Probes for LONG

ADNP syndrome, involving the ADNP transcription factor of the SWI/SNF chromatin-remodeling complex, is characterized by developmental delay, intellectual disability, and autism spectrum disorders (ASD). Although Adnp-haploinsufficient (Adnp-HT) mice display various phenotypic deficits, whether these mice display abnormal synaptic functions remain poorly understood. Here, we report synaptic plasticity deficits associated with cognitive inflexibility and CaMKIIα hyperactivity in Adnp-HT mice. These mice show impaired and inflexible contextual learning and memory, additional to social deficits, long after the juvenile-stage decrease of ADNP protein levels to ~10% of the newborn level. The adult Adnp-HT hippocampus shows hyperphosphorylated CaMKIIα and its substrates, including SynGAP1, and excessive long-term potentiation that is normalized by CaMKIIα inhibition. Therefore, Adnp haploinsufficiency in mice leads to cognitive inflexibility involving CaMKIIα hyperphosphorylation and excessive LTP in adults long after its marked expressional decrease in juveniles.

Myelin transcription factor 1 like (Myt1l), a zinc-finger transcription factor, promotes neuronal differentiation and is implicated in autism spectrum disorder (ASD) and intellectual disability. However, it remains unclear whether Myt1l promotes neuronal differentiation in vivo and its deficiency in mice leads to disease-related phenotypes. Here, we report that Myt1l-heterozygous mutant (Myt1l-HT) mice display postnatal age-differential ASD-related phenotypes: newborn Myt1l-HT mice, with strong Myt1l expression, show ASD-like transcriptomic changes involving decreased synaptic gene expression and prefrontal excitatory synaptic transmission and altered righting reflex. Juvenile Myt1l-HT mice, with markedly decreased Myt1l expression, display reverse ASD-like transcriptomes, increased prefrontal excitatory transmission, and largely normal behaviors. Adult Myt1l-HT mice show ASD-like transcriptomes involving astrocytic and microglial gene upregulation, increased prefrontal inhibitory transmission, and behavioral deficits. Therefore, Myt1l haploinsufficiency leads to ASD-related phenotypes in newborn mice, which are temporarily normalized in juveniles but re-appear in adults, pointing to continuing phenotypic changes long after a marked decrease of Myt1l expression in juveniles.

The role of postnatal experience in sculpting cortical circuitry, while long appreciated, is poorly understood at the level of cell types. We explore this in the mouse primary visual cortex (V1) using single-nucleus RNA sequencing, visual deprivation, genetics, and functional imaging. We find that vision selectively drives the specification of glutamatergic cell types in upper layers (L) (L2/3/4), while deeper-layer glutamatergic, GABAergic, and non-neuronal cell types are established prior to eye opening. L2/3 cell types form an experience-dependent spatial continuum defined by the graded expression of ∼200 genes, including regulators of cell adhesion and synapse formation. One of these genes, Igsf9b, a vision-dependent gene encoding an inhibitory synaptic cell adhesion molecule, is required for the normal development of binocular responses in L2/3. In summary, vision preferentially regulates the development of upper-layer glutamatergic cell types through the regulation of cell-type-specific gene expression programs.

Abstract Background A parallel downregulation of brain-derived neurotrophic factor (BDNF) and somatostatin (SST), a marker of inhibitory γ-amino-butyric acid (GABA) interneurons which target pyramidal cell dendrites, has been reported in several brain areas of subjects with major depressive disorder (MDD), and rodent genetic studies suggests they are linked and both contribute to the illness. However, the mechanism by which they contribute to the pathophysiology of the illness has remained elusive. Methods With qPCR, we determined the expression level of BDNF transcript variants and synaptic markers in the prefrontal cortex (PFC) of MDD patients and matched controls (n=19/group) and of C57BL/6J mice exposed to chronic stress or control conditions (n=12/group). We next suppressed BDNF transcripts with long 3’ untranslated region (L-3’-UTR) using small hairpin RNA (shRNA) and investigated changes in cell morphology, gene expression and behavior. Results L-3’-UTR containing BDNF mRNAs, which migrate to distal dendrites of pyramidal neurons, are selectively reduced and highly correlated with SST expression in the PFC of MDD subjects. A similar downregulation occurs in mice submitted to chronic stress. We next show that Bdnf L-3’-UTR knockdown is sufficient to induce (i) dendritic shrinkage in cortical neurons, (ii) cell-specific MDD-like gene changes (including Sst downregulation), and (iii) depressive-/anxiety-like behaviors. The translational validity of the Bdnf L-3’-UTR shRNA-treated mice was confirmed by significant cross-species correlation of changes in MDD-associated gene expression. Conclusions These findings provide evidence for a novel MDD-related pathological mechanism linking local neurotrophic support, pyramidal cell structure, dendritic inhibition and mood regulation.