Carboxypeptidase E knockout mice exhibit abnormal dendritic arborization and spine morphology in central nervous system neurons

Carboxypeptidase E (CPE) is involved in maturation of neuropeptides and sorting of brain‐derived neurotrophic factor (BDNF) to the regulated pathway for activity‐dependent secretion from CNS neurons. CPE knockout (CPE‐KO) mice have many neurological deficits, including deficits in learning and memory. Here, we analyzed the dendritic arborization and spine morphology of CPE‐KO mice to determine a possible correlation of defects in such structures with the neurological deficits observed in these animals. Analysis of pyramidal neurons in layer V of cerebral cortex and in hippocampal CA1 region in 14‐week‐old CPE‐KO mice showed more dendritic complexity compared with wild type (WT) mice. There were more dendritic intersections and more branch points in CPE‐KO vs. WT neurons. Comparison of pyramidal cortical neurons in 6‐ vs. 14‐week‐old WT mice showed a decrease in dendritic arborization, reflecting the occurrence of normal dendritic pruning. However, this did not occur in CPE‐KO neurons. Furthermore, analysis of spine morphology demonstrated a significant increase in the number of D‐type spines regarded as nonfunctional in the cortical neurons of CPE‐KO animals. Our findings suggest that CPE is an important, novel player in mediating appropriate dendritic patterning and spine formation in CNS neurons. © 2009 Wiley‐Liss, Inc.     

Kalirin loss results in cortical morphological alterations

Morphogenesis of pyramidal neuronal dendrites and spines is crucial for the formation and refinement of forebrain neuronal circuits underlying cognition. Aberrant dendrite and spine morphology is associated with neuropathological disorders. However, the molecular mechanisms controlling pyramidal neuronal dendrite and spine morphogenesis in vivo remain largely unknown. Kalirin is a brain-specific guanine-nucleotide exchange factor for Rho-like small GTPases, and an important regulator of spine morphogenesis in cultured neurons. Here we show that RNAi-dependent knockdown of kalirin in cultured neurons affected dendrite morphology. Cortical pyramidal neurons from KALRN-null mice showed reduced spine density and impaired activity-dependent spine plasticity; and they exhibited reduced complexity of dendritic trees. KALRN-null mice also displayed smaller neuronal cell bodies and reductions in the size of the cortex and cortical layers. These data demonstrate important roles for kalirin in the regulation of cortical structure, ultrastructure, and spine structural plasticity.     

Astroglial major histocompatibility complex class I following immune activation leads to behavioral and neuropathological changes

In the central nervous system, major histocompatibility complex class I (MHCI) molecules are mainly expressed in neurons, and neuronal MHCI have roles in synapse elimination and plasticity. However, the pathophysiological significance of astroglial MHCI remains unclear. We herein demonstrate that MHCI expression is up‐regulated in astrocytes in the medial prefrontal cortex (mPFC) following systemic immune activation by an intraperitoneal injection of polyinosinic‐polycytidylic acid (polyI:C) or hydrodynamic interferon (IFN)‐γ gene delivery in male C57/BL6J mice. In cultured astrocytes, MHCI/H‐2D largely co‐localized with exosomes. To investigate the role of astroglial MHCI, H‐2D, or sH‐2D was expressed in the mPFC of male C57/BL6J mice using an adeno‐associated virus vector under the control of a glial fibrillary acidic protein promoter. The expression of astroglial MHCI in the mPFC impaired sociability and recognition memory in mice. Regarding neuropathological changes, MHCI expression in astrocytes significantly activated microglial cells, decreased parvalbumin‐positive cell numbers, and reduced dendritic spine density in the mPFC. A treatment with GW4869 that impairs exosome synthesis ameliorated these behavioral and neuropathological changes. These results suggest that the overexpression of MHCI in astrocytes affects microglial proliferation as well as neuronal numbers and spine densities, thereby leading to social and cognitive deficits in mice, possibly via exosomes created by astrocytes.     

Lack of experience‐dependent intrinsic plasticity in the adolescent infralimbic medial prefrontal cortex

Fear extinction, an inhibitory learning that suppresses a previously learned fear memory, is diminished during adolescence. Earlier studies have shown that this suppressed fear extinction during adolescence involves an altered glutamatergic plasticity in infralimbic medial prefrontal cortical (IL‐mPFC) pyramidal neurons. However, it is unclear whether the excitability of IL‐mPFC pyramidal neurons plays a role in this development‐dependent suppression of fear extinction. Therefore, we examined whether fear conditioning and extinction affect the active and passive membrane properties of IL‐mPFC layer 5 pyramidal neurons in preadolescent, adolescent and adult mice. Both preadolescent and adult mice exhibited a bidirectional modulation of the excitability of IL‐mPFC layer 5 pyramidal neurons following fear conditioning and extinction, i.e., fear conditioning reduced membrane excitability, whereas fear extinction reversed this effect. However, the fear conditioning‐induced suppression of excitability was not reversed in adolescent mice following fear extinction training. Neither fear conditioning nor extinction affected GABAergic transmission in IL‐mPFC layer 5 pyramidal neurons, suggesting that GABAergic transmission did not play a role in experience‐dependent modulation of neuronal excitability. Our results suggest that the extinction‐specific modulation of excitability is impaired during adolescence.     

Increased proximal bifurcation of CA1 pyramidal apical dendrites in sema3A mutant mice

Semaphorin‐3A (Sema3A) is an attractive guidance molecule for cortical apical dendrites. To elucidate the role of Sema3A in hippocampal dendritic formation, we examined the Sema3A expression pattern in the perinatal hippocampal formation and analyzed hippocampal dendrites of the brains from young adult sema3A mutant mice. Sema3A protein was predominantly expressed in the hippocampal plate and the inner marginal zone at the initial period of apical dendritic growth. Neuropilin‐1 and plexin‐A, the receptor components for Sema3A, were also localized in the same regions. The Golgi impregnation method revealed that in wildtype mice more than 90% of hippocampal CA1 pyramidal neurons extended a single trunk or apical trunks bifurcated in stratum radiatum. Seven percent of the pyramidal neurons showed proximal bifurcation of apical trunks in stratum pyramidale or at the border of the stratum pyramidale and stratum radiatum. In sema3A mutant mice, proximally bifurcated apical dendrites were increased to 32%, while the single apical dendritic pyramidal neurons were decreased. We designate this phenotype in sema3A mutant mice as “proximal bifurcation.” In the dissociated culture system, approximately half of the hippocampal neurons from wildtype mice resembled pyramidal neurons, which possess a long, thick, and tapered dendrite. In contrast, only 30% of the neurons from sema3A mutants exhibited pyramidal‐like morphology. Proximal bifurcation of CA1 pyramidal neurons was also increased in the mutant mice of p35, an activator of cyclin‐dependent kinase 5 (Cdk5). Thus, Sema3A may facilitate the initial growth of CA1 apical dendrites via the activation of p35/Cdk5, which may in turn signal hippocampal development. J. Comp. Neurol. 516:360–375, 2009. © 2009 Wiley‐Liss, Inc.     

Serotonin transporter knockout and repeated social defeat stress: impact on neuronal morphology and plasticity in limbic brain areas

Low expression of the human serotonin transporter (5-HTT) gene presumably interacts with stressful life events enhancing susceptibility for affective disorders. 5-Htt knockout (KO) mice display an anxious phenotype, and behavioural differences compared to wild-type (WT) mice are exacerbated after repeated loser experience in a resident-intruder stress paradigm. To assess whether genotype-dependent and stress-induced behavioural differences are reflected in alterations of neuronal morphology in limbic areas, we studied dendritic length and complexity of pyramidal neurons in the anterior cingulate and infralimbic cortices (CG, IL), hippocampus CA1 region, and of pyramidal neurons and interneurons in the lateral (La) and basolateral (BL) amygdaloid nuclei in Golgi-Cox-stained brains of male WT and 5-Htt KO control and loser mice. Spine density was analysed for IL apical and amygdaloid apical and basal pyramidal neuron dendrites. While group differences were absent for parameters analysed in CG, CA1 and amygdaloid interneurons, pyramidal neurons in the IL displayed tendencies to shorter and less spinous distal apical dendrites in 5-Htt KO controls, and to extended proximal dendrites in WT losers compared to WT controls. In contrast, spine density of several dendritic compartments of amygdaloid pyramids was significantly higher in 5-Htt KO mice compared to WT controls. While a tendency to increased spine density was observed in the same dendritic compartments in WT after stress, changes were lacking in stressed compared to control 5-Htt KO mice. Our findings indicate that disturbed 5-HT homeostasis results in alterations of limbic neuronal morphology, especially in higher spinogenesis in amygdaloid pyramidal neurons. Social stress leads to similar but less pronounced changes in the WT, and neuroplasticity upon stress is reduced in 5-Htt KO mice.     

Kalirin‐7 prevents dendritic spine dysgenesis induced by amyloid beta‐derived oligomers

Synapse degeneration and dendritic spine dysgenesis are believed to be crucial early steps in Alzheimer's disease (AD), and correlate with cognitive deficits in AD patients. Soluble amyloid beta (Aβ)‐derived oligomers, also termed Aβ‐derived diffusible ligands (ADDLs), accumulate in the brain of AD patients and play a crucial role in AD pathogenesis. ADDLs bind to mature hippocampal neurons, induce structural changes in dendritic spines and contribute to neuronal death. However, mechanisms underlying structural and toxic effects are not fully understood. Here, we report that ADDLs bind to cultured mature cortical pyramidal neurons and induce spine dysgenesis. ADDL treatment induced the rapid depletion of kalirin‐7, a brain‐specific guanine‐nucleotide exchange factor for the small GTPase Rac1, from spines. Kalirin‐7 is a key regulator of dendritic spine morphogenesis and maintenance in forebrain pyramidal neurons and here we show that overexpression of kalirin‐7 prevents ADDL‐induced spine degeneration. Taken together, our results suggest that kalirin‐7 may play a role in the early events leading to synapse degeneration, and its pharmacological activation may prevent or delay synapse pathology in AD.     

Dendritic morphology of neurons in medial prefrontal cortex,hippocampus, and nucleus accumbens in adult SH rats

We have studied, in spontaneously hypertensive (SH) rats at different ages (2, 4, and 8 months old), the dendritic morphological changes of the pyramidal neurons of the medial prefrontal cortex (mPFC) and hippocampus and medium spiny neurons of the nucleus accumbens (NAcc) induced by the chronic effect of high‐blood pressure. As control animals, we used Wistar‐Kioto (WK) rats. Blood pressure was measured every 2 months to confirm the increase in arterial blood pressure. Spontaneous locomotor activity was assessed, and then brains were removed to study the dendritic morphology by the Golgi‐Cox stain method followed by Sholl analysis. SH animals at 4 and 8 months of age showed decreased spine density in pyramidal neurons from the mPFC and in medium spiny cells from the NAcc. At 8 months of age as well the pyramidal neurons from the hippocampus exhibited a reduction in the number of dendritic spines. An increase in locomotion in a novel environment at all ages in the SH rats was observed. Our results indicate that high‐blood pressure alters the neuronal dendrite morphology of the mPFC, hippocampus, and NAcc. The increased locomotion behavior supports the idea that dopaminergic transmission is altered in the SH rats. This could enhance our understanding of the consequences of chronic high‐blood pressure on brain structure, which may implicate cognitive impairment in hypertensive patients. Synapse, 2010. © 2010 Wiley‐Liss, Inc.     

Altered NMDA receptor function in primary cultures of hippocampal neurons from mice lacking the Homer2 gene

N‐Methyl‐D‐Aspartate (NMDA) receptors are inhibited during acute exposure to ethanol and are involved in changes in neuronal plasticity following repeated ethanol exposure. The postsynaptic scaffolding protein Homer2 can regulate the cell surface expression of NMDA receptors in vivo, and mice with a null mutation of the Homer2 gene exhibit an alcohol‐avoiding and ‐intolerant phenotype that is accompanied by a lack of ethanol‐induced glutamate sensitization. Thus, Homer2 deletion may perturb the function or acute ethanol sensitivity of the NMDA receptor. In this study, the function and ethanol sensitivity of glutamate receptors in cultured hippocampal neurons from wild‐type (WT) and Homer2 knock‐out (KO) mice were examined at 7 and 14 days in vitro (DIV) using standard whole‐cell voltage‐clamp electrophysiology. As compared with wild‐type controls, NMDA receptor current density was reduced in cultured hippocampal neurons from Homer2 KO mice at 14 DIV, but not at 7 DIV. There were no genotype‐dependent changes in whole‐cell capacitance or in currents evoked by kainic acid. The GluN2B‐selective antagonist ifenprodil inhibited NMDA‐evoked currents to a similar extent in both wild‐type and Homer2 KO neurons and inhibition was greater at 7 versus 14 DIV. NMDA receptor currents from both WT and KO mice were inhibited by ethanol (10–100 mM) and the degree of inhibition did not differ as a function of genotype. In conclusion, NMDA receptor function, but not ethanol sensitivity, is reduced in hippocampal neurons lacking the Homer2 gene. Synapse 70:33–39, 2016. © 2015 Wiley Periodicals, Inc.     

Glutamine synthetase deficiency in murine astrocytes results in neonatal death

Glutamine synthetase (GS) is a key enzyme in the “glutamine‐glutamate cycle” between astrocytes and neurons, but its function in vivo was thus far tested only pharmacologically. Crossing GS^fl/lacZ or GS^fl/fl mice with hGFAP‐Cre mice resulted in prenatal excision of the GS^fl allele in astrocytes. “GS‐KO/A” mice were born without malformations, did not suffer from seizures, had a suckling reflex, and did drink immediately after birth, but then gradually failed to feed and died on postnatal day 3. Artificial feeding relieved hypoglycemia and prolonged life, identifying starvation as the immediate cause of death. Neuronal morphology and brain energy levels did not differ from controls. Within control brains, amino acid concentrations varied in a coordinate way by postnatal day 2, implying an integrated metabolic network had developed. GS deficiency caused a 14‐fold decline in cortical glutamine and a sevenfold decline in cortical alanine concentration, but the rising glutamate levels were unaffected and glycine was twofold increased. Only these amino acids were uncoupled from the metabolic network. Cortical ammonia levels increased only 1.6‐fold, probably reflecting reduced glutaminolysis in neurons and detoxification of ammonia to glycine. These findings identify the dramatic decrease in (cortical) glutamine concentration as the primary cause of brain dysfunction in GS‐KO/A mice. The temporal dissociation between GS^fl elimination and death, and the reciprocal changes in the cortical concentration of glutamine and alanine in GS‐deficient and control neonates indicate that the phenotype of GS deficiency in the brain emerges coincidentally with the neonatal activation of the glutamine‐glutamate and the associated alanine‐lactate cycles. © 2010 Wiley‐Liss, Inc.     

Plasticity of L‐type Ca2+ channels after cocaine withdrawal

Increased reactivity of certain frontal cortical brain regions to cocaine re‐exposure or drug‐associated cues in cocaine‐abstinent human addicts is linked to drug craving. Similarly, in rats tested after withdrawal from repeated cocaine exposure, cocaine or other strong excitatory stimuli produce greater activation of pyramidal neurons in the medial prefrontal cortex (mPFC). Our recent findings indicate that the increased mPFC neuronal activation depends primarily upon enhanced voltage‐sensitive Ca²⁺ influx, most likely through high‐voltage activated (HVA) L‐type Ca²⁺ channels, but the mechanism underlying the enhanced Ca²⁺ currents is unknown. In this study, we used a protein crosslinking assay to show that repeated cocaine injections, resulting in behavioral sensitization, increased total protein levels and cell surface expression of HVA‐Ca_v1.2 L‐type channels in pyramidal neurons in deep layers of the mPFC. These changes in Ca_v1.2 L‐channels were time dependent and subtype specific (i.e., differed from those observed for Ca_v1.3 L‐channels). Furthermore, we found enhanced PKA activity in the mPFC of cocaine‐sensitized rats that persisted for 21 days after withdrawal. PKA phosphorylation of L‐channels increases their activity, so Ca²⁺ currents after cocaine withdrawal could be enhanced as a result of both increased activity and number of HVA‐Ca_v1.2 L‐channels on the cell surface. By increasing the suprafiring threshold excitability of mPFC pyramidal neurons, excessive upregulation of HVA L‐channel activity and number may contribute to the cortical hyper‐responsiveness that enhances vulnerability to cocaine craving and relapse. More generally, our results are the first to demonstrate that repeated cocaine exposure alters the membrane trafficking of a voltage‐sensitive ion channel. Synapse 63:690–697, 2009. © 2009 Wiley‐Liss, Inc.     

Cellular localization of epidermal‐type and brain‐type fatty acid‐binding proteins in adult hippocampus and their response to cerebral ischemia

This study aimed at an analysis of expression of epidermal‐type and brain‐type fatty acid‐binding proteins (E‐FABP and B‐FABP, also called FABP5 and FABP7, respectively) in adult hippocampus and their potential value as neuroprotective factors after ischemic brain damage in monkey model. The immunostaining and Western blotting results show that FABP5 was mainly expressed in neurons, whereas FABP7 was primarily expressed in astrocytes and progenitors of the subgranular zone (SGZ). Interestingly, FABP5 expression in neurons increased in cornu Ammonis 1 (CA1) and remains stable within dentate gyrus (DG) after ischemia; FABP7 expression increased within both CA1 and SGZ. This indicates a potential role for FABP5 and FABP7 in intracellular fatty acid transport within different neural cells. The change in FABP5–7 expression within CA1 and DG of the adult postischemic hippocampus was compatible with previous findings of downregulation in CA1 neurons and upregulation in SGZ progenitor cells after ischemia. Altogether, the present data suggest that polyunsaturated fatty acids, such as docosahexaenoic acid, may act via FABP5 or 7 to regulate adult postischemic hippocampal neuronal antiapoptosis or neurogenesis in primates. © 2009 Wiley‐Liss, Inc.     

SHATI/NAT8L regulates neurite outgrowth via microtubule stabilization

We previously identified a new molecule, “SHATI/NAT8L,” which has an inhibitory effect on methamphetamine (METH)‐induced hyperlocomotion, sensitization, and conditioned place preference. Nevertheless, the extent of SHATI localization and its functions are only partially understood. In this study, we used the FLAG‐tag method to investigate SHATI localization. We found that SHATI was localized to microtubules when expressed in COS7 cells and cortical primary neurons. This distribution of SHATI was less apparent after cells were treated with colchicine, a tubulin polymerization inhibitor that disrupts the microtubule structure. This finding suggests that SHATI is associated with microtubule structure. Interestingly, overexpression of SHATI in COS7 cells could attenuate the colchicine‐induced decrease in acetylated microtubules, indicating that SHATI plays a role in stabilizing microtubules. Furthermore, we showed that Shati deletion impaired neurite elongation. In cortical primary neurons, neurite length and complexity in Shati‐knockout (KO) mice were significantly decreased. In pyramidal neurons in the prefrontal cortex, dendrite length and complexity were also significantly decreased in Shati‐KO mice compared with wild‐type mice. These results suggest a novel function for SHATI, which may be a new member of the microtubule‐associated protein family. © 2013 Wiley Periodicals, Inc.     

A mental retardation gene,motopsin /neurotrypsin /prss12, modulates hippocampal function and social interaction

Motopsin is a mosaic serine protease secreted from neuronal cells in various brain regions, including the hippocampus. The loss of motopsin function causes nonsyndromic mental retardation in humans and impairs long‐term memory formation in Drosophila. To understand motopsin’s function in the mammalian brain, motopsin knockout (KO) mice were generated. Motopsin KO mice did not have significant deficits in memory formation, as tested using the Morris water maze, passive avoidance and Y‐maze tests. A social recognition test showed that the motopsin KO mice had the ability to recognize two stimulator mice, suggesting normal social memory. In a social novelty test, motopsin KO mice spent a longer time investigating a familiar mouse than wild‐type (WT) mice did. In a resident–intruder test, motopsin KO mice showed prolonged social interaction as compared with WT mice. Consistent with the behavioral deficit, spine density was significantly decreased on apical dendrites, but not on basal dendrites, of hippocampal pyramidal neurons of motopsin KO mice. In contrast, pyramidal neurons at the cingulate cortex showed normal spine density. Spatial learning and social interaction induced the phosphorylation of cAMP‐responsive element‐binding protein (CREB) in hippocampal neurons of WT mice, whereas the phosphorylation of CREB was markedly decreased in mutant mouse brains. Our results indicate that an extracellular protease, motopsin, preferentially affects social behaviors, and modulates the functions of hippocampal neurons.     

Neocortical neuronal morphology in the Siberian Tiger (Panthera tigris altaica) and the clouded leopard (Neofelis nebulosa)

Despite extensive investigations of the neocortex in the domestic cat, little is known about neuronal morphology in larger felids. To this end, the present study characterized and quantified the somatodendritic morphology of neocortical neurons in prefrontal, motor, and visual cortices of the Siberian tiger (Panthera tigris altaica) and clouded leopard (Neofelis nebulosa). After neurons were stained with a modified Golgi technique (N = 194), dendritic branching and spine distributions were analyzed using computer‐assisted morphometry. Qualitatively, aspiny and spiny neurons in both species appeared morphologically similar to those observed in the domestic cat. Although the morphology of spiny neurons was diverse, with the presence of extraverted, inverted, horizontal, and multiapical pyramidal neurons, the most common variant was the typical pyramidal neuron. Gigantopyramidal neurons in the motor cortex were extremely large, confirming the observation of Brodmann ([1909] Vergleichende Lokalisationlehre der Grosshirnrinde in ihren Prinzipien dargestellt auf Grund des Zellenbaues. Leipzig, Germany: J.A. Barth), who found large somata for these neurons in carnivores in general, and felids in particular. Quantitatively, a MARSplines analysis of dendritic measures differentiated typical pyramidal neurons between the Siberian tiger and the clouded leopard with 93% accuracy. In general, the dendrites of typical pyramidal neurons were more complex in the tiger than in the leopards. Moreover, dendritic measures in tiger pyramidal neurons were disproportionally large relative to body/brain size insofar as they were nearly as extensive as those observed in much larger mammals (e.g., African elephant). Comparison of neuronal morphology in a more diverse collection of larger felids may elucidate the comparative context for the relatively large size of the pyramidal neurons observed in the present study. J. Comp. Neurol. 524:3641–3665, 2016. © 2016 Wiley Periodicals, Inc.     

Stimulation of α(2A)-adrenoceptors promotes the maturation of dendritic spines in cultured neurons of the medial prefrontal cortex

Dendritic spines are tiny protrusions along dendrites that receive excitatory synaptic inputs and compartmentalize postsynaptic responses in the mature brain. It is known that change in spine morphology is associated with brain functions such as learning and memory. α_2A-Adrenoceptors (α_2A-ARs) are highly expressed in cortical neurons and play important roles in neuronal differentiation, growth and neurotrophy. However, little is known about the role of α_2A-ARs in the maturation of dendritic spines. Here, we report that stimulation of α_2A-ARs promotes the maturation of dendritic spines in cultured neurons of the medial prefrontal cortex of rodents. Our results show that, stimulation of α_2A-ARs by guanfacine induced significantly more stubby or mushroom spines in cultured mPFC neurons, with an enlargement of the spine head size. In parallel, the expression of PSD95 (a postsynaptic protein) in guanfacine-treated neurons was enhanced, while that of synapsin (a pre-synaptic protein) kept unchanged. These effects of guanfacine were blocked by co-administered yohimbine, a non-selective α₂-AR antagonist. The present results implicate a prominent role of α_2A-ARs in regulating the maturation of dendritic spines in the mPFC.     

Neocortical neuronal morphology in the newborn giraffe (Giraffa camelopardalis tippelskirchi) and African elephant (Loxodonta africana)

Although neocortical neuronal morphology has been documented in the adult giraffe (Giraffa camelopardalis tippelskirchi) and African elephant (Loxodonta africana), no research has explored the cortical architecture in newborns of these species. To this end, the current study examined the morphology of neurons from several cortical areas in the newborn giraffe and elephant. After cortical neurons were stained with a modified Golgi technique (N = 153), dendritic branching and spine distributions were analyzed by using computer‐assisted morphometry. The results showed that newborn elephant neurons were considerably larger in terms of all dendritic and spine measures than newborn giraffe neurons. Qualitatively, neurons in the newborns appeared morphologically comparable to those in their adult counterparts. Neurons in the newborn elephant differed considerably from those observed in other placental mammals, including the giraffe, particularly with regard to the morphology of spiny projection neurons. Projection neurons were observed in both species, with a much larger variety in the elephant (e.g., flattened pyramidal, nonpyramidal multipolar, and inverted pyramidal neurons). Although local circuit neurons (i.e., interneurons, neurogliaform, Cajal–Retzius neurons) resembled those observed in other eutherian mammals, these were usually spiny, which contrasts with their adult, aspiny equivalents. Newborn projection neurons were smaller than the adult equivalents in both species, but newborn interneurons were approximately the same size as their adult counterparts. Cortical neuromorphology in the newborn giraffe is thus generally consistent with what has been observed in other cetartiodactyls, whereas newborn and adult elephant morphology appears to deviate substantially from what is commonly observed in other placental mammals. J. Comp. Neurol. 524:257–287, 2016. © 2015 Wiley Periodicals, Inc.     

Effect of brain‐derived neurotrophic factor haploinsufficiency on stress‐induced remodeling of hippocampal neurons

Chronic restraint stress (CRS) induces the remodeling (i.e., retraction and simplification) of the apical dendrites of hippocampal CA3 pyramidal neurons in rats, suggesting that intrahippocampal connectivity can be affected by a prolonged stressful challenge. Since the structural maintenance of neuronal dendritic arborizations and synaptic connectivity requires neurotrophic support, we investigated the potential role of brain derived neurotrophic factor (BDNF), a neurotrophin enriched in the hippocampus and released from neurons in an activity‐dependent manner, as a mediator of the stress‐induced dendritic remodeling. The analysis of Golgi‐impregnated hippocampal sections revealed that wild type (WT) C57BL/6 male mice showed a similar CA3 apical dendritic remodeling in response to three weeks of CRS to that previously described for rats. Haploinsufficient BDNF mice (BDNF^±) did not show such remodeling, but, even without CRS, they presented shorter and simplified CA3 apical dendritic arbors, like those observed in stressed WT mice. Furthermore, unstressed BDNF^± mice showed a significant decrease in total hippocampal volume. The dendritic arborization of CA1 pyramidal neurons was not affected by CRS or genotype. However, only in WT mice, CRS induced changes in the density of dendritic spine shape subtypes in both CA1 and CA3 apical dendrites. These results suggest a complex role of BDNF in maintaining the dendritic and spine morphology of hippocampal neurons and the associated volume of the hippocampal formation. The inability of CRS to modify the dendritic structure of CA3 pyramidal neurons in BDNF^± mice suggests an indirect, perhaps permissive, role of BDNF in mediating hippocampal dendritic remodeling. © 2010 Wiley‐Liss, Inc.