived Neurons Reveal the Human Synaptic Activity-Regulated Adaptive Gene Program

“…Second, we detected CAMTA1 , which is associated with human episodic memory performance (Huentelman et al., 2007) and intellectual disability (Thevenon et al., 2012), to be upregulated by activity in hiPSCd neurons but not in mouse neurons (Table S7). This is exciting because CAMTA1 is linked to a conserved noncoding sequence with accelerated evolution in humans (Prabhakar et al., 2006), has several putative enhancer regions with human-specific epigenetic gains (Reilly et al., 2015), and knockdown of Camta1 in the mouse hippocampus specifically alters long-term memory (Bas-Orth et al., 2016), making CAMTA1 a good candidate for a factor that adjusts episodic memory in a human-specific, synaptic activity-dependent manner. Third, HIC1 , the gene with a prolonged increase in mRNA levels after synaptic activity in hiPSCd neurons compared to mouse neurons (Figure S7), negatively regulates expression of reelin receptor genes (Dubuissez et al., 2013).…”

Transcriptional Control Of Calmodulin By CAMTA Regulates Neural Excitability

“…In mouse, humans and flies, CAMTA transcription factors are expressed in many brain regions [8][9][10]26 . We generated a fosmid-based reporter to map the expression pattern of the CAMT-1a, the longest isoform of C. elegans CAMTA.…”

“…Mammals encode two CAMTA proteins that are enriched in heart and brain tissue 7 . Loss of CAMTA1 in the nervous system induces degeneration of cerebellar Purkinje cells, ataxia and defects in hippocampal-dependent memory formation 8,9 . A variety of neurological disorders, including intellectual disability, attention deficit hyperactivity disorder (ADHD), cerebellar ataxia, and reduced memory performance have been reported in individuals with lesions in the human CAMTA1 gene [10][11][12] .…”