Association of Missense Mutation in FOLH1 With Decreased NAAG Levels and Impaired Working Memory Circuitry and Cognition.

OBJECTIVE: Altering the metabotropic glutamate receptor 3 (mGluR3) by pharmacology or genetics is associated with differences in learning and memory in animals and humans. GRM3 (the gene coding for mGluR3) is also genome-wide associated with risk for schizophrenia. The neurotransmitter N-acetyl-aspartyl-glutamate (NAAG) is the selective endogenous agonist of mGluR3, and increasing NAAG may improve cognition. Glutamate carboxypeptidase II (GCPII), coded by the gene folate hydrolase 1 (FOLH1), regulates the amount of NAAG in the synapse. The goal of this study was to determine the relationship between FOLH1, NAAG levels, measures of human cognition, and neural activity associated with cognition. METHODS: The effects of genetic variation in FOLH1 on mRNA expression in human brain and NAAG levels using 7-T magnetic resonance spectroscopy (MRS) were measured. NAAG levels and FOLH1 genetic variation were correlated with measures of cognition in subjects with psychosis and unaffected subjects. Additionally, FOLH1 genetic variation was correlated with neural activity during working memory, as measured by functional MRI (fMRI). RESULTS: A missense mutation in FOLH1 (rs202676 G allele) was associated with increased FOLH1 mRNA in the dorsolateral prefrontal cortex of brains from unaffected subjects and schizophrenia patients. This FOLH1 variant was associated with decreased NAAG levels in unaffected subjects and patients with psychosis. NAAG levels were positively correlated with visual memory performance. Carriers of the FOLH1 variant associated with lower NAAG levels had lower IQ scores. Carriers of this FOLH1 variant had less efficient cortical activity during working memory. CONCLUSIONS: These data show that higher NAAG levels are associated with better cognition, suggesting that increasing NAAG levels through FOLH1/GCPII inhibition may improve cognition. Additionally, NAAG levels measured by MRS and cortical efficiency during working memory measured by fMRI have the potential to be neuroimaging biomarkers for future clinical trials.

Molecularly Defined Hippocampal Inputs Regulate Population Dynamics in the Prelimbic Cortex to Suppress Context Fear Memory Retrieval.

BACKGROUND: Context fear memory dysregulation is a hallmark symptom of several neuropsychiatric disorders, including generalized anxiety disorder and posttraumatic stress disorder. The hippocampus (HC) and prelimbic (PrL) subregion of the medial prefrontal cortex have been linked with context fear memory retrieval in rodents, but the mechanisms by which HC-PrL circuitry regulates this process remain poorly understood. METHODS: Spatial and genetic targeting of HC-PrL circuitry was used for RNA sequencing (n = 31), chemogenetic stimulation (n = 44), in vivo calcium imaging (n = 20), ex vivo electrophysiology (n = 8), and molecular regulation of plasticity cascades during fear behavior (context fear retrieval) (n = 16). RESULTS: We showed that ventral HC (vHC) neurons with projections to the PrL cortex (vHC-PrL projectors) are a transcriptomically distinct subpopulation compared with adjacent nonprojecting neurons, and we showed complementary enrichment for diverse neuronal processes and central nervous system-related clinical gene sets. We further showed that stimulation of this population of vHC-PrL projectors suppresses context fear memory retrieval and impairs the ability of PrL neurons to dynamically distinguish between distinct phases of fear learning. Using transgenic and circuit-specific molecular targeting approaches, we demonstrated that unique patterns of activity-dependent gene transcription associated with brain-derived neurotrophic factor signaling within vHC-PrL projectors causally regulated activity in excitatory and inhibitory PrL neurons during context fear memory retrieval. CONCLUSIONS: Together, our data show that activity-dependent brain-derived neurotrophic factor release from molecularly distinct vHC-PrL projection neurons modulates postsynaptic signaling in both inhibitory and excitatory PrL neurons, modifying activity in discrete populations of PrL neurons to suppress freezing during context fear memory retrieval.

Faces under continuous flash suppression capture attention faster than objects, but without a face-evoked steady-state visual potential: Is curvilinearity responsible for the behavioral effect?

Face perception is a vital part of human social interactions. The social value of faces makes their efficient detection evolutionarily advantageous. It has been suggested that this might occur nonconsciously, but experimental results are equivocal thus far. Here, we probe nonconscious face perception using a novel combination of binocular rivalry with continuous flash suppression and steady-state visually evoked potentials. In the first two experiments, participants viewed either non-face objects, neutral faces (Study 1), or fearful faces (Study 2). Consistent with the hypothesis that faces are processed nonconsciously, we found that faces broke through suppression faster than objects. We did not, however, observe a concomitant face-selective steady-state visually evoked potential. Study 3 was run to reconcile this paradox. We hypothesized that the faster breakthrough time was due to a mid-level visual feature, curvilinearity, rather than high-level category membership, which would explain the behavioral difference without neural evidence of face-selective processing. We tested this hypothesis by presenting participants with four different groups of stimuli outside of conscious awareness: rectilinear objects (e.g., chessboard), curvilinear objects (e.g., dartboard), faces, and objects that were not dominantly curvilinear or rectilinear. We found that faces and curvilinear objects broke through suppression faster than objects and rectilinear objects. Moreover, there was no difference between faces and curvilinear objects. These results support our hypothesis that the observed behavioral advantage for faces is due to their curvilinearity, rather than category membership.

Manipulation of a genetically and spatially defined sub-population of BDNF-expressing neurons potentiates learned fear and decreases hippocampal-prefrontal synchrony in mice.

Brain-derived neurotrophic factor (BDNF) signaling regulates synaptic plasticity in the hippocampus (HC) and prefrontal cortex (PFC), and has been extensively linked with fear memory expression in rodents. Notably, disrupting BDNF production from promoter IV-derived transcripts enhances fear expression in mice, and decreases fear-associated HC-PFC synchrony, suggesting that Bdnf transcription from promoter IV plays a key role in HC-PFC function during fear memory retrieval. To better understand how promoter IV-derived BDNF controls HC-PFC connectivity and fear expression, we generated a viral construct that selectively targets cells expressing promoter IV-derived Bdnf transcripts ("p4-cells") for tamoxifen-inducible Cre-mediated recombination (AAV8-p4Bdnf-ERT2CreERT2-PEST). Using this construct, we found that ventral hippocampal (vHC) p4-cells are recruited during fear expression, and that activation of these cells causes exaggerated fear expression that co-occurs with disrupted vHC-PFC synchrony in mice. Our data highlight how this novel construct can be used to interrogate genetically defined cell types that selectively contribute to BDNF-dependent behaviors.