Shank3 is an excitatory postsynaptic scaffolding protein implicated in multiple brain disorders, including autism spectrum disorders (ASD) and Phelan-McDermid syndrome (PMS). Although previous neurobiological studies on Shank3 and Shank3-mutant mice have revealed diverse roles of Shank3 in the regulation of synaptic, neuronal and brain functions, whether Shank3 expression in specific cell types distinctly contributes to mouse phenotypes remains largely unclear. In the present study, we generated two Shank3-mutant mouse lines (exons 14–16) carrying global and GABA neuron-specific deletions and characterized their electrophysiological and behavioral phenotypes. These mouse lines show similar decreases in excitatory synaptic input onto dorsolateral striatal neurons. In addition, the abnormal social and locomotor behaviors observed in global Shank3-mutant mice are strongly mimicked by GABA neuron-specific Shank3-mutant mice, whereas the repetitive and anxiety-like behaviors are only partially mimicked. These results suggest that GABAergic Shank3 (exons 14–16) deletion has strong influences on striatal excitatory synaptic transmission and social and locomotor behaviors in mice.

Dysfunction of cholinergic signaling in the brain has long been believed to be associated with depressive disorders. However, the functional impact of habenular cholinergic signaling on the specified depressive behaviors is not well understood. Here, we demonstrated that the expression levels of cholinergic signaling genes (CHAT, VACHT, CHT, CHRNA3, CHRNB3 and CHRNB4) were down-regulated in a chronic restraint stress (CRS) rat model of depression, in which rats display depression-like behaviors such as anhedonia and mood despair. Moreover, knockdown of CHAT in the rat habenula was sufficient to evoke anhedonia-like behavior. The anhedonia-like behavior induced by CHAT knockdown was not reversed by chronic administration of the selective serotonin reuptake inhibitor fluoxetine. To determine whether habenular cholinergic signaling is associated with regulation of dopamine neurons in the ventral tegmental area ( Major depressive disorder (MDD) is a serious psychiatric disorder that is frequently associated with suicide attempts and a major contributor to the global burden of disease 1 . Cholinergic transmission in the brain has long been thought to underlie depression endophenotypes [2][3][4] . Enhancement of extracellular acetylcholine (ACh) level through administration of acetylcholinesterase inhibitors can elicit depression symptoms in both humans and rodents 5,6 . Moreover, inhibition of nicotinic acetylcholine receptors (nAChRs) or muscarinic acetylcholine receptors (mAChRs) ameliorates depression symptoms 7,8 . Although these lines of evidence clearly suggest that ACh signaling contributes to depression, it is not yet clear which specific cholinergic neuronal populations are responsible for specific depression symptoms.The habenula of the epithalamus anatomically and functionally links the forebrain with the midbrain structures that are involved in the release of dopamine (i.e., the substantia nigra pars compacta and VTA) and serotonin (i.e., raphe nucleus) 9,10 . The habenula can be subdivided into the medial habenula (MHb) and the lateral habenula (LHb). Several lines of evidence from studies in animal models and humans suggest that the MHb plays a major role in nicotine addiction [11][12][13] , whereas dysregulation of the LHb is likely to be involved in several psychiatric disorders, including depression. Deep brain stimulation of the LHb produces marked remission of therapy-refractory depression in patients 14 and congenitally learned helplessness in rats 15 . However, the role of the MHb in the pathophysiology of depression remains unclear.Considering that the habenular cholinergic projection through the fasciculus retroflexus (fr) is one of the major cholinergic pathways in the brain 16 , and that dysfunction of central cholinergic signaling is critical for depression [5][6][7][8] , we asked whether the activity of habenular cholinergic signaling is associated with depression. In the present study, we demonstrate that cholinergic genes in the habenula are down-regulated in both rat models of depression...

Nav1.2, a voltage-gated sodium channel subunit encoded by the Scn2a gene, has been implicated in various brain disorders, including epilepsy, autism spectrum disorder, intellectual disability, and schizophrenia. Nav1.2 is known to regulate the generation of action potentials in the axon initial segment and their propagation along axonal pathways. Nav1.2 also regulates synaptic integration and plasticity by promoting back-propagation of action potentials to dendrites, but whether Nav1.2 deletion in mice affects neuronal excitability, synaptic transmission, synaptic plasticity, and/or disease-related animal behaviors remains largely unclear. Here, we report that mice heterozygous for the Scn2a gene ( Scn2a +/- mice) show decreased neuronal excitability and suppressed excitatory synaptic transmission in the presence of network activity in the hippocampus. In addition, Scn2a +/- mice show suppressed hippocampal long-term potentiation (LTP) in association with impaired spatial learning and memory, but show largely normal locomotor activity, anxiety-like behavior, social interaction, repetitive behavior, and whole-brain excitation. These results suggest that Nav1.2 regulates hippocampal neuronal excitability, excitatory synaptic drive, LTP, and spatial learning and memory in mice.

IRSp53 (also known as BAIAP2) is an abundant excitatory postsynaptic scaffolding protein implicated in autism spectrum disorders (ASD), schizophrenia, and attention-deficit/hyperactivity disorder (ADHD). IRSp53 is expressed in different cell types across different brain regions, although it remains unclear how IRSp53 deletion in different cell types affects brain functions and behaviors in mice. Here, we deleted IRSp53 in excitatory and inhibitory neurons in mice and compared resulting phenotypes in males and females. IRSp53 deletion in excitatory neurons driven by Emx1 leads to strong social deficits and hyperactivity without affecting anxiety-like behavior, whereas IRSp53 deletion in inhibitory neurons driven by Viaat has minimal impacts on these behaviors in male mice. In female mice, excitatory neuronal IRSp53 deletion induces hyperactivity but moderate social deficits. Excitatory neuronal IRSp53 deletion in male mice induces an increased ratio of evoked excitatory and inhibitory synaptic transmission (E/I ratio) in layer V pyramidal neurons in the prelimbic region of the medial prefrontal cortex (mPFC), whereas the same mutation does not alter the E/I ratio in female neurons. These results suggest that IRSp53 deletion in excitatory and inhibitory neurons and in male and female mice has distinct impacts on behaviors and synaptic transmission.

Glycine transporters (GlyT1 and GlyT2) that regulate levels of brain glycine, an inhibitory neurotransmitter with co‐agonist activity for NMDA receptors (NMDARs), have been considered to be important targets for the treatment of brain disorders with suppressed NMDAR function such as schizophrenia. However, it remains unclear whether other amino acid transporters expressed in the brain can also regulate brain glycine levels and NMDAR function. Here, we report that SLC6A20A, an amino acid transporter known to transport proline based on in vitro data but is understudied in the brain, regulates proline and glycine levels and NMDAR function in the mouse brain. SLC6A20A transcript and protein levels were abnormally increased in mice carrying a mutant PTEN protein lacking the C terminus through enhanced β‐catenin binding to the Slc6a20a gene. These mice displayed reduced extracellular levels of brain proline and glycine and decreased NMDAR currents. Elevating glycine levels back to normal ranges by antisense oligonucleotide‐induced SLC6A20 knockdown, or the competitive GlyT1 antagonist sarcosine, normalized NMDAR currents and repetitive climbing behavior observed in these mice. Conversely, mice lacking SLC6A20A displayed increased extracellular glycine levels and NMDAR currents. Lastly, both mouse and human SLC6A20 proteins mediated proline and glycine transports, and SLC6A20 proteins could be detected in human neurons. These results suggest that SLC6A20 regulates proline and glycine homeostasis in the brain and that SLC6A20 inhibition has therapeutic potential for brain disorders involving NMDAR hypofunction.