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Severe loss of excitatory synapses in key brain regions is thought to be one of the major mechanisms underlying stress-induced cognitive impairment. To date, however, the identity of the affected circuits remains elusive. Here we examined the effect of exposure to repeated multiple concurrent stressors (RMS) on the connectivity of the posterior parietal cortex (PPC) in adolescent male mice. We found that RMS led to layer-specific elimination of excitatory synapses with the most pronounced loss observed in deeper cortical layers. Quantitative analysis of cortical projections to the PPC revealed a significant loss of sensory and retrosplenial inputs to the PPC while contralateral and frontal projections were preserved. These results were confirmed by decreased synaptic strength from sensory, but not from contralateral, projections in stress-exposed animals. Functionally, RMS disrupted visuospatial working memory performance, implicating disrupted higher-order visual processing. These effects were not observed in mice subjected to restraint-only stress for an identical period of time. The PPC is considered to be a cortical hub for multisensory integration, working memory, and perceptual decision-making. Our data suggest that sensory information streams targeting the PPC may be impacted by recurring stress, likely contributing to stress-induced cognitive impairment.SIGNIFICANCE STATEMENT Repeated exposure to stress profoundly impairs cognitive functions like memory, attention, or decision-making. There is emerging evidence that stress not only impacts high-order regions of the brain, but may affect earlier stages of cognitive processing. Our work focuses on the posterior parietal cortex, a brain region supporting short-term memory, multisensory integration, and decision-making. We show evidence that repeated stress specifically damages sensory inputs to this region. This disruption of synaptic connectivity is linked to working memory impairment and is specific to repeat

Fragile X Syndrome (FXS) is the most common cause of inherited intellectual disability with prevalence rates estimated to be 1:5,000 in males and 1:8,000 in females. The increase of >200 Cytosine Guanine Guanine (CGG) repeats in the 5' untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene results in transcriptional silencing on the FMR1 gene with a subsequent reduction or absence of fragile X mental retardation protein (FMRP), an RNA binding protein involved in the maturation and elimination of synapses. In addition to intellectual disability, common features of FXS are behavioral problems, autism, language deficits and atypical physical features. There are still no currently approved curative therapies for FXS, and clinical management continues to focus on symptomatic treatment of comorbid behaviors and psychiatric problems. Here we discuss several treatments that target the neurobiological pathway abnormal in FXS. These medications are clinically available at present and the data suggest that these medications can be helpful for those with FXS.

Fragile X Syndrome (FXS) is the most common cause of inherited intellectual disability with prevalence rates estimated to be 1:5,000 in males and 1:8,000 in females. The increase of >200 Cytosine Guanine Guanine (CGG) repeats in the 5' untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene results in transcriptional silencing on the FMR1 gene with a subsequent reduction or absence of fragile X mental retardation protein (FMRP), an RNA binding protein involved in the maturation and elimination of synapses. In addition to intellectual disability, common features of FXS are behavioral problems, autism, language deficits and atypical physical features. There are still no currently approved curative therapies for FXS, and clinical management continues to focus on symptomatic treatment of comorbid behaviors and psychiatric problems. Here we discuss several treatments that target the neurobiological pathway abnormal in FXS. These medications are clinically available at present and the data suggest that these medications can be helpful for those with FXS.

There is a need for treatments that can safely promote regulatory lymphocyte responses. T cells express GABA receptors (GABAA-Rs) and GABA administration can inhibit Th1-mediated processes such as type 1 diabetes and rheumatoid arthritis in mouse models. Whether GABAA-R agonists can also inhibit Th17-driven processes such as experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), is an open question. GABA does not pass through the blood-brain barrier (BBB) making it ill-suited to inhibit the spreading of autoreactivity within the CNS. Homotaurine is a BBB-permeable amino acid that antagonizes amyloid fibril formation and was found to be safe but ineffective in long-term Alzheimer's disease clinical trials. Homotaurine also acts as GABAA-R agonist with better pharmacokinetics than that of GABA. Working with both monophasic and relapsing-remitting mouse models of EAE, we show that oral administration of homotaurine can (1) enhance CD8+CD122+PD-1+ and CD4+Foxp3+ Treg, but not Breg, responses, (2) inhibit autoreactive Th17 and Th1 responses, and (3) effectively ameliorate ongoing disease. These observations demonstrate the potential of BBB-permeable GABAA-R agonists as a new class of treatment to enhance CD8+ and CD4+ Treg responses and limit Th17 and Th1-medaited inflammation in the CNS.

There is a need for treatments that can safely promote regulatory lymphocyte responses. T cells express GABA receptors (GABAA-Rs) and GABA administration can inhibit Th1-mediated processes such as type 1 diabetes and rheumatoid arthritis in mouse models. Whether GABAA-R agonists can also inhibit Th17-driven processes such as experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), is an open question. GABA does not pass through the blood-brain barrier (BBB) making it ill-suited to inhibit the spreading of autoreactivity within the CNS. Homotaurine is a BBB-permeable amino acid that antagonizes amyloid fibril formation and was found to be safe but ineffective in long-term Alzheimer's disease clinical trials. Homotaurine also acts as GABAA-R agonist with better pharmacokinetics than that of GABA. Working with both monophasic and relapsing-remitting mouse models of EAE, we show that oral administration of homotaurine can (1) enhance CD8+CD122+PD-1+ and CD4+Foxp3+ Treg, but not Breg, responses, (2) inhibit autoreactive Th17 and Th1 responses, and (3) effectively ameliorate ongoing disease. These observations demonstrate the potential of BBB-permeable GABAA-R agonists as a new class of treatment to enhance CD8+ and CD4+ Treg responses and limit Th17 and Th1-medaited inflammation in the CNS.

The present study examined synaptic communication between direct and indirect output pathway striatal medium-sized spiny neurons (MSNs) and their target structures, the substantia nigra pars reticulata (SNr) and the external globus pallidus (GPe) in two mouse models of Huntington's disease (HD). Cre recombination, optogenetics, and whole-cell patch-clamp recordings were used to determine alterations in intrinsic and synaptic properties of SNr and GPe neurons from both male and female symptomatic R6/2 (>60 d) and presymptomatic (2 months) or symptomatic (10-12 months) YAC128 mice. Cell membrane capacitance was decreased, whereas input resistance was increased in SNr neurons from R6/2, but not YAC128 mice. The amplitude of GABAergic responses evoked by optogenetic stimulation of direct pathway terminals was reduced in SNr neurons of symptomatic mice of both models. A decrease in spontaneous GABA synaptic activity, in particular large-amplitude events, in SNr neurons also was observed. Passive membrane properties of GPe neurons were not different between R6/2 or YAC128 mice and their control littermates. Similarly, the amplitude of GABA responses evoked by activation of indirect pathway MSN terminals and the frequency of spontaneous GABA synaptic activity were similar in HD and control animals. In contrast, the decay time of the evoked GABA response was significantly longer in cells from HD mice. Interestingly, activation of indirect pathway MSNs within the striatum evoked larger-amplitude responses in direct pathway MSNs. Together, these results demonstrate differential alterations in responses evoked by direct and indirect pathway terminals in SNr and GPe leading to striatal output imbalance and motor dysfunction.SIGNIFICANCE STATEMENT Previous work on Huntington's disease (HD) focused on striatal medium-sized spiny neurons (MSNs) almost exclusively. Little is known about the effects that alterations in the striatum have on output structures of the direct and indi

Motor skills depend on the reuse of individual gestures in multiple sequential contexts (e.g., a single phoneme in different words). Yet optimal performance requires that a given gesture be modified appropriately depending on the sequence in which it occurs. To investigate the neural architecture underlying such context-dependent modifications, we studied Bengalese finch song, which, like speech, consists of variable sequences of "syllables." We found that when birds are instructed to modify a syllable in one sequential context, learning generalizes across contexts; however, if unique instruction is provided in different contexts, learning is specific for each context. Using localized inactivation of a cortical-basal ganglia circuit specialized for song, we show that this balance between generalization and specificity reflects a hierarchical organization of neural substrates. Primary motor circuitry encodes a core syllable representation that contributes to generalization, while top-down input from cortical-basal ganglia circuitry biases this representation to enable context-specific learning.

UnlabelledApolipoprotein E4 (apoE4) is the major genetic risk factor for Alzheimer's disease (AD). However, the underlying mechanisms are still poorly understood. We previously reported that female apoE4 knock-in (KI) mice had an age-dependent decline in hilar GABAergic interneurons that correlated with the extent of learning and memory deficits, as determined by Morris water maze (MWM), in aged mice. Enhancing GABA signaling by treating aged apoE4-KI mice with the GABAA receptor potentiator pentobarbital (PB) for 4 weeks before and during MWM rescued the learning and memory deficits. Here, we report that withdrawal of PB treatment for 2 weeks before MWM abolished the rescue in aged apoE4-KI mice, suggesting the importance of continuously enhancing GABA signaling in the rescue. However, treating apoE4-KI mice during middle adulthood (9-11 months of age) with PB for 6 weeks prevented age-dependent hilar GABAergic interneuron decline and learning and memory deficits, when examined at 16 month of age. These data imply that increasing inhibitory tone after substantial GABAergic interneuron loss may be an effective symptomatic, but not a disease-modifying, treatment for AD related to apoE4, whereas a similar intervention before substantial interneuron loss could be a disease-modifying therapeutic.Significance statementWe previously reported that female apoE4-KI mice had an age-dependent decline in hilar GABAergic interneurons that correlated with the extent of cognitive deficits in aged mice. The current study demonstrates that enhancing GABA signaling by treating aged apoE4-KI mice with a GABAA receptor potentiator pentobarbital (PB) before and during behavioral tests rescued the cognitive deficits; but withdrawal of PB treatment for 2 weeks before the tests abolished the rescue, suggesting the importance of continuously enhancing GABA signaling. However, treating apoE4-KI mice during middle adulthood with PB for a short period of time prevented age-dependent hilar GABA

Apolipoprotein E4 (apoE4) is the major genetic risk factor for Alzheimer's disease (AD). However, the underlying mechanisms are still poorly understood. We previously reported that female apoE4 knock-in (KI) mice had an age-dependent decline in hilar GABAergic interneurons that correlated with the extent of learning and memory deficits, as determined by Morris water maze (MWM), in aged mice. Enhancing GABA signaling by treating aged apoE4-KI mice with the GABAA receptor potentiator pentobarbital (PB) for 4 weeks before and during MWM rescued the learning and memory deficits. Here, we report that withdrawal of PB treatment for 2 weeks before MWM abolished the rescue in aged apoE4-KI mice, suggesting the importance of continuously enhancing GABA signaling in the rescue. However, treating apoE4-KI mice during middle adulthood (9-11 months of age) with PB for 6 weeks prevented age-dependent hilar GABAergic interneuron decline and learning and memory deficits, when examined at 16 month of age. These data imply that increasing inhibitory tone after substantial GABAergic interneuron loss may be an effective symptomatic, but not a disease-modifying, treatment for AD related to apoE4, whereas a similar intervention before substantial interneuron loss could be a disease-modifying therapeutic.Significance statementWe previously reported that female apoE4-KI mice had an age-dependent decline in hilar GABAergic interneurons that correlated with the extent of cognitive deficits in aged mice. The current study demonstrates that enhancing GABA signaling by treating aged apoE4-KI mice with a GABAA receptor potentiator pentobarbital (PB) before and during behavioral tests rescued the cognitive deficits; but withdrawal of PB treatment for 2 weeks before the tests abolished the rescue, suggesting the importance of continuously enhancing GABA signaling. However, treating apoE4-KI mice during middle adulthood with PB for a short period of time prevented age-dependent hilar GABAergic inte

The prefrontal cortex (PFC) plays a key role in controlling goal-directed behavior. Although a variety of task-related signals have been observed in the PFC, whether they are differentially encoded by various cell types remains unclear. Here we performed cellular-resolution microendoscopic Ca(2+) imaging from genetically defined cell types in the dorsomedial PFC of mice performing a PFC-dependent sensory discrimination task. We found that inhibitory interneurons of the same subtype were similar to each other, but different subtypes preferentially signaled different task-related events: somatostatin-positive neurons primarily signaled motor action (licking), vasoactive intestinal peptide-positive neurons responded strongly to action outcomes, whereas parvalbumin-positive neurons were less selective, responding to sensory cues, motor action, and trial outcomes. Compared to each interneuron subtype, pyramidal neurons showed much greater functional heterogeneity, and their responses varied across cortical layers. Such cell-type and laminar differences in neuronal functional properties may be crucial for local computation within the PFC microcircuit.

Fragile X spectrum disorder (FXSD) includes: fragile X syndrome (FXS), fragile X-associated tremor ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI), as well as other medical, psychiatric and neurobehavioral problems associated with the premutation and gray zone alleles. FXS is the most common monogenetic cause of autism (ASD) and intellectual disability (ID). The understanding of the neurobiology of FXS has led to many targeted treatment trials in FXS. The first wave of phase II clinical trials in FXS were designed to target the mGluR5 pathway; however the results did not show significant efficacy and the trials were terminated. The advances in the understanding of the GABA system in FXS have shifted the focus of treatment trials to GABA agonists, and a new wave of promising clinical trials is under way. Ganaxolone and allopregnanolone (GABA agonists) have been studied in individuals with FXSD and are currently in phase II trials. Both allopregnanolone and ganaxolone may be efficacious in treatment of FXS and FXTAS, respectively. Allopregnanolone, ganaxolone, riluzole, gaboxadol, tiagabine, and vigabatrin are potential GABAergic treatments. The lessons learned from the initial trials have not only shifted the targeted system, but also have refined the design of clinical trials. The results of these new trials will likely impact further clinical trials for FXS and other genetic disorders associated with ASD.

The prefrontal cortex (PFC) plays a key role in controlling goal-directed behavior. Although a variety of task-related signals have been observed in the PFC, whether they are differentially encoded by various cell types remains unclear. Here we performed cellular-resolution microendoscopic Ca(2+) imaging from genetically defined cell types in the dorsomedial PFC of mice performing a PFC-dependent sensory discrimination task. We found that inhibitory interneurons of the same subtype were similar to each other, but different subtypes preferentially signaled different task-related events: somatostatin-positive neurons primarily signaled motor action (licking), vasoactive intestinal peptide-positive neurons responded strongly to action outcomes, whereas parvalbumin-positive neurons were less selective, responding to sensory cues, motor action, and trial outcomes. Compared to each interneuron subtype, pyramidal neurons showed much greater functional heterogeneity, and their responses varied across cortical layers. Such cell-type and laminar differences in neuronal functional properties may be crucial for local computation within the PFC microcircuit.

In this study, we analyzed the impact that spontaneous seizures might have on the plasma membrane expression, composition and function of GABAA receptors (GABAARs). For this, the tissue of chronically epileptic rats was collected within 3h of seizure occurrence (≤3h group) or at least 24h after seizure occurrence (≥24h group). A retrospective analysis of seizure frequency revealed that selecting animals on the bases of seizure proximity also grouped animals in terms of overall seizure burden with a higher seizure burden observed in the ≤3h group. A biochemical analysis showed that although animals with more frequent/recent seizures (≤3h group) had similar levels of GABAAR at the plasma membrane they showed deficits in inhibitory neurotransmission. By contrast, the tissue obtained from animals experiencing infrequent seizures (≥24h group) had increased plasma membrane levels of GABAAR and showed no deficit in inhibitory function. Together, our findings offer an initial insight into the molecular changes that might help to explain how alterations in GABAAR function can be associated with differential seizure burden. Our findings also suggest that increased plasma membrane levels of GABAAR might act as a compensatory mechanism to more effectively maintain inhibitory function, repress hyperexcitability and reduce seizure burden. This study is an initial step towards a fuller characterization of the molecular events that trigger alterations in GABAergic neurotransmission during chronic epilepsy.

GABAergic and cholinergic systems in the neuromuscular system of the parasitic nematodes are the main target of action for anthelmintic drugs. In the nematode cholinergic system pharmacological importance has primarily nicotinic-acetylcholine receptor (nAChR). On the other hand, the GABA-receptor was originally identified as the main site of action for the Avermectins and Milbemicins. However, later was shown that these drugs work on a new, previously never described glutamate-gated chloride ion channel, located in the nematode pharynx. The most important problems that are endangering the success of antiparasitic therapy are the development of resistance in the parasites and often occurrences of the toxic effects of antiparasitic drugs in host. In the order to elucidate the mechanisms of action of GABAergičkih and cholinergic anthelmintic, we examined the pharmacological characteristics of the representatives of these two groups of drugs in the isolated nerve-muscle preparation of large pig nematode Ascaris suum. Also, it was important to examine comparatively differences in the effects of cholinergic and GABAergic anthelmintic on the corresponding receptors in mammals (investigations were performed on isolated rat diaphragm and ileum), and thus to analyze the mechanisms of their adverse effects. In presented investigations we measured the effects of contraction or relaxation on isolated nematode or mammalian preparations and analyzed the results by using appropriate statistical methods (non-linear regression, ANOVA, t-test). Based on the results obtained in our investigations the following conclusions may be presented: (1) Agonists of L, N and B type of nematode nicotinic acetylcholine receptor (nAChR) studied on a model of neuromuscular preparations of A. suum, showed variable efficacy. Highest efficiency in the first group of tested agonists has pyrantel (agonist of L-type nAChR, EC50=0.010 μM, Emax=2.5g), then bephenium (agonist of B-type nAChR, EC50=0.37μM, Ema, Gabaergički i holinergički sistem u neuro-mišićnom sistemu parazitskih nematoda su glavna ciljna mesta delovanja antihelmintika. U okviru holinergičkog sistema nematoda, farmakološki značaj ima pre svega nikotinski-acetilholinski receptor (nAChR). S druge strane, GABA-receptor parazitskih nematoda je prvobitno označen kao glavno mesto dejstva avermektina i milbemicina. Međutim, vremenom se pokazalo da ovi lekovi deluju i na jedan potpuno nov, do tada neopisani glutamat-zavisni hloridni jonski kanal u farinksu nematoda. Pored toga, značajno je da neki aktivni principi etarskih ulja imaju dokazana antiparazitska svojstva, i da postoje indicije da deluju upravo preko ova dva receptorska sistema. Osnovni problemi koji danas ugrožavaju antiparazitsku terapiju su razvoj rezistencije i često ispoljavanje toksičnih efekata antiparazitskih lekova. Da bi se bolje razumeli mehanizmi dejstva gabaergičkih i holinergičkih antihelmintika ispitali smo farmakološke karakteristike predstavnika ove dve grupe lekova na neuro-mišićnom preparatu velike nematode svinja Ascaris suum. Takođe, značajno je bilo komparativno ispitati razlike u dejstvu gabaergičkih i holinergičkih antihelmintika na odgovarajuće receptore sisara (ispitivanja su izvršena na izolovanoj dijafragmi i ileumu pacova) i na taj način analizirati mehanizme njihovih neželjenih efekata. U našim istražvanjima mereni su efekti kontrakcije ili relaksacije izolovanih preparata i odgovarajućim statističkim metodama obrađivani dobijeni rezultati (nelinearna regresija, ANOVA, t-tets). Na osnovu rezultata dobijenih u ispitivanjima doneti su sledeći zaključci: (1) Agonisti L, N i B tipa nikotinskog-acetilholinskog receptora (nAChR) nematoda, ispitivani na modelu neuro-mišićnog preparata A. suum, ispoljili su različitu efikasnost. Najvišu efikasnost u prvoj grupi ispitivanih agonista, ispoljio je pirantel (agonista L-tipa nikotinskog receptora EC50=0.010μM, Emax=2.5g), zatim befinijum (agonista B-tipa nikotinskog receptora EC50=0.37

Gabaergički i holinergički sistem u neuro-mišićnom sistemu parazitskih nematoda su glavna ciljna mesta delovanja antihelmintika. U okviru holinergičkog sistema nematoda, farmakološki značaj ima pre svega nikotinski-acetilholinski receptor (nAChR). S druge strane, GABA-receptor parazitskih nematoda je prvobitno označen kao glavno mesto dejstva avermektina i milbemicina. Međutim, vremenom se pokazalo da ovi lekovi deluju i na jedan potpuno nov, do tada neopisani glutamat-zavisni hloridni jonski kanal u farinksu nematoda. Pored toga, značajno je da neki aktivni principi etarskih ulja imaju dokazana antiparazitska svojstva, i da postoje indicije da deluju upravo preko ova dva receptorska sistema. Osnovni problemi koji danas ugrožavaju antiparazitsku terapiju su razvoj rezistencije i često ispoljavanje toksičnih efekata antiparazitskih lekova. Da bi se bolje razumeli mehanizmi dejstva gabaergičkih i holinergičkih antihelmintika ispitali smo farmakološke karakteristike predstavnika ove dve grupe lekova na neuro-mišićnom preparatu velike nematode svinja Ascaris suum. Takođe, značajno je bilo komparativno ispitati razlike u dejstvu gabaergičkih i holinergičkih antihelmintika na odgovarajuće receptore sisara (ispitivanja su izvršena na izolovanoj dijafragmi i ileumu pacova) i na taj način analizirati mehanizme njihovih neželjenih efekata. U našim istražvanjima mereni su efekti kontrakcije ili relaksacije izolovanih preparata i odgovarajućim statističkim metodama obrađivani dobijeni rezultati (nelinearna regresija, ANOVA, t-tets). Na osnovu rezultata dobijenih u ispitivanjima doneti su sledeći zaključci: (1) Agonisti L, N i B tipa nikotinskog-acetilholinskog receptora (nAChR) nematoda, ispitivani na modelu neuro-mišićnog preparata A. suum, ispoljili su različitu efikasnost. Najvišu efikasnost u prvoj grupi ispitivanih agonista, ispoljio je pirantel (agonista L-tipa nikotinskog receptora EC50=0.010μM, Emax=2.5g), zatim befinijum (agonista B-tipa nikotinskog receptora EC50=0.37, GABAergic and cholinergic systems in the neuromuscular system of the parasitic nematodes are the main target of action for anthelmintic drugs. In the nematode cholinergic system pharmacological importance has primarily nicotinic-acetylcholine receptor (nAChR). On the other hand, the GABA-receptor was originally identified as the main site of action for the Avermectins and Milbemicins. However, later was shown that these drugs work on a new, previously never described glutamate-gated chloride ion channel, located in the nematode pharynx. The most important problems that are endangering the success of antiparasitic therapy are the development of resistance in the parasites and often occurrences of the toxic effects of antiparasitic drugs in host. In the order to elucidate the mechanisms of action of GABAergičkih and cholinergic anthelmintic, we examined the pharmacological characteristics of the representatives of these two groups of drugs in the isolated nerve-muscle preparation of large pig nematode Ascaris suum. Also, it was important to examine comparatively differences in the effects of cholinergic and GABAergic anthelmintic on the corresponding receptors in mammals (investigations were performed on isolated rat diaphragm and ileum), and thus to analyze the mechanisms of their adverse effects. In presented investigations we measured the effects of contraction or relaxation on isolated nematode or mammalian preparations and analyzed the results by using appropriate statistical methods (non-linear regression, ANOVA, t-test). Based on the results obtained in our investigations the following conclusions may be presented: (1) Agonists of L, N and B type of nematode nicotinic acetylcholine receptor (nAChR) studied on a model of neuromuscular preparations of A. suum, showed variable efficacy. Highest efficiency in the first group of tested agonists has pyrantel (agonist of L-type nAChR, EC50=0.010 μM, Emax=2.5g), then bephenium (agonist of B-type nAChR, EC50=0.37μM, Ema

A 79-year-old man with end-stage renal disease treated by automated peritoneal dialysis was referred to the emergency department for altered consciousness. The first investigations, including toxicology screening, failed to reveal the precise etiology. The patient was treated for a possible seizure. After the progression of central nervous system depression with bradypnea, the patient was intubated and mechanically ventilated. It appeared later on that he had ingested by mistake one of his wife's medications, baclofen. Baclofen was detected in the blood sampled on admission at a level above the therapeutic range. Baclofen is mainly excreted by the kidney. A short-term administration of low-dose of baclofen is not effectively removed by peritoneal dialysis and may result in prolonged but reversible coma.