A new tau dephosphorylation-targeting chimera for the treatment of tauopathies.

Abnormal accumulation of hyperphosphorylated tau protein plays a pivotal role in a collection of neurodegenerative diseases named tauopathies, including Alzheimer's disease (AD). We have recently conceptualized the design of hetero-bifunctional chimeras for selectively promoting the proximity between tau and phosphatase, thus specifically facilitating tau dephosphorylation and removal. Here, we sought to optimize the construction of tau dephosphorylating-targeting chimera (DEPTAC) and obtained a new chimera D14, which had high efficiency in reducing tau phosphorylation both in cell and tauopathy mouse models, while showing limited cytotoxicity. Moreover, D14 ameliorated neurodegeneration in primary cultured hippocampal neurons treated with toxic tau-K18 fragments, and improved cognitive functions of tauopathy mice. These results suggested D14 as a cost-effective drug candidate for the treatment of tauopathies.

Recent Advances in and Application of Fluorescent Microspheres for Multiple Nucleic Acid Detection.

Traditional single nucleic acid assays can only detect one target while multiple nucleic acid assays can detect multiple targets simultaneously, providing comprehensive and accurate information. Fluorescent microspheres in multiplexed nucleic acid detection offer high sensitivity, specificity, multiplexing, flexibility, and scalability advantages, enabling precise, real-time results and supporting clinical diagnosis and research. However, multiplexed assays face challenges like complexity, costs, and sample handling issues. The review explores the recent advancements and applications of fluorescent microspheres in multiple nucleic acid detection. It discusses the versatility of fluorescent microspheres in various fields, such as disease diagnosis, drug screening, and personalized medicine. The review highlights the possibility of adjusting the performance of fluorescent microspheres by modifying concentrations and carrier forms, allowing for tailored applications. It emphasizes the potential of fluorescent microsphere technology in revolutionizing nucleic acid detection and advancing health, disease treatment, and medical research.

Targeting vulnerable microcircuits in the ventral hippocampus of male transgenic mice to rescue Alzheimer-like social memory loss.

BACKGROUND: Episodic memory loss is a prominent clinical manifestation of Alzheimer's disease (AD), which is closely related to tau pathology and hippocampal impairment. Due to the heterogeneity of brain neurons, the specific roles of different brain neurons in terms of their sensitivity to tau accumulation and their contribution to AD-like social memory loss remain unclear. Therefore, further investigation is necessary. METHODS: We investigated the effects of AD-like tau pathology by Tandem mass tag proteomic and phosphoproteomic analysis, social behavioural tests, hippocampal electrophysiology, immunofluorescence staining and in vivo optical fibre recording of GCaMP6f and iGABASnFR. Additionally, we utilized optogenetics and administered ursolic acid (UA) via oral gavage to examine the effects of these agents on social memory in mice. RESULTS: The results of proteomic and phosphoproteomic analyses revealed the characteristics of ventral hippocampal CA1 (vCA1) under both physiological conditions and AD-like tau pathology. As tau progressively accumulated, vCA1, especially its excitatory and parvalbumin (PV) neurons, were fully filled with mislocated and phosphorylated tau (p-Tau). This finding was not observed for dorsal hippocampal CA1 (dCA1). The overexpression of human tau (hTau) in excitatory and PV neurons mimicked AD-like tau accumulation, significantly inhibited neuronal excitability and suppressed distinct discrimination-associated firings of these neurons within vCA1. Photoactivating excitatory and PV neurons in vCA1 at specific rhythms and time windows efficiently ameliorated tau-impaired social memory. Notably, 1 month of UA administration efficiently decreased tau accumulation via autophagy in a transcription factor EB (TFEB)-dependent manner and restored the vCA1 microcircuit to ameliorate tau-impaired social memory. CONCLUSION: This study elucidated distinct protein and phosphoprotein networks between dCA1 and vCA1 and highlighted the susceptibility of the vCA1 microcircuit to AD-like tau accumulation. Notably, our novel findings regarding the efficacy of UA in reducing tau load and targeting the vCA1 microcircuit may provide a promising strategy for treating AD in the future.

Generation of tau dephosphorylation-targeting chimeras for the treatment of Alzheimer's disease and related tauopathies.

Abnormal hyperphosphorylation and accumulation of tau protein play a pivotal role in neurodegeneration in Alzheimer's disease (AD) and many other tauopathies. Selective elimination of hyperphosphorylated tau is promising for the therapy of these diseases. We have conceptualized a strategy, named dephosphorylation-targeting chimeras (DEPTACs), for specifically hijacking phosphatases to tau to debilitate its hyperphosphorylation. Here, we conducted the step-by-step optimization of each constituent motif to generate DEPTACs with reasonable effectiveness in facilitating the dephosphorylation and subsequent clearance of pathological tau. Specifically, for one of the selected chimeras, D16, we demonstrated its significant efficiency in rescuing the neurodegeneration caused by neurotoxic K18-tau seeds in vitro. Moreover, intravenous administration of D16 also alleviated tau pathologies in the brain and improved memory deficits in AD mice. These results suggested DEPTACs as targeted modulators of tau phosphorylation, which hold therapeutic potential for AD and other tauopathies.

Selenium nanoparticles improve nickel-induced testosterone synthesis disturbance by down-regulating miR-708-5p/p38 MAPK pathway in Leydig cells.

The present study was designed to investigate the role of miR-708-5p/p38 mitogen-activated protein kinase (MAPK) pathway during the mechanism of selenium nanoparticles (Nano-Se) against nickel (Ni)-induced testosterone synthesis disorder in rat Leydig cells. We conducted all procedures based on in vitro culture of rat primary Leydig cells. After treating Leydig cells with Nano-Se and NiSO4 alone or in combination for 24 h, we determined the cell viability, reactive oxygen species (ROS) levels, testosterone production, and the protein expression of key enzymes involved in testosterone biosynthesis: steroidogenic acute regulatory (StAR) and cytochrome P450 cholesterol side chain cleavage enzyme (CYP11A1). The results indicated that Nano-Se antagonized cytotoxicity and eliminated ROS generation induced by NiSO4 , suppressed p38 MAPK protein phosphorylation and reduced miR-708-5p expression. Importantly, we found that Nano-Se upregulated the expression of testosterone synthase and increased testosterone production in Leydig cells. Furthermore, we investigated the effects of p38 MAPK and miR-708-5p using their specific inhibitor during Nano-Se against Ni-induced testosterone synthesis disorder. The results showed that Ni-inhibited testosterone secretion was alleviated by Nano-Se co-treatment with p38 MAPK specific inhibitor SB203580 and miR-708-5p inhibitor, respectively. In conclusion, these findings suggested Nano-Se could inhibit miR-708-5p/p38 MAPK pathway, and up-regulate the key enzymes protein expression for testosterone synthesis, thereby antagonizing Ni-induced disorder of testosterone synthesis in Leydig cells.

Targeting a vulnerable septum-hippocampus cholinergic circuit in a critical time window ameliorates tau-impaired memory consolidation.

BACKGROUND: Abnormal tau accumulation and cholinergic degeneration are hallmark pathologies in the brains of patients with Alzheimer's disease (AD). However, the sensitivity of cholinergic neurons to AD-like tau accumulation and strategies to ameliorate tau-disrupted spatial memory in terms of neural circuits still remain elusive. METHODS: To investigate the effect and mechanism of the cholinergic circuit in Alzheimer's disease-related hippocampal memory, overexpression of human wild-type Tau (hTau) in medial septum (MS)-hippocampus (HP) cholinergic was achieved by specifically injecting pAAV-EF1α-DIO-hTau-eGFP virus into the MS of ChAT-Cre mice. Immunostaining, behavioral analysis and optogenetic activation experiments were used to detect the effect of hTau accumulation on cholinergic neurons and the MS-CA1 cholinergic circuit. Patch-clamp recordings and in vivo local field potential recordings were used to analyze the influence of hTau on the electrical signals of cholinergic neurons and the activity of cholinergic neural circuit networks. Optogenetic activation combined with cholinergic receptor blocker was used to detect the role of cholinergic receptors in spatial memory. RESULTS: In the present study, we found that cholinergic neurons with an asymmetric discharge characteristic in the MS-hippocampal CA1 pathway are vulnerable to tau accumulation. In addition to an inhibitory effect on neuronal excitability, theta synchronization between the MS and CA1 subsets was significantly disrupted during memory consolidation after overexpressing hTau in the MS. Photoactivating MS-CA1 cholinergic inputs within a critical 3 h time window during memory consolidation efficiently improved tau-induced spatial memory deficits in a theta rhythm-dependent manner. CONCLUSIONS: Our study not only reveals the vulnerability of a novel MS-CA1 cholinergic circuit to AD-like tau accumulation but also provides a rhythm- and time window-dependent strategy to target the MS-CA1 cholinergic circuit, thereby rescuing tau-induced spatial cognitive functions.

Leveraging the ATP-P2X7 receptor signalling axis to alleviate traumatic CNS damage and related complications.

The P2X7 receptor is an exceptional member of the P2X purinergic receptor family, with its activation requiring high concentrations of extracellular adenosine 5'-triphosphate (ATP) that are often associated with tissue damage and inflammation. In the central nervous system (CNS), it is highly expressed in glial cells, particularly in microglia. In this review, we discuss the role and mechanisms of the P2X7 receptor in mediating neuroinflammation and other pathogenic events in a variety of traumatic CNS damage conditions, which lead to loss of neurological and cognitive functions. We raise the perspective on the steady progress in developing CNS-penetrant P2X7 receptor-specific antagonists that leverage the ATP-P2X7 receptor signaling axis as a potential therapeutic strategy to alleviate traumatic CNS damage and related complications.

Effects of transgenic cotton lines expressing dsAgCYP6CY3-P1 on the growth and detoxification ability of Aphis gossypii glover.

BACKGROUND: The pest Aphis gossypii Glover globally causes considerable economic losses on various crops by its feeding damage and disease transmission. Transgenic plants that produce double-stranded RNA (dsRNA) targeted to insect genes are being developed as a pest control strategy. In this study, we evaluated the effects of transgenic cotton-mediated RNA interference (RNAi) on the growth and detoxification ability of A. gossypii after the transgenic cotton lines expressing dsAgCYP6CY3-P1 (the TG cotton lines) were obtained on the basis of exploring the functions of CYP6CY3 in our previous research. RESULTS: The developmental time of third- and fourth-instar nymphs which fed on the TG cotton lines were significantly prolonged. Life table parameters showed that the fitness of cotton aphids from the TG cotton lines decreased. Additionally, the relative expression level of CYP6CY3 in cotton aphids which fed on the TG cotton lines was significantly reduced by 47.3 % at 48 h compared with that from the nontransgenic cotton (the NT cotton). Bioassay showed that silencing of CYP6CY3 increased mortality of the nymphs to imidacloprid by 28.49 % (at 24 h) and to acetamiprid by 73.77 % (at 48 h), respectively. CONCLUSION: These results indicated that the TG cotton lines delayed the growth and development of A. gossypii, but also decreased population density and increased its sensitivity to imidacloprid and acetamiprid, respectively. The results provide further support for the development and application of plant-mediated RNAi. © 2022 Society of Chemical Industry.

P301S-hTau acetylates KEAP1 to trigger synaptic toxicity via inhibiting NRF2/ARE pathway: A novel mechanism underlying hTau-induced synaptic toxicities.

BACKGROUND: Human Tau (hTau) accumulation and synapse loss are two pathological hallmarks of tauopathies. However, whether and how hTau exerts toxic effects on synapses remain elusive. METHODS: Mutated hTau (P301S) was overexpressed in the N2a cell line, primary hippocampal neurons and hippocampal CA3. Western blotting and quantitative polymerase chain reaction were applied to examine the protein and mRNA levels of synaptic proteins. The protein interaction was tested by co-immunoprecipitation and proximity ligation assays. Memory and emotion status were evaluated by a series of behavioural tests. The transcriptional activity of nuclear factor-erythroid 2-related factor 2 (NRF2) was detected by dual luciferase reporter assay. Electrophoresis mobility shift assay and chromosome immunoprecipitation were conducted to examine the combination of NRF2 to specific anti-oxidative response element (ARE) sequences. Neuronal morphology was analysed after Golgi staining. RESULTS: Overexpressing P301S decreased the protein levels of post-synaptic density protein 93 (PSD93), PSD95 and synapsin 1 (SYN1). Simultaneously, NRF2 was decreased, whereas Kelch-like ECH-associated protein 1 (KEAP1) was elevated. Further, we found that NRF2 could bind to the specific AREs of DLG2, DLG4 and SYN1 genes, which encode PSD93, PSD95 and SYN1, respectively, to promote their expression. Overexpressing NRF2 ameliorated P301S-reduced synaptic proteins and synapse. By means of acetylation at K312, P301S increased the protein level of KEAP1 via inhibiting KEAP1 degradation from ubiquitin-proteasome pathway, thereby decreasing NRF2 and reducing synapse. Blocking the P301S-KEAP1 interaction at K312 rescued the P301S-suppressed expression of synaptic proteins and memory deficits with anxiety efficiently. CONCLUSIONS: P301S-hTau could acetylate KEAP1 to trigger synaptic toxicity via inhibiting the NRF2/ARE pathway. These findings provide a novel and potential target for the therapeutic intervention of tauopathies.

A novel dephosphorylation targeting chimera selectively promoting tau removal in tauopathies.

Intraneuronal accumulation of hyperphosphorylated tau is a hallmark pathology shown in over twenty neurodegenerative disorders, collectively termed as tauopathies, including the most common Alzheimer's disease (AD). Therefore, selectively removing or reducing hyperphosphorylated tau is promising for therapies of AD and other tauopathies. Here, we designed and synthesized a novel DEPhosphorylation TArgeting Chimera (DEPTAC) to specifically facilitate the binding of tau to Bα-subunit-containing protein phosphatase 2A (PP2A-Bα), the most active tau phosphatase in the brain. The DEPTAC exhibited high efficiency in dephosphorylating tau at multiple AD-associated sites and preventing tau accumulation both in vitro and in vivo. Further studies revealed that DEPTAC significantly improved microtubule assembly, neurite plasticity, and hippocampus-dependent learning and memory in transgenic mice with inducible overexpression of truncated and neurotoxic human tau N368. Our data provide a strategy for selective removal of the hyperphosphorylated tau, which sheds new light for the targeted therapy of AD and related-tauopathies.

A Novel Bilinear Feature and Multi-Layer Fused Convolutional Neural Network for Tactile Shape Recognition.

Convolutional neural networks (CNNs) can automatically learn features from pressure information, and some studies have applied CNNs for tactile shape recognition. However, the limited density of the sensor and its flexibility requirement lead the obtained tactile images to have a low-resolution and blurred. To address this issue, we propose a bilinear feature and multi-layer fused convolutional neural network (BMF-CNN). The bilinear calculation of the feature improves the feature extraction capability of the network. Meanwhile, the multi-layer fusion strategy exploits the complementarity of different layers to enhance the feature utilization efficiency. To validate the proposed method, a 26 class letter-shape tactile image dataset with complex edges was constructed. The BMF-CNN model achieved a 98.64% average accuracy of tactile shape. The results show that BMF-CNN can deal with tactile shapes more effectively than traditional CNN and artificial feature methods.

TRPM2 channel: A novel target for alleviating ischaemia-reperfusion, chronic cerebral hypo-perfusion and neonatal hypoxic-ischaemic brain damage.

The transient receptor potential melastatin-related 2 (TRPM2) channel, a reactive oxygen species (ROS)-sensitive cation channel, has been well recognized for being an important and common mechanism that confers the susceptibility to ROS-induced cell death. An elevated level of ROS is a salient feature of ischaemia-reperfusion, chronic cerebral hypo-perfusion and neonatal hypoxia-ischaemia. The TRPM2 channel is expressed in hippocampus, cortex and striatum, the brain regions that are critical for cognitive functions. In this review, we examine the recent studies that combine pharmacological and/or genetic interventions with using in vitro and in vivo models to demonstrate a crucial role of the TRPM2 channel in brain damage by ischaemia-reperfusion, chronic cerebral hypo-perfusion and neonatal hypoxic-ischaemia. We also discuss the current understanding of the underlying TRPM2-dependent cellular and molecular mechanisms. These new findings lead to the hypothesis of targeting the TRPM2 channel as a potential novel therapeutic strategy to alleviate brain damage and cognitive dysfunction caused by these conditions.

Tau inhibits PKA by nuclear proteasome-dependent PKAR2α elevation with suppressed CREB/GluA1 phosphorylation.

Intraneuronal accumulation of wild-type tau plays a key role in Alzheimer's disease, while the mechanisms underlying tauopathy and memory impairment remain unclear. Here, we report that overexpressing full-length wild-type human tau (hTau) in mouse hippocampus induces learning and memory deficits with remarkably reduced levels of multiple synapse- and memory-associated proteins. Overexpressing hTau inhibits the activity of protein kinase A (PKA) and decreases the phosphorylation level of cAMP-response element binding protein (CREB), GluA1, and TrkB with reduced BDNF mRNA and protein levels both in vitro and in vivo. Simultaneously, overexpressing hTau increased PKAR2α (an inhibitory subunit of PKA) in nuclear fraction and inactivated proteasome activity. With an increased association of PKAR2α with PA28γ (a nuclear proteasome activator), the formation of PA28γ-20S proteasome complex remarkably decreased in the nuclear fraction, followed by a reduced interaction of PKAR2α with 20S proteasome. Both downregulating PKAR2α by shRNA and upregulating proteasome by expressing PA28γ rescued hTau-induced PKA inhibition and CREB dephosphorylation, and upregulating PKA improved hTau-induced cognitive deficits in mice. Together, these data reveal that intracellular tau accumulation induces synapse and memory impairments by inhibiting PKA/CREB/BDNF/TrkB and PKA/GluA1 signaling, and deficit of PA28γ-20S proteasome complex formation contributes to PKAR2α elevation and PKA inhibition.

Adenosine Triphosphate Release and P2 Receptor Signaling in Piezo1 Channel-Dependent Mechanoregulation.

Organs and tissues and their constituent cells are physiologically submitted to diverse types of mechanical forces or stress, one common sequence of which is release of intracellular ATP into extracellular space. Extracellular ATP is a well-established autocrine or paracrine signaling molecule that regulates multiple cell functions and mediates cell-to-cell communications via activating the purinergic P2 receptors, more specifically, ligand-gated ion channel P2X receptors and some of the G-protein-coupled P2Y receptors. The molecular mechanisms that sense mechanical and transduce forces to trigger ATP release are poorly understood. The Piezo1, a newly identified mechanosensing ion channel, shows widespread expression and confers mechanosensitivity in many different types of cells. In this mini-review, we briefly introduce the Piezo1 channel and discuss the evidence that supports its important role in the mechanoregulation of diverse cell functions and, more specifically, critical engagement of ATP release and subsequent P2 receptor activation in Piezo1 channel-dependent mechanoregulation. Such ATP release-mediated coupling of the Piezo1 channel and P2 receptors may serve a signaling mechanism that is more common than we currently understand in transducing mechanical information to regulation of the attendant cell functions in various organs and tissues.

Increasing the TRPM2 Channel Expression in Human Neuroblastoma SH-SY5Y Cells Augments the Susceptibility to ROS-Induced Cell Death.

Human neuroblastoma SH-SY5Y cells are a widely-used human neuronal cell model in the study of neurodegeneration. A recent study shows that, 1-methyl-4-phenylpyridine ion (MPP), which selectively causes dopaminergic neuronal death leading to Parkinson's disease-like symptoms, can reduce SH-SY5Y cell viability by inducing H2O2 generation and subsequent TRPM2 channel activation. MPP-induced cell death is enhanced by increasing the TRPM2 expression. By contrast, increasing the TRPM2 expression has also been reported to support SH-SY5Y cell survival after exposure to H2O2, leading to the suggestion of a protective role for the TRPM2 channel. To clarify the role of reactive oxygen species (ROS)-induced TRPM2 channel activation in SH-SY5Y cells, we generated a stable SH-SY5Y cell line overexpressing the human TRPM2 channel and examined cell death and cell viability after exposure to H2O2 in the wild-type and TRPM2-overexpressing SH-SY5Y cells. Exposure to H2O2 resulted in concentration-dependent cell death and reduction in cell viability in both cell types. TRPM2 overexpression remarkably augmented H2O2-induced cell death and reduction in cell viability. Furthermore, H2O2-induced cell death in both the wild-type and TRPM2-overexpressing cells was prevented by 2-APB, a TRPM2 inhibitor, and also by PJ34 and DPQ, poly(ADP-ribose) polymerase (PARP) inhibitors. Collectively, our results show that increasing the TRPM2 expression renders SH-SY5Y cells to be more susceptible to ROS-induced cell death and reinforce the notion that the TRPM2 channel plays a critical role in conferring ROS-induced cell death. It is anticipated that SH-SY5Y cells can be useful for better understanding the molecular and signaling mechanisms for ROS-induced TRPM2-mediated neurodegeneration in the pathogenesis of neurodegenerative diseases.

ATP-activated P2X7 receptor in the pathophysiology of mood disorders and as an emerging target for the development of novel antidepressant therapeutics.

Mood disorders are a group of psychiatric conditions that represent leading global disease burdens. Increasing evidence from clinical and preclinical studies supports that innate immune system dysfunction plays an important part in the pathophysiology of mood disorders. P2X7 receptor, belonging to the ligand-gated ion channel P2X subfamily of purinergic P2 receptors for extracellular ATP, is highly expressed in immune cells including microglia in the central nervous system (CNS) and has a vital role in mediating innate immune response. The P2X7 receptor is also important in neuron-glia signalling in the CNS. The gene encoding human P2X7 receptor is located in a locus of susceptibility to mood disorders. In this review, we will discuss the recent progress in understanding the role of the P2X7 receptor in the pathogenesis and development of mood disorders and in discovering CNS-penetrable P2X7 antagonists for potential uses in in vivo imaging to monitor brain inflammation and antidepressant therapeutics.

[Effect of NaHS on ATP-induced P2X receptor expression in rat microglia].

OBJECTIVE: To observed the effect of sodium hydrosulphide (NaHS), a donor of H2S on the cell viability,the membrane permeability and the expression of P2X7 receptor induced by adenosine triphosphate(ATP) in rat microglia. METHODS: Rat microglia in logarithmic growth phase was randomly divided into 4 groups. In control group, the cells were cultured without ATP treatment. In ATP group, the cells were treatment with ATP after cultured for 24 hours. In NaHS+ATP group, the cells were incubated with NaHS for 30 min before ATP, and NaHS always existed in the reaction system. In KN-62+ATP group, the cells were pretreated with KN-62 for 30 min, the others were as the same as NaHS+ATP group. The cell viability was detected by MTT. Fluorescent dyes YO-PRO-1 was used to observe the membrane permeability. The expression of P2X7 receptor was examined by immunofluorescence staining. RESULTS: ① Compared with control group, the cell viability dropped after treatment with ATP (1、3、5、10 mmol/L) for 3 hours. When pre-incubation with NaHS(200 µmol/L), the cell viability was apparently higher than that of ATP alone group(P<0.01), while 400 µmol/L had no further beneficial.②The YO-PRO-1 fluorescence intensity was obviously elevated by ATP in rat microglia, but this effect was counteracted by NaHS pretreatment (P<0.01). ③ The expression of P2X7 receptor protein was significantly increased after ATP(3 mmol/L) for 3 h. While the expression upregulation of P2X7 receptor protein induced by ATP was significantly counteracted by pretreating with NaHS(200 µmol/L) (P<0.01). CONCLUSIONS: NaHS could reduce the expression of P2X7 receptor, decrease membrane permeability, and increase the cell viability in rat microglia injured by ATP. So the cytoprotection of hydrogen sulfide may be related to the expression and function of P2X7 receptor.

Two subdivisions of macaque LIP process visual-oculomotor information differently.

Although the cerebral cortex is thought to be composed of functionally distinct areas, the actual parcellation of area and assignment of function are still highly controversial. An example is the much-studied lateral intraparietal cortex (LIP). Despite the general agreement that LIP plays an important role in visual-oculomotor transformation, it remains unclear whether the area is primary sensory- or motor-related (the attention-intention debate). Although LIP has been considered as a functionally unitary area, its dorsal (LIPd) and ventral (LIPv) parts differ in local morphology and long-distance connectivity. In particular, LIPv has much stronger connections with two oculomotor centers, the frontal eye field and the deep layers of the superior colliculus, than does LIPd. Such anatomical distinctions imply that compared with LIPd, LIPv might be more involved in oculomotor processing. We tested this hypothesis physiologically with a memory saccade task and a gap saccade task. We found that LIP neurons with persistent memory activities in memory saccade are primarily provoked either by visual stimulation (vision-related) or by both visual and saccadic events (vision-saccade-related) in gap saccade. The distribution changes from predominantly vision-related to predominantly vision-saccade-related as the recording depth increases along the dorsal-ventral dimension. Consistently, the simultaneously recorded local field potential also changes from visual evoked to saccade evoked. Finally, local injection of muscimol (GABA agonist) in LIPv, but not in LIPd, dramatically decreases the proportion of express saccades. With these results, we conclude that LIPd and LIPv are more involved in visual and visual-saccadic processing, respectively.