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Objective: To examine the characteristics and the prognostic influence of pulmonary infections in neurologic disease patients with mild-to-severe hypoproteinemia., Methods: We used a retrospective survey method to analyze the characteristics and prognoses of 220 patients with hypoproteinemia complicated with pulmonary infection in the Internal Medicine-Neurology Intensive Care Unit at the First Affiliated Hospital of Chongqing Medical University from January 2010 to December 2013. The patients were divided into mild, moderate and severe hypoproteinemia groups according to their serum albumin levels. The analysis included patient age, sex, acute physiology and chronic health evaluation (APACHE II score), and characteristics of the pulmonary infection, nutritional support and prognosis, among others., Results: Differences in the general information of the 220 cases of hypoalbuminemia patients complicated with varying degrees of pulmonary infection (APACHE II score, age, disease distribution) were statistically significant. The pulmonary infection onset time and pathogen susceptibility in the patients with mild-to-severe hypoalbuminemia were not significantly different. Pulmonary infection onset was more frequently observed within the first 3-11 days following admission in all groups. The nutritional support method did not significantly influence serum albumin protein levels. However, the neurological intensive care unit stay length, total hospitalization cost and disease distribution were significantly different among the patient groups., Conclusions: Patients with cerebrovascular disease, intracranial infections and epilepsy complicated with pulmonary infection represent the high-risk groups for hypoalbuminemia. The Acinetobacter baumannii complex represents the main group of pathogenic bacteria causing lung infections, and the high-risk period for lung infections is 3-11 days after the occurrence of hypoalbuminemia. Patients with severe hypoalbuminemia complicated with pulmonary infection have the worst prognoses.

Objective: To explore the expression of ATP (adenosine triphosphate)-binding gene mRNA (messenger ribonucleic acid) in brain tissues of patients with drug-resistant epilepsy and understand their biological characteristics., Methods: The postoperative brain tissues were collected randomly from 40 patients with drug-refractory epilepsy. Based on the expected results of complementary DNA (cDNA) microarray, reverse transcription-polymerase chain reaction (RT-PCR) was used to evaluate ATP-binding gene mRNA expression in brain tissues of 40 patients with drug-resistant epilepsy and 8 normal controls., Results: As compared with 8 normal control cases, the candidate genes of ATP-binding mRNA were higherly expressed in the brain tissues of patients with drug-resistant epilepsy. The rates of Cy5/Cy3 were CDC2L5 2.159, ROCK1 2.538, STCH 2.106, OXSR1 3.791 and ABCB6 2.583 respectively. And the results of RT-PCR corresponded with those of cDNA chip., Conclusion: The significant neuronal up-regulation of ATP-binding gene mRNA suggests that abnormal energy metabolism exist in brain tissues of patients with drug-resistant epilepsy. And the apoptosis of neurons and synaptic plasticity caused by abnormal energy metabolism may play an important role in the occurrence and development of patients with drug-resistant epilepsy.

Tau exists in neuronal axons and glial cells of the central nervous system and contributes to the maintenance of the unique cell morphology. It functions in axon elongation, cell polarity formation and microtubule stabilization. Aggregates and hyper-phosphorylated tau proteins are classical components of neurofibrillary lesions in numerous neurodegenerative disorders, which are called "tauopathies". Recent studies have demonstrated that tau-associated genes and proteins and tau phosphorylation were abnormal in intractable epilepsy. Therefore, the discovery of the dysfunctional tau in intractable epilepsy opens a new window in the study of central tauopathy., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

We investigated the expression of laminin β1 and integrin α2 in the anterior temporal neocortex tissue of patients with intractable epilepsy and explored the role of these molecules in the pathogenesis of this disease. Immunohistochemistry and immunofluorescence were used to test the expression of laminin β1 and integrin α2 in samples (from the brain bank of our department, n=32) of surgically removed anterior temporal neocortex tissues from intractable epilepsy patients, and the results were compared with those of controls (n=10). We found that laminin β1 and integrin α2 protein expression was significantly increased in the anterior temporal neocortex as compared with controls (immunohistochemistry optical density: laminin β1 = 0.36 ± 0.01 vs. 0.10 ± 0.03 for control; integrin α2=0.42 ± 0.02 vs. 0.04 ± 0.01 for control; p<.05). Immunofluorescence staining indicated that laminin β1 and integrin α2 accumulated in the plasma membrane and cytoplasm, with strong fluorescence intensity in the anterior temporal neocortex tissue of patients with intractable epilepsy. Thus, our work demonstrates that laminin β1 and integrin α2 expression is elevated in the anterior temporal neocortex tissue from patients with intractable epilepsy., (Copyright © 2011 Informa Healthcare USA, Inc.)

Drug refractory is an important clinical problem in epilepsy, affecting a substantial number of patients globally. Mechanisms underlying drug refractory need to be understood to develop rational therapies. Current two prevailing theories on drug refractory epilepsy (DRE) include the target hypothesis and the transporter hypothesis. However, those hypotheses could not be adequate to explain the mechanisms of all the DRE. Thus, we propose another possible mechanism of DRE, which is neural network hypothesis. It is hypothesized that seizure-induced alterations of brain plasticity including axonal sprouting, synaptic reorganization, neurogenesis and gliosis could contribute to the formation of abnormal neural network, which has not only avoided the inhibitory effect of endogenous antiepileptic system but also prevented the traditional antiepileptic drugs from entering their targets, eventually leading to DRE. We will illustrate this hypothesis at molecular and structural level based on our recent studies and other related researches., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Annexin A7 is a member of the family of annexins, which are thought to function in the regulation of calcium homeostasis and the fusion of vesicles. Refractory epilepsy may be related to the imbalance of calcium homeostasis. Our aims are to investigate the expression of Annexin A7 in epileptic brains in comparison with human controls and to explore Annexin A7's possible role in refractory epilepsy. We examined the expression of Annexin A7 via immunohistochemistry, double-label immunofluorescence and western blot. The expression of Annexin A7 was shown to be significantly increased in patients with refractory epilepsy. Double-label immunofluorescence and confocal microscopy disclosed Annexin A7 immunoreactivity in the neurons, which were recognized by the antibody of neuron specific enolase (NSE). The result showed that Annexin A7 may be involved in the pathophysiology of refractory epilepsy and may play a role in developing and maintaining the epilepsy.

To elucidate the molecular basis of intractable epilepsy (IE), we used a whole-genome transcriptomic approach to identify genes involved in the pathogenesis of this disease. Using a complementary DNAs microarray representing 4096 human genes, we analyzed differential gene expression in the anterior temporal neocortex (ATN) of IE patients relative to control patients who had an operation to relieve head trauma-related intracranial pressure. The results were validated by real-time fluorescence-quantitative polymerase chain reaction (FQ-PCR) and reverse transcription-PCR (RT-PCR). The expression of 143 genes (3.5%) was significantly altered in IE patients. Thirty-seven genes (26%) were reduced relative to controls, and 106 (74%) were elevated (more than twofold change vs. controls), including genes involved in immunity, signal transduction, apoptosis, stress, synaptic plasticity, structural, and cellular reorganization, among other processes. Results for 13 of the 14 differentially expressed genes tested by FQ-PCR were consistent with the microarray. Twelve abnormally expressed cytoskeletal genes were confirmed by RT-PCR. Expression of 11 was significantly higher in the ATN of IE patients than in controls. Gene products altered in IE, namely HSPBAP1, TRAP220, glycogen synthase kinase-3beta (GSK-3beta), and cyclin-dependent kinase 5 (CDK5), were tested by immunohistochemistry and immunoblotting. GSK-3beta and CDK5 levels were significantly higher in the ATN of IE patients. Our gene chip data are generally in agreement with the published findings on epilepsy. Thus, gene chips may serve as a screening tool to elucidate the pathophysiology of IE. Investigation of some of these newly identified genes should enhance our understanding of the molecular mechanisms of epileptogenesis.

Epithelial membrane protein-1 (EMP-1), called Tumor-associated membrane protein, is the marker of a drug-resistant tumor and take part in the drug-resistant mechanism of tumor, with the relationship of epidermal growth factor receptor (EGFR). Because there are some similarities between the pathogenesis and the drug resistance mechanism of tumor and the drug resistance mechanisms in epilepsy. EMP1 expression may be connected with the drug-resistance mechanism of epilepsy. We detected EMP-1 by gene scanning and immunohistochemistry staining, comparing the IE group and the control group, and we investigated the relationship between EMP-1 and EGFR by double-label immunofluorescence staining in the IE group. We found expression of EMP-1 mRNA was higher in IE per the gene scanning, EMP-1 immunoreactivity was apparent in neurons of IE patients but not in the control group, and the expression of EMP-1 and EGFR occurred in the same neuron. We confirm EMP-1 is abnormally expressed in IE and suggest the interaction of EGFR and EMP-1 plays a role in the mechanism of drug resistance in epilepsy and may be a new gene for drug resistance.

Synaptotagmin I is a key synaptic protein involved in both exocytosis and endocytosis. We aimed to investigate Synaptotagmin I expression in the anterior temporal neocortex of epilepsy patients, and to explore the possible role of Synaptotagmin I in refractory epilepsy. In the present study, 30 epilepsy patients were divided into refractory epilepsy and non-refractory epilepsy groups, another 15 histologically normal anterior temporal lobes from head trauma patients were used as control group. The results were compared among different groups. The findings were consistently observed using immunohistochemistry, immunofluorescence, and Western blotting technique. Synaptotagmin I was mainly expressed in the cytoplasm and cytomembrane of neurons. The expression of Synaptotagmin I in refractory epilepsy group was significantly higher than that in the control and non-refractory epilepsy groups. These findings provide new information in the epileptogenesis of refractory epilepsy, and suggest that Synaptotagmin I might be involved in human refractory epilepsy. Further studies will be required to elucidate the mechanism by which Synaptotagmin I plays role in refractory epilepsy.

In this study, we examined differences in serum laminin expression in patients with intractable epilepsy. Our results suggest that elevated laminin may contribute to the pathogenesis of intractable epilepsy. ELISA and western blots were used to measure laminin in the serum of 30 intractable epilepsy patients, 46 nonintractable epilepsy patients, and 20 normal subjects. By ELISA, serum laminin levels were greater in intractable epilepsy patients (177.396 +/- 30.602) and nonintractable epilepsy patients (121.915 +/- 35.215) than in normal control subjects (67.474 +/- 7.197); laminin was significantly greater in the intractable epilepsy group than in the nonintractable epilepsy group. In western blots, the optical density ratio of laminin to ss-actin was 0.871 +/- 0.032 for the intractable epilepsy group, 0.686 +/- 0.017 for the nonintractable epilepsy group, and 0.385 +/- 0.024 for the normal control group. The optical density ratios of the intractable and nonintractable epilepsy groups were higher than those for the normal control group, and the intractable epilepsy group was even greater than the nonintractable epilepsy group. Thus, laminin is significantly increased in epilepsy patients, and this increase is more profound in intractable epilepsy patients.

Objective: To study the protein expression of adenylate kinases (AK)-2 in the brain tissues of patients with drug-refractory temporal epilepsy and the clinical value thereof., Methods: Specimens of brain from 40 patients with refractory temporal epilepsy, and 20 sex- and age-matched persons with brain trauma. Immunohistochemistry and immunofluorescence examination were used to test the levels of AK2., Results: AK2 was expressed in the temporal lobes and hippocampuses of all epileptics, mainly in the cell bodies, and not in the brain tissues of the controls., Conclusion: The overexpression of AK2 may be involved in the pathogenesis of drug-refractory epilepsy and become an important symbol thereof.

We investigated laminin beta1 expression in the hippocampi of patients with intractable epilepsy and explored the role of laminin beta1 in the pathogenesis of this condition. Fluorescence quantitative PCR, immunofluorescence, immunohistochemistry and Western blotting were used to measure laminin beta1 expression in surgically removed hippocampi of patients with intractable epilepsy, and the results were compared with control hippocampi. Fluorescence quantitative PCR showed increased expression of laminin beta1 mRNA in patient hippocampi compared with control tissues. Immunohistochemical staining demonstrated that laminin beta1 protein expression was significantly increased in patient hippocampi, and immunofluorescence microscopy showed accumulation of laminin beta1 in the cell membrane and cytoplasm of patient hippocampi. These findings were confirmed by Western blotting of protein preparations from patient hippocampi. Elevated expression of laminin beta1 mRNA and protein in the hippocampus suggests that laminin beta1 may play a role in the development of epileptic seizures in patients with intractable epilepsy.

Neuronal circuit remodeling is the most critical pathological characteristic closely associated with the initiation and maintenance of epilepsy; however, the exact mechanisms of neuronal remodeling need further elucidation. Neuronal Wiskott-Aldrich syndrome protein (N-WASP) is a key regulator of the actin cytoskeleton that causes actin polymerization and thus neurite extension. Our previous research demonstrated that the upstream regulator of N-WASP, cell division cycle 42 GTP-binding protein (Cdc42), is significantly upregulated in the brains of patients with intractable epilepsy (IE). In addition, cDNA microarray analysis has shown that gene expression of N-WASP is notably enhanced in the epileptic brain, suggesting a possible role for N-WASP in epileptogenesis. Here, we investigated the expression of N-WASP and its downstream effector, actin-related protein 2/3 (Arp2/3), at the protein level in the temporal lobe of IE patient brains to explore its possible role in the genesis of IE. Forty surgical samples from brains of patients with IE and 20 control brain tissues were obtained for this study. The expression of N-WASP in the anterior temporal neocortex was detected using immunohistochemistry, immunofluorescence and western blotting; Arp2/3 expression was detected by western blotting. Compared with controls, N-WASP expression in brains of IE patients was significantly higher; similarly, Arp2/3 level was markedly increased in the IE patient group. These results suggest that increased expression of N-WASP in the human brain may be associated with human IE.

TDAG51 (T cell death-associated gene 51) is an apoptosis-associated protein. Our aim was to investigate TDAG51 expression in the anterior temporal neocortex of patients with intractable epilepsy (IE), and then to discuss the possible role of TDAG51 in IE. Tissue samples from the anterior temporal neocortex of 33 patients who had surgery for IE were used to detect TDAG51 expression by immunohistochemistry, immunofluorescence, and Western blotting. We compared these tissues with nine histologically normal anterior temporal lobes from intracranial hypertension patients who had decompression procedures. TDAG51 was mainly expressed in the cytoplasm of neurons and glial cells. TDAG51 in IE was significantly higher than that in the controls. These findings were consistently observed using Western blotting, immunofluorescence, and immunohistochemistry techniques. TDAG51 in patients with IE was significantly higher when compared with levels in the controls. This finding suggests TDAG51 is consistent with a possible role of this gene in the evolution of the pathology in IE.

Heat Shock Protein BAP1 (heat shock 27-kDa-associated protein 1, HSPBAP1) inhibits the function of heat shock protein 27, which has a neuroprotective effect during experimentally induced epileptic neuropathology. In our study, fluorescence quantitative polymerase chain reaction, immunohistochemistry, immunofluorescence, western blot were used to test the levels of HSPBAP1 mRNA and protein in surgical samples of the anterior temporal neocortex of patients with intractable epilepsy (IE) and normal controls samples. HSPBAP1 mRNA was abnormally expressed in the anterior temporal neocortex of patients with IE. Moreover, HSPBAP1 was found extensively in the cytoplasm of neurons and glial cells in all epilepsy specimens. Western blot showed a clear immunoreactive band of HSPBAP1 in IE specimens whereas it was absent in control specimens. The expression of HSPBAP1 mRNA and protein in the anterior temporal neocortex from patients with IE may play a role in the development of epileptic seizures in patients with cell loss in this brain region. Additional studies will be required to elucidate the mechanism by which HSPBAP1 affects brain function in IE.

Objective: To investigate the expression of cell division cycle 42 GTP-binding protein (Cdc42) in the brain tissue of patients with intractable temporal epilepsy and discuss its effect on epileptogenesis., Methods: Twenty samples brain tissues were collected from the brain tissue bank of intractable temporal epilepsy established by Epilepsy Preventive and Therapeutic Center of Chongqing. The expression of Cdc42 was determined by immunohistochemistry and fluoroimmunoassay. Twenty brain tissue samples were collected from autopsy on 20 sex and age-matched persons who died from accident were used as controls., Results: The absorption values of Cdc42 in the temporal lobe of the patients was 0.038 +/- 0.016, significantly higher than that of the controls (0.020 +/- 0.005, t = 14.59, P < 0.01). The absorption values of Cdc42 in the hippocampus of the patients was 0.049 +/- 0.009, t = 12.01, P < 0.01). Fluoroimmunoassay showed that the fluorescence intensity of Cdc42 in the temporal lobe of the patients was 18.3 +/- 2.5, significantly higher than that of the controls (11.8 +/- 2.9, t = 33.77, P < 0.01), and the Fluorescence intensity of Cdc42 in the hippocampus of the patients was and control hippocampus were 23.8 +/- 3.3, significantly higher than that of the controls (10.1 +/- 2.6, t = 12.01, P < 0.01)., Conclusion: The overexpression of Cdc42 in the cortex of temporal lobe and hippocampus may play an important role in the epileptogenic mechanisms of intractable epilepsy.

Objective: To investigate the expression of PSD-93 mRNA and NR2B mRNA in the brain tissue from the patients with epilepsy so as to explore the possible mechanisms of the pathogenesis of the epilepsy., Methods: Fifty-six patients with epilepsy were divided into intractable epilepsy (IE) and non-intractable epilepsy (NIE) groups. cDNA microarrays prepared from the brain tissues obtained from these two groups were scanned and comparison to those from the non-epileptogenic control (C) was made. Expression level of PSD-93mRNA and NR2BmRNA were examined by reverse transcription polymerase chain reaction (GAPDH gene, internal control). Expression ratio (target gene/GAPDH) was used to evaluate each gene relative expression level., Results: The cDNA microarray analysis showed that the expression of PSD-93 mRNA related to the function of NMDAR-NO signal transduction pathway was significantly higher in epilepsy patients than those in the controlled group. The results of RT-PCR were consistent with those of the cDNA microarrays. The relative expression ratio of PSD-93 in patients with non-epileptogenic control, NIE, and IE was 0.159, 0.368, and 0.341, respectively. Correspondingly, that of NR2B was 0.198, 0.738, and 0.903, respectively. The expressions of PSD-93 and NR2B in the NIE and IE were significantly higher than those of control, respectively (P<0.05). However, there was no significantly difference the expression of PSD-93 between NIE and IE. (P>0.05), neither do that of NR2B (P>0.05)., Conclusions: The upregulated expressions of PSD-93 mRNA and NR2BmRNA may be involved in the pathogenesis of epilepsy.

Objective: To investigate the clinical and epidemiological feature of the five kinds of new epilectically syndrome., Method: A retrospective study was conducted, by computer inquiry and manual retrieval, on 5300 patients with complete history records who had been followed up regularly in the epilepsy center of the First Affiliated Hospital of Chongqing University in the past 20 years to discover the cases that could be diagnosed as with the five kinds of new epileptic syndromes., Results: Survey was finished in 4894 of the 5300 patients. Two cases of familial temporal lobe epilepsy, one case of familial partial epilepsy with variable foci, fourteen cases with mesial temporal epilepsy, and five cases with startle-provoked epileptic were discovered., Conclusion: Patients with the five kinds of new epileptic syndrome have been discovered in China too. It is beneficial to study the clinical and epidemiological features of those new epileptic syndromes.

Purpose: TRAP220 (thyroid hormone receptor-associated protein) functions as a coactivator for nuclear receptors and stimulates transcription by recruiting the TRAP mediator complex to hormone responsive promoter regions. Thus, TRAP220 enhances the function of thyroid/steroid hormone receptors such as thyroid hormone and oestrogen receptors. This study investigated the expression of TRAP220 mRNA and protein level in epileptic brains comparing with human control., Methods: We examined the expression of TRAP220 mRNA and protein levels in temporal lobes from patients with chronic pharmacoresistant epilepsy who have undergone surgery., Results: Expression of TRAP220 mRNA and protein was shown to be decreased significantly in the temporal cortex of the patients with epilepsy., Conclusions: Our work showed that a decrease in TRAP220 mRNA and protein levels may be involved in the pathophysiology of epilepsy and may be associated with impairment of the brain caused by frequent seizures.

The research and treatment of epilepsy is entering a new era. In order to meet the arrival of this era, organizations such as International League Against Epilepsy (ILAE) have proposed a series of reform measures, which will bring new concepts to the prevention and treatment of epilepsy, establish a new knowledge framework, and promote scientific progress in this field. This article introduces the significance of the transition from anti-epileptic to anti-seizure, the new classification of epilepsy syndromes of the ILAE, the new international standard of EEG, and discusses the international treatment methods for status epilepticus (SE).

Epilepsy is a neurological disease, and the main clinical manifestation is recurrent seizures. The exact etiology of epilepsy and the pathogenesis of the disorder are not yet fully understood. Atlastin‐1, a dynamin‐like GTPase, interacts with microtubules and is responsible for vesicle formation, both of which are highly associated with the development of epilepsy. Here, we reported that the expression level of atlastin‐1 protein was reduced in the temporal neocortex of patients with temporal lobe epilepsy and in the hippocampus and adjacent cortex of a pentylenetetrazol‐kindled epileptic mouse model. Cells expressing atlastin‐1 coexpressed the inhibitory synaptic marker GAD67 in the temporal cortex and hippocampus of patients with epilepsy and an epileptic mouse model. The lentivirus‐mediated overexpression of atlastin‐1 protein in the hippocampus of mice suppressed seizure activity in behavioral experiments. Patch‐clamp recordings in the Mg2+‐free epilepsy cell model showed that atlastin‐1 overexpression inhibited neuronal excitability by suppressing the discharge frequency of spontaneous action potentials rather than by changing the passive and active properties of action potentials. Inhibitory synaptic transmission, but not excitatory synaptic currents, increased after atlastin‐1 overexpression. These findings suggest that atlastin‐1 likely contributes to the occurrence and development of epilepsy through inhibitory synaptic transmission. [ABSTRACT FROM AUTHOR]

ABSTRACT Dynamin 1 is a neuron-specific guanosine triphosphatase (GTPase) that is an essential component of membrane fission during synaptic vesicle recycling and endocytosis. This study evaluated the dynamin 1 expression pattern in the acute lithium-pilocarpine rat model and in patients with temporal lobe epilepsy (TLE) and investigated whether altering the dynamin 1 expression pattern affects epileptic seizures in vivo and in vitro. The immunofluorescence, western blot analysis, and reverse transcription-PCR results show that the dynamin 1 expression level increased significantly in experimental rats from day 1 to day 7 after the onset of seizures and was significantly higher in TLE patients. The behavioral study revealed that inhibiting dynamin 1 increased the latency time of the first seizure and decreased the frequency and severity of the seizures. In addition, electrophysiological recordings from brain slices showed that inhibiting dynamin 1 reduces the frequency of Mg-free induced seizure-like activity. The anticonvulsant effect of dynasore was more effective at 10 µM than at 1 µM or 160 µM. These results indicate that the altered level of dynamin 1 may contribute to the development of epileptic seizures and that the targeted regulation of dynamin 1 activity may control epileptic seizures. Synapse 69:67-77, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Acid-sensing ion channels (ASICs) are H+-gated, Na+-permeable channels formed by six different subunits which are coded by four genes. These channels open when the extracellular pH decreases. Studies show that ASICs play an important role in the pathological process of inflammation, ischemia, pain and etc. Extracellular pH decreases obviously in the process of epilepsy, resulting in the open of ASICs. However, recent studies have indicated that ASICs may also play a significant role in the termination of epilepsy. So far, the homo - or heteromeric association of six subunits and their specific inhibitors have been found, and they may be novel targets for the development of new drugs. [ABSTRACT FROM AUTHOR]

Pure grand mal epilepsy (PGME) is a common subtype of idiopathic generalized epilepsy (IGE) with an unclear mode of inheritance. Several studies with the multiple families have provided evidence for the disorder to be linked to chromosome 8q24 and 8p. In this work, we performed an autosomal-wide scan linkage analysis using microsatellite markers in a large Chinese family with PGME and found seven markers with likelihood of odds (LOD), scores ≥1.0 (θ=0) in chromosome 11q22.1–23.3. The highest LOD score for two-point and multi-point linkage analysis are 1.99 (θ=0) at marker D11S4159 and 2.18 between markers D11S1782 and D11S3178, respectively, which reached the level of a suggested positive linkage LOD score (Z≥1.9), under an autosomal dominant manner of inheritance with a penetrance of 65% but no significant positive LOD score (Z≥3.3) was found after high density of microsatellite markers used in the regions. Obviously, our data do not support the linkage of the disease to chromosome 8q24 and 8p but implicate that chromosome 11q22.1–23.3 may be a new locus linked to PGME, which indicates the existence of genetic heterogeneity in the disorder. [Copyright &y& Elsevier]

Neuronal connectivity is essential for adaptive brain responses and can be modulated by dendritic spine plasticity and the intrinsic excitability of individual neurons. Dysregulation of these processes can lead to aberrant neuronal activity, which has been associated with numerous neurological disorders including autism, epilepsy, and Alzheimer's disease. Nonetheless, the molecular mechanisms underlying abnormal neuronal connectivity remain unclear. We previously found that the serine/threonine kinase Microtubule Affinity Regulating Kinase 2 (MARK2), also known as Partitioning Defective 1b (Par1b), is important for the formation of dendritic spines in vitro. However, despite its genetic association with several neurological disorders, the in vivo impact of MARK2 on neuronal connectivity and cognitive functions remains unclear. Here, we demonstrate that the loss of MARK2 in vivo results in changes to dendritic spine morphology, which in turn leads to a decrease in excitatory synaptic transmission. Additionally, the loss of MARK2 produces substantial impairments in learning and memory, reduced anxiety, and defective social behavior. Notably, MARK2 deficiency results in heightened seizure susceptibility. Consistent with this observation, electrophysiological analysis of hippocampal slices indicates underlying neuronal hyperexcitability in MARK2‐deficient neurons. Finally, RNAseq analysis reveals transcriptional changes in genes regulating synaptic transmission and ion homeostasis. These results underscore the in vivo role of MARK2 in governing synaptic connectivity, neuronal excitability, and cognitive functions. [ABSTRACT FROM AUTHOR]