Uncoupling DISC1 × D2R Protein-Protein Interactions Facilitates Latent Inhibition in Disc1-L100P Animal Model of Schizophrenia and Enhances Synaptic Plasticity via D2 Receptors

Both Disrupted-In-Schizophrenia-1 (DISC1) and dopamine receptors D2R have significant contributions to the pathogenesis of schizophrenia. Our previous study demonstrated that DISC1 binds to D2R and such protein-protein interaction is enhanced in patients with schizophrenia and Disc1-L100P mouse model of schizophrenia (Su et al., 2014). By uncoupling DISC1 × D2R interaction (trans-activator of transcription (TAT)-D2pep), the synthesized TAT-peptide elicited antipsychotic-like effects in pharmacological and genetic animal models, without motor side effects as tardive dyskinesia commonly seen with typical antipsychotic drugs (APDs), indicating that the potential of TAT-D2pep of becoming a new APD. Therefore, in the current study, we further explored the APD-associated capacities of TAT-D2pep. We found that TAT-D2pep corrected the disrupted latent inhibition (LI), as a hallmark of schizophrenia associated endophenotype, in Disc1-L100P mutant mice—a genetic model of schizophrenia, supporting further APD’ capacity of TAT-D2pep. Moreover, we found that TAT-D2pep elicited nootropic effects in C57BL/6NCrl inbred mice, suggesting that TAT-D2pep acts as a cognitive enhancer, a desirable feature of APDs of the new generation. Namely, TAT-D2pep improved working memory in T-maze, and cognitive flexibility assessed by the LI paradigm, in C57BL/6N mice. Next, we assessed the impact of TAT-D2pep on hippocampal long-term plasticity (LTP) under basal conditions and upon stimulation of D2 receptors using quinpirole. We found comparable effects of TAT-D2pep and its control TAT-D2pep-scrambled peptide (TAT-D2pep-sc) under basal conditions. However, under stimulation of D2R by quinpirole, LTP was enhanced in hippocampal slices incubated with TAT-D2pep, supporting the notion that TAT-D2pep acts in a dopamine-dependent manner and acts as synaptic enhancer. Overall, our experiments demonstrated implication of DISC1 × D2R protein-protein interactions into mechanisms of cognitive and synaptic plasticity, which help to further understand molecular-cellular mechanisms of APD of the next generation

Neto1 Is a Novel CUB-Domain NMDA Receptor–Interacting Protein Required for Synaptic Plasticity and Learning

The N-methyl-D-aspartate receptor (NMDAR), a major excitatory ligand-gated ion channel in the central nervous system (CNS), is a principal mediator of synaptic plasticity. Here we report that neuropilin tolloid-like 1 (Neto1), a complement C1r/C1s, Uegf, Bmp1 (CUB) domain-containing transmembrane protein, is a novel component of the NMDAR complex critical for maintaining the abundance of NR2A-containing NMDARs in the postsynaptic density. Neto1-null mice have depressed long-term potentiation (LTP) at Schaffer collateral-CA1 synapses, with the subunit dependency of LTP induction switching from the normal predominance of NR2A- to NR2B-NMDARs. NMDAR-dependent spatial learning and memory is depressed in Neto1-null mice, indicating that Neto1 regulates NMDA receptor-dependent synaptic plasticity and cognition. Remarkably, we also found that the deficits in LTP, learning, and memory in Neto1-null mice were rescued by the ampakine CX546 at doses without effect in wild-type. Together, our results establish the principle that auxiliary proteins are required for the normal abundance of NMDAR subunits at synapses, and demonstrate that an inherited learning defect can be rescued pharmacologically, a finding with therapeutic implications for humans

Abnormalities in brain structure and behavior in GSK-3alpha mutant mice

<p>Abstract</p> <p>Background</p> <p>Glycogen synthase kinase-3 (GSK-3) is a widely expressed and highly conserved serine/threonine protein kinase encoded by two genes that generate two related proteins: GSK-3α and GSK-3β. Mice lacking a functional GSK-3α gene were engineered in our laboratory; they are viable and display insulin sensitivity. In this study, we have characterized brain functions of GSK-3α KO mice by using a well-established battery of behavioral tests together with neurochemical and neuroanatomical analysis.</p> <p>Results</p> <p>Similar to the previously described behaviours of GSK-3β^+/-mice, GSK-3α mutants display decreased exploratory activity, decreased immobility time and reduced aggressive behavior. However, genetic inactivation of the GSK-3α gene was associated with: decreased locomotion and impaired motor coordination, increased grooming activity, loss of social motivation and novelty; enhanced sensorimotor gating and impaired associated memory and coordination. GSK-3α KO mice exhibited a deficit in fear conditioning, however memory formation as assessed by a passive avoidance test was normal, suggesting that the animals are sensitized for active avoidance of a highly aversive stimulus in the fear-conditioning paradigm. Changes in cerebellar structure and function were observed in mutant mice along with a significant decrease of the number and size of Purkinje cells.</p> <p>Conclusion</p> <p>Taken together, these data support a role for the GSK-3α gene in CNS functioning and possible involvement in the development of psychiatric disorders.</p

Neuronal lack of PDE7a disrupted working memory, spatial learning, and memory but facilitated cued fear memory in mice

12 p.-5 fig.Background: PDEs regulate cAMP levels which is critical for PKA activity-dependent activation of CREB-mediated transcription in learning and memory. Inhibitors of PDEs like PDE4 and Pde7 improve learning and memory in rodents. However, the role of PDE7 in cognition or learning and memory has not been reported yet.Methods:Therefore, we aimed to explore the cognitive effects of a PDE7 subtype, PDE7a, using combined pharmacological and genetic approaches.Results: PDE7a-nko mice showed deficient working memory, impaired novel object recognition, deficient spatial learning & memory, and contextual fear memory, contrary to enhanced cued fear memory, highlighting the potential opposite role of PDE7a in the hippocampal neurons. Further, pharmacological inhibition of PDE7 by AGF2.20 selectively strengthens cued fear memory in C57BL/6 J mice, decreasing its extinction but did not affect cognitive processes assessed in other behavioral tests. The further biochemical analysis detected deficient cAMP in neural cell culture with genetic excision of the PDE7a gene, as well as in the hippocampus of PDE7a-nko mice in vivo. Importantly, we found overexpression of PKA-R and the reduced level of pPKA-C in the hippocampus of PDE7a-nko mice, suggesting a novel mechanism of the cAMP regulation by PDE7a. Consequently, the decreased phosphorylation of CREB, CAMKII, eif2a, ERK, and AMPK, and reduced total level of NR2A have been found in the brain of PDE7a-nko animals. Notably, genetic excision of PDE7a in neurons was not able to change the expression of NR2B, BDNF, synapsin1, synaptophysin, or snap25.Conclusion: Altogether, our current findings demonstrated, for the first time, the role of PDE7a in cognitive processes. Future studies will untangle PDE7a-dependent neurobiological and molecular-cellular mechanisms related to cAMP-associated disorders.This work was supported by the Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions No: 2022SHIBS0004: Basic research and free exploration project of Shenzhen Science and technology innovation Commission (JCYJ20190808113007570).Peer reviewe

Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition

Cognitive dysfunction is a core feature of dementia and a prominent feature in psychiatric disease. As non-redundant regulators of intracellular cAMP gradients, phosphodiesterases (PDE) mediate fundamental aspects of brain function relevant to learning, memory, and higher cognitive functions. Phosphodiesterase-4B (PDE4B) is an important phosphodiesterase in the hippocampal formation, is a major Disrupted in Schizophrenia 1 (DISC1) binding partner and is itself a risk gene for psychiatric illness. To define the effects of specific inhibition of the PDE4B subtype, we generated mice with a catalytic domain mutant form of PDE4B (Y358C) that has decreased ability to hydrolyze cAMP. Structural modelling predictions of decreased function and impaired binding with DISC1 were confirmed in cell assays. Phenotypic characterization of the PDE4BY358C mice revealed facilitated phosphorylation of CREB, decreased binding to DISC1, and upregulation of DISC1 and β-Arrestin in hippocampus and amygdala. In behavioural assays, PDE4BY358C mice displayed decreased anxiety and increased exploration, as well as cognitive enhancement across several tests of learning and memory, consistent with synaptic changes including enhanced long-term potentiation and impaired depotentiation ex vivo. PDE4BY358C mice also demonstrated enhanced neurogenesis. Contextual fear memory, though intact at 24 hours, was decreased at 7 days in PDE4BY358C mice, an effect replicated pharmacologically with a non-selective PDE4 inhibitor, implicating cAMP signalling by PDE4B in a very late phase of consolidation. No effect of the PDE4BY358C mutation was observed in the pre-pulse inhibition and forced swim tests. Our data establish specific inhibition of PDE4B as a promising therapeutic approach for disorders of cognition and anxiety, and a putative target for pathological fear memory

Ultrasonic Vocalizations in Mice During Exploratory Behavior are Context-Dependent.

While rat ultrasonic vocalizations (USVs) are known to vary with anticipation of an aversive versus positive stimulus, little is known about USVs in adult mice in relation to behaviors. We recorded the calls of adult C57BL/6J male mice under different environmental conditions by exposing mice to both novel and familiar environments that varied in stress intensity through the addition of bright light or shallow water. In general, mouse USVs were significantly more frequent and of longer duration in novel environments. Particularly, mice in dimly-lit novel environments performed more USVs while exhibiting unsupported rearing and walking behavior, and these calls were mostly at high frequency. In contrast, mice exhibited more low frequency USVs when engaging in supported rearing behavior in novel environments. These findings are consistent with data from rats suggesting that low-frequency calls are made under aversive conditions and high-frequency calls occur in non-stressful conditions. Our finding increase understanding of acoustic signals associated with exploratory behaviors relevant to cognitive and motivational aspects of behavior

Conditioned stimulus presentations alter anxiety level in fear-conditioned mice

Abstract It is generally believed that fear is rapidly triggered by a distinct cue while anxiety onset is less precise and not associated with a distinct cue. Although it has been claimed that both processes can be measured with certain independence of each other, it is unclear how exactly they differ. In this study, we measured anxiety in mice that received discriminative fear conditioning using behavioral, heart rate and calcium (Ca2+) responses in the ventral hippocampal CA1 (vCA1) neurons. We found that the occurrence of fear significantly interfered with anxiety measurements under various conditions. Diazepam reduced basal anxiety level but had no effect during the presentation of conditioned stimulus (CS). Injection of an inhibitory peptide of PKMzeta (ZIP) into the basolateral amygdala almost entirely abolished CS-triggered fear expression and reduced anxiety to basal level. Heart rate measures suggested a small reduction in anxiety during CS-. Calcium responses in the lateral hypothalamus-projecting vCA1 neurons showed a steady decay during CS suggesting a reduced anxiety. Thus, under our experimental conditions, CS presentations likely reduce anxiety level in the fear-conditioned mice