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Objective: BCORL1, a transcriptional co-repressor, has a role in cortical migration, neuronal differentiation, maturation, and cerebellar development. We describe BCORL1 as a new genetic cause for major brain malformations., Methods and Results: We report three patients from two unrelated families with neonatal onset intractable epilepsy and profound global developmental delay. Brain MRI of two siblings from the first family depicted hypoplastic corpus callosum and septal agenesis (ASP) in the older brother and unilateral perisylvian polymicrogyria (PMG) in the younger one. MRI of the patient from the second family demonstrated complete agenesis of corpus callosum (CC). Whole Exome Sequencing revealed a novel hemizygous variant in NM_021946.5 (BCORL1):c.796C>T (p.Pro266Ser) in the two siblings from the first family and the NM_021946.5 (BCORL1): c.3376G>A; p.Asp1126Asn variant in the patient from the second family, both variants inherited from healthy mothers. We reviewed the patients' charts and MRIs and compared the phenotype to the other published BCORL1-related cases. Brain malformations have not been previously described in association with the BCORL1 phenotype. We discuss the potential influence of BCORL1 on brain development., Conclusions: We suggest that BCORL1 variants present with a spectrum of neurodevelopmental disorders and can lead to major brain malformations originating at different stages of fetal development. We suggest adding BCORL1 to the genetic causes of PMG, ASP, and CC dysgenesis., (© 2021. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Availability of genome-scale in situ hybridization data allows systematic analysis of genetic neuroanatomical architecture. Within the hippocampus, electrophysiology and lesion and imaging studies demonstrate functional heterogeneity along the septotemporal axis, although precise underlying circuitry and molecular substrates remain uncharacterized. Application of unbiased statistical component analyses to genome-scale hippocampal gene expression data revealed robust septotemporal molecular heterogeneity, leading to the identification of a large cohort of genes with robust regionalized hippocampal expression. Manual mapping of heterogeneous CA3 pyramidal neuron expression patterns demonstrates an unexpectedly complex molecular parcellation into a relatively coherent set of nine expression domains in the septal/temporal and proximal/distal axes with reciprocal, nonoverlapping boundaries. Unique combinatorial profiles of adhesion molecules within these domains suggest corresponding differential connectivity, which is demonstrated for CA3 projections to the lateral septum using retrograde labeling. This complex, discrete molecular architecture provides a novel paradigm for predicting functional differentiation across the full septotemporal extent of the hippocampus.

There is controversy in the literature in the results of various septal lesions on the sleep-waking cycle (SWC) ultradian structure. Current investigation was aimed to study the effects of interruption of septo-hippocampal cholinergic/GABAergic afferentation on the ultradian structure of SWC and on PS major indices. Experiments were carried out on 12 adult cats, operated under overall anesthesia (Nembutal, 35-40 mg/kg). Three groups of animals were used: I. Implanted sham lesioned control; II. With isolated lesion of medial septal part; III. With combined lesion of medial and lateral septal parts. Lesion was made by passing of direct current. Continuous EEG registration of SWC was lasted 12 hour. Results were evaluated statistically with Student's t test. Isolated lesion of medial septum doesn't produce significant changes of motivational-emotional behavior, but combined lesion of medial and lateral septal parts lead to enhancement of food and water motivation, development of hyper emotionality and hyperactivity. Interruption of septo-hippocampal cholinergic/GABAergic input, increased sleep onset latency, incidence and percentage of active waking (AW) and passive waking (PW) and PS latency but the last effect was dependent from sleep latency change. In the period from appearance of first PS episode to the end of EEG registration PS incidence and percentage wasn't changed significantly. This surgery completely abolished theta rhythm in waking and PS. Combined lesion of medial and lateral septal parts increased sleep latency still more. Total time of AW and PW increased twice. DSWS was significantly decreased. In this case PS latency was also increased still more. PS incidence and total percentage in whole 12 h registration period were reduced substantially, but for the period calculated after appearance of first PS episode until to the end of EEG registration PS mean value was the same as in sham lesioned animals. It is concluded that: 1.Septo-hippocampal cholinergic/GABAergic relationship doesn't play significant role in the triggering mechanisms of SWC ultradian structure; 2. GABAergic part of this input as well as hippocampo-mesodiecephalic descending pathways through the lateral septum have powerful modulatory influence on basic triggering mechanisms of SWS; 3. Development of hippocampal theta rhythm is the only event of PS affected after medial septal lesion; 4. Septo-hippocampal cholinergic input is not essential in triggering mechanisms of PS.

Intra-septal infusions of the gamma-aminobutyric acid (GABA) agonist muscimol impair learning and memory in a variety of tasks. This experiment determined whether hippocampal or entorhinal infusions of the acetylcholinesterase inhibitor physostigmine would reverse such impairing effects on spontaneous alternation performance, a measure of spatial working memory. Male Sprague-Dawley rats were given intra-septal infusions of vehicle or muscimol (1 nmole/0.5 microL) combined with unilateral intra-hippocampal or intra-entorhinal infusions of vehicle or physostigmine (10 microg/microL for the hippocampus; 7.5 microg/microL or 1.875 microg/0.25 microL for the entorhinal cortex). Fifteen minutes later, spontaneous alternation performance was assessed. The results indicated that intra-septal infusions of muscimol significantly decreased percentage-of-alternation scores, whereas intra-hippocampal or intra-entorhinal infusions of physostigmine had no effect. More importantly, intra-hippocampal or intra-entorhinal infusions of physostigmine, at doses that did not influence performance when administered alone, completely reversed the impairing effects of the muscimol infusions. These findings indicate that increasing cholinergic levels in the hippocampus or entorhinal cortex is sufficient to reverse the impairing effects of septal GABA receptor activation and support the hypothesis that the impairing effects of septal GABAergic activity involve cholinergic processes in the hippocampus and the entorhinal cortex.

The roles of dietary tryptophan (Trp) were evaluated in regulation of production of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin (NT)-3 in the various brain regions in ddY mice. Feeding the mice a Trp-deficient diet for 2 weeks significantly decreased in the hippocampal level of NGF but not those of BDNF and NT-3, as compared with feeding an adequate Trp diet. The mice fed excess Trp did not have different levels of any of these neurotrophins than in the mice fed an adequate Trp diet. The levels of BDNF in the cerebral cortex were also significantly lower in the mice fed on a Trp-deficient diet, while the levels of NGF and NT-3 in the region were not modulated upon feeding of the diet. The dietary Trp level had no significant effect on the levels of NGF, BDNF, or NT-3 in the entorhinal cortex nor septum of the mice. These results demonstrate that the brain levels of NGF and BDNF are dependent on the dietary content of tryptophan.

The androgen receptor (AR) is generally considered an autoregulated protein. However, studies in brain have produced mixed results regarding sex differences, which should be present given the higher endogenous levels of androgens in males, and the effects of gonadectomy, which presumably should lead to a loss of AR. Resolving these issues is a necessary step in developing a model of AR regulation in the central nervous system and, more broadly, in determining how regulation of this receptor may mediate neural target tissue responsiveness to androgen. To further investigate these issues, the distribution, density, and regulation of neural AR were compared among male and female mice that were intact, gonadectomized, or gonadectomized and given testosterone propionate (TP) through immunocytochemical and Western blot analyses. Four brain areas that have been linked to the regulation of male-typical behavior were evaluated: bed nucleus of the stria terminalis, posterior aspect, medial preoptic area, and dorsal and ventral aspects of the lateral septum. In the immunocytochemical study, integrated particle density, which reflects the average intensity of AR staining, was assessed among the six groups 24 h after surgery using PG-21, a peptide-based AR antiserum. Major findings included regional differences in the intensity of immunostaining; a robust sexual dimorphism in each region, with males exhibiting more intense staining than females; a loss of AR in both sexes after gonadectomy, with more dramatic changes evident in males; and significant up-regulation of AR in response to TP that was equivalent in both sexes. The Western blot analyses of AR in limbic system extracts prepared from the six groups showed a pattern of differences that mirrored the immunocytochemical results, indicating that PG-21 recognized both liganded and unliganded AR. In addition, a dose-response study, in which gonadectomized males and females were administered from 25-1000 microg TP, demonstrated a significant linear trend in up-regulation of AR in both males and females, with no sexual dimorphism in the response to hormone treatment. These results demonstrate that the regulation of AR in both male and female neural tissue is comparable and that the critical determinant of AR expression is the presence or absence of androgen.

Emerging evidence suggests that the p75 neurotrophin receptor (p75NTR) mediates cell death; however, it is not known whether p75NTR negatively regulates other neuronal phenotypes. We found that mice null for p75NTR displayed highly significant increases in the size of basal forebrain cholinergic neurons, including those that are TrkA-positive. Cholinergic hippocampal target innervation also was increased significantly. Activity of the cholinergic neurotransmitter synthetic enzyme choline acetyltransferase (ChAT) was increased in both the medial septum and hippocampus. Upregulation of these cholinergic features was not associated with increased basal forebrain or hippocampal target NGF levels. In contrast, striatal cholinergic neurons, which do not express p75NTR, showed no difference in neuronal number, size, or ChAT activity between wild-type and p75NTR null mutant mice. These findings indicate that p75NTR negatively regulates cholinergic neuronal phenotype of the basal forebrain cholinergic neurons, including cell size, target innervation, and neurotransmitter synthesis.

The effects of acute, systemic administration of the putative atypical antipsychotic drug amperozide on c-fos expression in the rat forebrain were studied by means of Fos immunohistochemistry. Amperozide significantly increased the number of Fos-immunoreactive nuclei in the medial prefrontal cortex and the lateral septum but not in the nucleus accumbens (shell or core), the striatum, or the amygdala. With the exception of the nucleus accumbens-shell, where amperozide failed to produce statistically significant increases, the regional distribution of Fos immunoreactivity following amperozide was similar to that induced by atypical, but not by typical, antipsychotic drugs. In addition, after amperozide the number of Fos-positive nuclei was higher in the nucleus accumbens than in the dorsolateral striatum, a characteristic that is common to all known atypical antipsychotic agents.

The effects of the peptides TSKYR and DY isolated from the brain of hibernating ground squirrels on Ca2+ current were studied. TSKYR activated Ca2+ current in frog auricle fibers and in single cells from frog ventricle whereas DY blocked Ca2+ current in both preparations. In isolated rat and ground squirrel cardiocytes, TSKYR had no effect on Ca2+ current, and DY increased it. In brain slices of rat, DY blocked the activity of medial septal neurons. TSKYR increased activity of septal neurons at the initial phase, which was followed by decrease of neuronal activity.

(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD), an agonist for metabotropic glutamate receptors (mGluRs), causes depolarization and burst firing in rat dorsolateral septal nucleus (DLSN) neurons and results in long-term potentiation (LTP) at DLSN synapses. In the present study, we investigated whether these actions of 1S,3R-ACPD are attributable to the release of calcium from an inositol triphosphate-sensitive store after activation of mGluRs coupled to phospholipase C. Our data demonstrated that the ACPD-induced depolarization was associated with a small but significant decrease, not an increase, in [Ca2+]i; however, changes of [Ca2+]i, during ACPD-induced bursting were up to seven times larger than those produced by regular firing. Depletion of internal calcium stores by thapsigargin or ryanodine had a small to insignificant effect on the maximum changes of [Ca2+]i, associated with ACPD-induced bursting. Thus, elevation of [Ca2+]i, during firing by 1S,3R-ACPD is likely attributable to enhancement of calcium influx through voltage-gated channels and not to calcium release from internal stores. ACPD-induced burst firing elevated somatic and dendritic calcium levels up to 3 and 6 microM, respectively. Such an increase may be the underlying mechanism for ACPD-induced LTP as well as ACPD-induced acute cell death in rat DLSN.

NGF found in the basal forebrain is believed to be localized to NGF-dependent cholinergic neurons and derived via retrograde axonal transport from NGF-synthesizing target hippocampal and cortical neurons. The basis for this concept of target-derived NGF is the detection of only limited amounts of NGF mRNA in the basal forebrain, despite relatively high NGF levels there. Our work, using a more sensitive and quantitative RNase protection method for detecting relative NGF mRNA levels, suggested, instead, relatively high levels of NGF mRNA synthesis in the septal region of the basal forebrain (BF-S), a region which contained primarily cells that project to the hippocampus. Similar results were obtained in analyses of a larger portion of the basal forebrain, designated "BF," that encompassed cholinergic neurons that project to both the hippocampus and the cortex. The level of NGF mRNA measured in both BF-S and BF was equivalent to approximately 50% of the amount observed in the hippocampus. Furthermore, relative NGF mRNA levels detected in the BF-S, cortex, and hippocampus were shown to be proportional to NGF protein levels quantitated in each region. The detection of relatively high amounts of NGF synthesis in the BF-S was supported in studies demonstrating rapid NGF receptor (Trk) activation in the basal forebrain by exogenous NGF and in experiments showing that NGF mRNA was inducible in the BF-S by 1,25 dihydroxyvitamin D3. The extent of NGF mRNA induction was similar (approximately twofold) in the BF-S, hippocampus, and cortex, suggesting similar regulatory mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

1. We describe a dual effect of the peptide TRH (thyrotrophin-releasing hormone) and its derivatives at concentrations between 0.1 and 1 microM on the K+ currents and cytosolic Ca2+ concentration in enzymatically dispersed septal neurones. 2. In response to membrane depolarization, septal neurones recorded under whole-cell patch clamp can generate two major K+ currents: (i) a fast and transient K+ current (I(t)), that after a maximum at 2-5 ms inactivates completely at all membrane potentials in less than 50 ms; and (ii) a slowly activating current (I(s)), which reaches a maximum in 15-20 ms and does not exhibit appreciable inactivation during short-lasting voltage pulses. 3. In about 70% of the neurones tested (n = 48) TRH induced a reversible, and often transient, increase of I(t), I(s) or both K+ conductaNces. In approximately 10% of the cells the peptide had an opposite effect and caused a more protracted and partially reversible attenuation of the amplitude of I(t) and I(s). 4. The dual action of TRH on the K+ currents was mimicked by its derivatives but the effects varied depending on their structural relationship with the precursor neuropeptide. The physiological metabolite cyclo-His-Pro and the synthetic analogue methyl-TRH, in which the carboxyl terminus of the molecule is conserved, increased the K+ currents, whereas depression of the K+ conductances was predominantly observed in the presence of TRH-OH, in which the amino end of TRH is maintained intact. 5. In fura-2-loaded unclamped cells, TRH induced either release of Ca2+ from internal stores, Ca2+ entry, or both. With TRH-OH we never observed mobilization of internal Ca2+ but this peptide evoked a large Ca2+ influx. 6. The results demonstrate that the physiological metabolites of brain TRH (cyclo-His-Pro and TRH-OH) have biological activity. TRH and its derivatives exert two types of regulatory actions on the voltage-gated K+ channels and cytosolic Ca2+ concentration in central neurones, which can be explained assuming that TRH and TRH-derived products interact with different subtypes of brain receptors recognizing preferentially either the amino or the carboxyl termini of the TRH molecule.

Cholinergic properties of the SN56.B5.G4 cell line derived from the fusion of neurons of the mouse postnatal day 21 septum and the murine neuroblastoma cell line N18TG2 were investigated and correlated with morphological differentiation. In basal serum-containing growth medium, few cells developed neurites. Neurite extension occurred in cells grown for 2 d with forskolin or dibutyryl cAMP (dbcAMP) but not with butyrate. In cells treated with these compounds, the activity of ChAT and ACh content were two- to threefold higher relative to controls. The cells synthesized ACh from choline taken up by the sodium-dependent high-affinity transport. Forskolin-, dbcAMP-, and butyrate-treated cells (but not the controls) were capable of spontaneous and depolarization-evoked ACh release. The results indicate that the morphological and the neurochemical aspects of SN56.B5.G4 cell differentiation are independently regulated.

In rats, chronic treatment with lithium elicits a dose-dependent increase in the [Met5]enkephalin content of nucleus caudatus and globus pallidus. A single injection of lithium fails to change the striatal [Met5]enkephalin content. The increase in [Met5]enkephalin caused by chronic lithium is proportional to the serum lithium level. The extent of the increase in striatal [Met5]enkephalin content levels off at a value of about 250% that of untreated rats. This increase has a time latency of 2--3 days and reaches a plateau at 5 days. The increase that was present at 5 days was no longer evident if the treatment was continued for 2 weeks. Lithium also increases striatal [Leu5]enkephalin content by an extent equal to the increase of [Met 5]enkephalin. Based on the characteristics of the lithium-induced increase in [Met6]enkephalin content, it is proposed that lithium may reduce the rate of release of [Met5]enkephalin from the small enkephalinergic neurons that are intrinsic to the striatum; this action may be related to a change in the regulation of striatal neurons.

We employed quantitative autoradiography to examine the distribution of thyrotropin-releasing hormone (TRH) receptors in the rat CNS. The binding of [3H]3-methyl-histidine-TRH [( 3H]MeTRH) to TRH receptors in frozen rat brain sections was saturable, of a high affinity (Kd = 5 nM), and specific for TRH analogs. Autoradiograms of [3H]MeTRH binding showed highest concentrations of TRH receptors in the rhinencephalon, including accessory olfactory bulb, nuclei of the amygdala, and the ventral dentate gyrus and subiculum of the hippocampus. Moderate TRH receptor concentrations were found within the thalamus and hypothalamus, in most regions of the rhombencephalon, such as the cranial nerve nuclei, and in the substantia gelatinosa of the spinal cord. Neocortex and basal ganglia contained low densities of TRH receptors. This distribution correlates well with the sensitivity of brain regions to the known effects of TRH, and suggests that TRH receptors may mediate the actions of TRH in the rat CNS.

Regulation of acetylcholine metabolism varied in brain slices from hippocampus and septum which have different proportions of cholinergic nerve cell bodies and nerve endings. Anoxia (0% oxygen) inhibited acetylcholine synthesis (-77%) and its calcium-dependent release (-87%) from hippocampal slices but had no effect on synthesis or release by septal slices. [1,5-14C]Citrate incorporation into acetylcholine was higher in septum than in hippocampus, which suggested that citrate metabolism differs regionally. (-)Hydroxycitrate, a specific inhibitor of ATP citrate (pro3S)-lyase (EC 4.1.3.8), reduced [U-14C]glucose incorporation into acetylcholine more in septal than in hippocampal slices. 14CO2 production from glucose or citrate was similar in control and experimental conditions in the two regions. These findings indicate that acetylcholine metabolism varies regionally, which may partially explain the selective vulnerability of certain brain areas to anoxia and other metabolic insults.

Specific binding sites for 3H-arginine8-vasopressin (AVP) have been characterized in rat septal membranes. Scatchard analyses revealed a single class of high-affinity binding sites having an equilibrium dissociation constant of 1.7 +/- 0.3 nM and total binding capacity of 22.6 +/- 4.2 fmol/mg protein. Binding displacement studies with peptide analogs of AVP indicate that this binding site is similar to the V1 (pressor)-type receptor for AVP. When added to rat brain septal slices that had been prelabeled with 3H-myo-inositol, vasopressin stimulated the accumulation of 3H-inositol-1-phosphate (IP1) in the presence of 7 mM lithium. This effect was dose dependent with maximal stimulation (65% over basal) occurring at a concentration of 0.5 microM AVP. Higher concentrations, however, tended to inhibit phosphoinositide hydrolysis. The vasopressin-stimulated accumulation of 3H-IP1 was completely inhibited by the vasopressin V1 antagonist, d(CH2)5[Tyr(Me)2]AVP, in a concentration-dependent manner. Oxytocin, at concentrations of 10(-8) and 10(-5) M, only slightly increased 3H-IP1 accumulation (17-20% over basal). In contrast, the V2 agonist deamino-D-arginine vasopressin (dDAVP), failed to produce significant stimulation of 3H-IP1 accumulation, even at high concentrations. The effects of these analogs on phosphoinositide hydrolysis is consistent with their potencies in displacing 3H-AVP from septal binding sites. These results indicate that vasopressin stimulates hydrolysis of inositol phospholipids in rat brain septum through an interaction with V1-type vasopressin receptors.