Precocious emergence of cognitive and synaptic dysfunction in 3xTg-AD mice exposed prenatally to ethanol.

Alzheimer's disease (AD) is the most common cause of dementia, affecting approximately 50 million people worldwide. Early life risk factors for AD, including prenatal exposures, remain underexplored. Exposure of the fetus to alcohol (ethanol) is not uncommon during pregnancy, and may result in physical, behavioral, and cognitive changes that are first detected during childhood but result in lifelong challenges. Whether or not prenatal ethanol exposure may contribute to Alzheimer's disease risk is not yet known. Here we exposed a mouse model of Alzheimer's disease (3xTg-AD), bearing three dementia-associated transgenes, presenilin1 (PS1M146V), human amyloid precursor protein (APPSwe), and human tau (TauP301S), to ethanol on gestational days 13.5-16.5 using an established binge-type maternal ethanol exposure paradigm. We sought to investigate whether prenatal ethanol exposure resulted in a precocious onset or increased severity of AD progression, or both. We found that a brief binge-type gestational exposure to ethanol during a period of peak neuronal migration to the developing cortex resulted in an earlier onset of spatial memory deficits and behavioral inflexibility in the progeny, as assessed by performance on the modified Barnes maze task. The observed cognitive changes coincided with alterations to both GABAergic and glutamatergic synaptic transmission in layer V/VI neurons, diminished GABAergic interneurons, and increased ß-amyloid accumulation in the medial prefrontal cortex. These findings provide the first preclinical evidence for prenatal ethanol exposure as a potential factor for modifying the onset of AD-like behavioral dysfunction and set the groundwork for more comprehensive investigations into the underpinnings of AD-like cognitive changes in individuals with fetal alcohol spectrum disorders.

L-Type Calcium Channels Contribute to Ethanol-Induced Aberrant Tangential Migration of Primordial Cortical GABAergic Interneurons in the Embryonic Medial Prefrontal Cortex.

Exposure of the fetus to alcohol (ethanol) via maternal consumption during pregnancy can result in fetal alcohol spectrum disorders (FASD), hallmarked by long-term physical, behavioral, and intellectual abnormalities. In our preclinical mouse model of FASD, prenatal ethanol exposure disrupts tangential migration of corticopetal GABAergic interneurons (GINs) in the embryonic medial prefrontal cortex (mPFC). We postulated that ethanol perturbed the normal pattern of tangential migration via enhancing GABAA receptor-mediated membrane depolarization that prevails during embryonic development in GABAergic cortical interneurons. However, beyond this, our understanding of the underlying mechanisms is incomplete. Here, we tested the hypothesis that the ethanol-enhanced depolarization triggers downstream an increase in high-voltage-activated nifedipine-sensitive L-type calcium channel (LTCC) activity and provide evidence implicating calcium dynamics in the signaling scheme underlying the migration of embryonic GINs and its aberrance. Tangentially migrating Nkx2.1+ GINs expressed immunoreactivity to Cav1.2, the canonical neuronal isoform of the L-type calcium channel. Prenatal ethanol exposure did not alter its protein expression profile in the embryonic mPFC. However, exposing ethanol concomitantly with the LTCC blocker nifedipine prevented the ethanol-induced aberrant migration both in vitro and in vivo In addition, whole-cell patch clamp recording of LTCCs in GINs migrating in embryonic mPFC slices revealed that acutely applied ethanol potentiated LTCC activity in migrating GINs. Based on evidence reported in the present study, we conclude that calcium is an important intracellular intermediary downstream of GABAA receptor-mediated depolarization in the mechanistic scheme of an ethanol-induced aberrant tangential migration of embryonic GABAergic cortical interneurons.

Prenatal Exposure to Ethanol Alters Synaptic Activity in Layer V/VI Pyramidal Neurons of the Somatosensory Cortex.

Fetal alcohol spectrum disorder (FASD) encompasses a range of cognitive and behavioral deficits, with aberrances in the function of cerebral cortical pyramidal neurons implicated in its pathology. However, the mechanisms underlying these aberrances, including whether they persist well beyond ethanol exposure in utero, remain to be explored. We addressed these issues by employing a mouse model of FASD in which pregnant mice were exposed to binge-type ethanol from embryonic day 13.5 through 16.5. In both male and female offspring (postnatal day 28-32), whole-cell patch clamp recording of layer V/VI somatosensory cortex pyramidal neurons revealed increases in the frequency of excitatory and inhibitory postsynaptic currents. Furthermore, expressing channelrhodopsin in either GABAergic interneurons (Nkx2.1Cre-Ai32) or glutamatergic pyramidal neurons (Emx1IRES Cre-Ai32) revealed a shift in optically evoked paired-pulse ratio. These findings are consistent with an excitatory-inhibitory imbalance with prenatal ethanol exposure due to diminished inhibitory but enhanced excitatory synaptic strength. Prenatal ethanol exposure also altered the density and morphology of spines along the apical dendrites of pyramidal neurons. Thus, while both presynaptic and postsynaptic mechanisms are affected following prenatal exposure to ethanol, there is a prominent presynaptic component that contributes to altered inhibitory and excitatory synaptic transmission in the somatosensory cortex.

The NKCC1 antagonist bumetanide mitigates interneuronopathy associated with ethanol exposure in utero.

Prenatal exposure to ethanol induces aberrant tangential migration of corticopetal GABAergic interneurons, and long-term alterations in the form and function of the prefrontal cortex. We have hypothesized that interneuronopathy contributes significantly to the pathoetiology of fetal alcohol spectrum disorders (FASD). Activity-dependent tangential migration of GABAergic cortical neurons is driven by depolarizing responses to ambient GABA present in the cortical enclave. We found that ethanol exposure potentiates the depolarizing action of GABA in GABAergic cortical interneurons of the embryonic mouse brain. Pharmacological antagonism of the cotransporter NKCC1 mitigated ethanol-induced potentiation of GABA depolarization and prevented aberrant patterns of tangential migration induced by ethanol in vitro. In a model of FASD, maternal bumetanide treatment prevented interneuronopathy in the prefrontal cortex of ethanol exposed offspring, including deficits in behavioral flexibility. These findings position interneuronopathy as a mechanism of FASD symptomatology, and posit NKCC1 as a pharmacological target for the management of FASD.

Ethanol Exposure In Utero Disrupts Radial Migration and Pyramidal Cell Development in the Somatosensory Cortex.

Deficits in sensory processing in Fetal Alcohol Spectrum Disorders (FASD) implicate dysfunction in the somatosensory cortex. However, the effects of prenatal ethanol exposure on the development of this region await elucidation. Here, we used an established mouse model of FASD with binge-type ethanol exposure from embryonic day 13.5-16.5 to investigate the effects of prenatal ethanol exposure on pyramidal neurons in the somatosensory cortex. Specifically, we focused on the radial migration of primordial pyramidal neurons during embryonic corticogenesis and their morphology and function during active synaptogenesis in early postnatal development. We found that prenatal ethanol exposure resulted in aberrant radial migration, particularly affecting the populations of postmitotic pyramidal neurons. In addition, there was an enduring effect of prenatal ethanol exposure on glutamate-mediated synaptic transmission in layer V/VI pyramidal neurons. This persisted beyond a transient decrease in pyramidal neuron dendritic complexity that was evident only during early postnatal development. Adolescent mice exposed prenatally to ethanol also displayed decreased tactile sensitivity, as revealed by a modified adhesive tape removal assay. Our findings demonstrate the persistent effects of binge-type in utero ethanol exposure on pyramidal neuron form and function and ultimately sensory processing, the latter being reminiscent of that seen in individuals with FASD.

Chronic Gestational Exposure to Ethanol Leads to Enduring Aberrances in Cortical Form and Function in the Medial Prefrontal Cortex.

BACKGROUND: Exposure to ethanol (EtOH) in utero alters the disposition of tangentially migrating GABAergic interneurons in the fetal brain. The medial ganglionic eminence (MGE) gives rise to a large portion of cortical GABAergic interneurons, including the parvalbumin-expressing interneurons that shape and contribute to inhibitory/excitatory (I/E) balance of the intracortical circuit. Here, we investigated in the mouse medial prefrontal cortex (mPFC) the hypothesis that low levels of maternal EtOH consumption from closure of the neural tube embryonic day (E) 9.5 until birth result in an enduring interneuronopathy. METHODS: Pregnant mice were subjected to a 2% w/w EtOH consumption regimen starting at neural tube closure and ending at parturition. Neurogenesis in the MGE was assessed by 5-bromo-2-deoxyuridine (BrdU) immunofluorescence at E12.5. The count and distribution of parvalbumin-expressing interneurons were determined in adult animals, and patch clamp electrophysiology was performed to determine GABAergic function and I/E balance. Open-field behavior in adult mice was assessed to determine whether the EtOH-exposed cohort displayed a lasting alteration in exploratory behavior. RESULTS: In embryos exposed to EtOH in utero, we found increased BrdU labeling in the MGE, pointing to increased neurogenesis. Adult mice prenatally exposed to EtOH were hyperactive, and this was associated with an increase in parvalbumin-expressing GABAergic interneurons in the mPFC. In addition, prenatal EtOH exposure altered the balance between spontaneous inhibitory and excitatory synaptic input and attenuated GABAergic tone in layer V mPFC pyramidal neurons in juvenile mice. CONCLUSIONS: These findings underscore that altered migration of GABAergic interneurons contributes to the EtOH-induced aberration of cortical development and that these effects persist into adulthood as altered cortical form and function.

Persistent Interneuronopathy in the Prefrontal Cortex of Young Adult Offspring Exposed to Ethanol In Utero.

Gestational exposure to ethanol has been reported to alter the disposition of tangentially migrating GABAergic cortical interneurons, but much remains to be elucidated. Here we first established the migration of interneurons as a proximal target of ethanol by limiting ethanol exposure in utero to the gestational window when tangential migration is at its height. We then asked whether the aberrant tangential migration of GABAergic interneurons persisted as an enduring interneuronopathy in the medial prefrontal cortex (mPFC) later in the life of offspring prenatally exposed to ethanol. Time pregnant mice with Nkx2.1Cre/Ai14 embryos harboring tdTomato-fluorescent medial ganglionic eminence (MGE)-derived cortical GABAergic interneurons were subjected to a 3 day binge-type 5% w/w ethanol consumption regimen from embryonic day (E) 13.5-16.5, spanning the peak of corticopetal interneuron migration in the fetal brain. Our binge-type regimen increased the density of MGE-derived interneurons in the E16.5 mPFC. In young adult offspring exposed to ethanol in utero, this effect persisted as an increase in the number of mPFC layer V parvalbumin-immunopositive interneurons. Commensurately, patch-clamp recording in mPFC layer V pyramidal neurons uncovered enhanced GABA-mediated spontaneous and evoked synaptic transmission, shifting the inhibitory/excitatory balance toward favoring inhibition. Furthermore, young adult offspring exposed to the 3 day binge-type ethanol regimen exhibited impaired reversal learning in a modified Barnes maze, indicative of decreased PFC-dependent behavioral flexibility, and heightened locomotor activity in an open field arena. Our findings underscore that aberrant neuronal migration, inhibitory/excitatory imbalance, and thus interneuronopathy contribute to indelible abnormal cortical circuit form and function in fetal alcohol spectrum disorders. SIGNIFICANCE STATEMENT: The significance of this study is twofold. First, we demonstrate that a time-delimited binge-type ethanol exposure in utero during early gestation alters corticopetal tangential migration of GABAergic interneurons in the fetal brain. Second, our study is the first to integrate neuroanatomical, electrophysiological, and behavioral evidence that this "interneuronopathy" persists in the young adult offspring and contributes to enduring changes in (1) the distribution of parvalbumin-expressing GABAergic cortical interneurons in the medial prefrontal cortex, (2) GABA-mediated synaptic transmission that resulted in an inhibitory/excitatory synaptic imbalance, and (3) behavioral flexibility. These findings alert women of child-bearing age that fetal alcohol spectrum disorders can be rooted very early in fetal brain development, and reinforce evidence-based counseling against binge drinking even at the earliest stages of pregnancy.

Effects of ethanol exposure in utero on Cajal-Retzius cells in the developing cortex.

BACKGROUND: Prenatal exposure to ethanol exerts teratogenic effects on the developing brain. Here, we tested the hypothesis that exposure to ethanol in utero alters the disposition of Cajal-Retzius cells that play a key role in orchestrating proliferation, migration, and laminar integration of cortical neurons in the embryonic cortex. METHODS: Pregnant Ebf2-EGFP mice, harboring EGFP-fluorescent Cajal-Retzius cells, were subjected to a 2% w/w ethanol consumption regimen starting at neural tube closure and lasting throughout gestation. Genesis of Cajal-Retzius cells was assessed by means of 5-bromo-2-deoxyuridine (BrdU) immunofluorescence at embryonic day 12.5, their counts and distribution were determined between postnatal day (P)0 and P4, patch clamp electrophysiology was performed between P2 and P3 to analyze GABA-mediated synaptic activity, and open-field behavioral testing was conducted in P45-P50 adolescents. RESULTS: In Ebf2-EGFP embryos exposed to ethanol in utero, we found increased BrdU labeling and expanded distribution of Cajal-Retzius cells in the cortical hem, pointing to increased genesis and proliferation. Postnatally, we found an increase in Cajal-Retzius cell number in cortical layer I. In addition, they displayed altered patterning of spontaneous GABA-mediated synaptic barrages and enhanced GABA-mediated synaptic activity, suggesting enhanced GABAergic tone. CONCLUSIONS: These findings, together, underscore that Cajal-Retzius cells contribute to the ethanol-induced aberration of cortical development and abnormal GABAergic neurotransmission at the impactful time when intracortical circuits form.

Low concentrations of ethanol protect against synaptotoxicity induced by Aß in hippocampal neurons.

Epidemiological studies have reported a reduction in the prevalence of Alzheimer's disease in individuals that ingest low amounts of alcohol. Also, it has been found that moderate consumption of ethanol might protect against ß-amyloid (Aß) toxicity. However, the mechanism underlying its potential neuroprotection is largely unknown. In the present study, we found that ethanol improved the cognitive processes of learning and memory in 3xTgAD mice. In addition, we found that a low concentration of ethanol (equivalent to moderate ethanol consumption) decreased the binding of Aß (1 and 5 µM) to neuronal membranes and, consequently, its synaptotoxic effect in rat hippocampal and cortical neurons under acute (30 minutes) and chronic (24 hours) incubation conditions. This effect appears to be exerted by a direct action of ethanol on Aß because electron microscopy studies showed that ethanol altered the degree of Aß aggregation. The action of ethanol on Aß also prevented the peptide from perforating the neuronal membrane, as assayed with patch clamp experiments. Taken together, these results contribute to elucidating the mechanism by which low concentrations of ethanol protect against toxicity induced by Aß oligomers in primary neuronal cultures. These results may also provide an explanation for the decrease in the risk of Alzheimer's disease in people who consume moderate doses of alcohol.

Exposure to Kynurenic Acid during Adolescence Increases Sign-Tracking and Impairs Long-Term Potentiation in Adulthood.

Changes in brain reward systems are thought to contribute significantly to the cognitive and behavioral impairments of schizophrenia, as well as the propensity to develop co-occurring substance abuse disorders. Presently, there are few treatments for persons with a dual diagnosis and little is known about the neural substrates that underlie co-occurring schizophrenia and substance abuse. One goal of the present study was to determine if a change in the concentration of kynurenic acid (KYNA), a tryptophan metabolite that is increased in the brains of people with schizophrenia, affects reward-related behavior. KYNA is an endogenous antagonist of NMDA glutamate receptors and α7 nicotinic acetylcholine receptors, both of which are critically involved in neurodevelopment, plasticity, and behavior. In Experiment 1, rats were treated throughout adolescence with L-kynurenine (L-KYN), the precursor of KYNA. As adults, the rats were tested drug-free in an autoshaping procedure in which a lever was paired with food. Rats treated with L-KYN during adolescence exhibited increased sign-tracking behavior (lever pressing) when they were tested as adults. Sign-tracking is thought to reflect the lever acquiring incentive salience (motivational value) as a result of its pairing with reward. Thus, KYNA exposure may increase the incentive salience of cues associated with reward, perhaps contributing to an increase in sensitivity to drug-related cues in persons with schizophrenia. In Experiment 2, we tested the effects of exposure to KYNA during adolescence on hippocampal long-term potentiation (LTP). Rats treated with L-KYN exhibited no LTP after a burst of high-frequency stimulation that was sufficient to produce robust LTP in vehicle-treated rats. This finding represents the first demonstrated consequence of elevated KYNA concentration during development and provides insight into the basis for cognitive and behavioral deficits that result from exposure to KYNA during adolescence.

Nerve growth factor in the hippocamposeptal system: evidence for activity-dependent anterograde delivery and modulation of synaptic activity.

Neurotrophins have been implicated in regulating neuronal differentiation, promoting neuronal survival, and modulating synaptic efficacy and plasticity. The prevailing view is that, depending on the target and mode of action, most neurotrophins can be trafficked and released either anterogradely or retrogradely in an activity-dependent manner. However, the prototypic neurotrophin, nerve growth factor (NGF), is not thought to be anterogradely delivered. Here we provide the neuroanatomical substrate for an anterograde hippocamposeptal transport of NGF by demonstrating its presence in mouse hippocampal GABAergic neurons and in their hippocamposeptal axons that ramify densely and abut neurons in the medial septum/diagonal band of Broca (MS/DB). We also demonstrate an activity-dependent increase in septal NGF levels that is dependent on the pattern of intrahippocampal stimulation. In addition, we show that acute exposure to NGF, via activation of TrkA, attenuates GABA(A) receptor-mediated inhibitory synaptic currents and reduces sensitivity to exogenously applied GABA. These acute actions of NGF display cell type and functional selectivity insofar as (1) they were found in cholinergic, but not GABAergic, MS/DB neurons, and (2) glutamate-mediated excitatory synaptic activity as well as AMPA-activated current responses were unaffected. Our results advocate a novel anterograde, TrkA-mediated NGF signaling in the CNS.

GABAA receptor subunit profiles of tangentially migrating neurons derived from the medial ganglionic eminence.

During rodent corticogenesis, a sizeable subpopulation of γ-aminobutyric acid (GABA)ergic interneurons arises extracortically from the medial ganglionic eminence (MGE). These neurons progressively acquire responsiveness to GABA in the course of corticopetal tangential migration, a process regulated by ambient GABA and mediated by GABA(A) receptors. Here, we combined patch clamp electrophysiology and single-cell reverse transcription-polymerase chain reaction to examine GABA(A) receptor expression in green fluorescent MGE-derived (eGFP+) cells in telencephalic slices from gestational day 14.5 BAC-Lhx6 embryos. GABA concentration-response curves revealed lower apparent affinity and efficacy in eGFP+ cells in and around the MGE than their counterparts in the cortex. Pharmacological tests revealed subunit-selective response profiles in the MGE and cortex consistent with differential expression of GABA(A) receptor isoforms. Profiling of GABA(A) receptor subunit transcripts (α1-5, ß1-3, and γ1-3, δ) uncovered increased expression of the α1-, α2-, α5-, γ2-, and γ3-subunit messenger RNAs in the cortex. We propose that the dynamic expression of certain GABA(A) receptor subunits contributes to assembling receptor isoforms that confer functional attributes important in regulating the migration and maturation of primordial GABAergic cortical interneurons.

Acute ethanol exposure elevates muscarinic tone in the septohippocampal system.

The septohippocampal system has been implicated in the cognitive deficits associated with ethanol consumption, but the cellular basis of ethanol action awaits full elucidation. In the medial septum/diagonal band of Broca (MS/DB), a muscarinic tone, reflective of firing activity of resident cholinergic neurons, regulates that of their noncholinergic, putatively GABAergic, counterparts. Here we tested the hypothesis that ethanol alters this muscarinic tone. The spontaneous firing activity of cholinergic and noncholinergic MS/DB neurons were monitored in acute MS/DB slices from C57Bl/6 mice. Exposing the entire slice to ethanol increased firing in both cholinergic and noncholinergic neurons. However, applying ethanol focally to individual MS/DB neurons increased firing only in cholinergic neurons. The differential outcome suggested different mechanisms of ethanol action on cholinergic and noncholinergic neurons. Indeed, with bath-perfused ethanol, the muscarinic antagonist methyl scopolamine prevented the increase in firing in noncholinergic, but not cholinergic, MS/DB neurons. Thus, the effect on noncholinergic neuronal firing was secondary to ethanol's direct action of acutely increasing muscarinic tone. We propose that the acute ethanol-induced elevation of muscarinic tone in the MS/DB contributes to the altered net flow of neuronal activity in the septohippocampal system that underlies compromised cognitive function.

M1 receptors mediate cholinergic modulation of excitability in neocortical pyramidal neurons.

ACh release into the rodent prefrontal cortex is predictive of successful performance of cue detection tasks, yet the cellular mechanisms underlying cholinergic modulation of cortical function are not fully understood. Prolonged ("tonic") muscarinic ACh receptor (mAChR) activation increases the excitability of cortical pyramidal neurons, whereas transient ("phasic") mAChR activation generates inhibitory and/or excitatory responses, depending on neuron subtype. These cholinergic effects result from activation of "M1-like" mAChRs (M1, M3, and M5 receptors), but the specific receptor subtypes involved are not known. We recorded from cortical pyramidal neurons from wild-type mice and mice lacking M1, M3, and/or M5 receptors to determine the relative contribution of M1-like mAChRs to cholinergic signaling in the mouse prefrontal cortex. Wild-type neurons in layer 5 were excited by tonic mAChR stimulation, and had biphasic inhibitory followed by excitatory, responses to phasic ACh application. Pyramidal neurons in layer 2/3 were substantially less responsive to tonic and phasic cholinergic input. Cholinergic effects were largely absent in neurons from mice lacking M1 receptors, but most were robust in neurons lacking M3, M5, or both M3 and M5 receptors. The exception was tonic cholinergic suppression of the afterhyperpolarization in layer 5 neurons, which was absent in cells lacking either M1 or M3 receptors. Finally, we confirm a role for M1 receptors in behavior by demonstrating cue detection deficits in M1-lacking mice. Together, our results demonstrate that M1 receptors facilitate cue detection behaviors and are both necessary and sufficient for most direct effects of ACh on pyramidal neuron excitability.

Id2 is required for specification of dopaminergic neurons during adult olfactory neurogenesis.

Understanding the biology of adult neural stem cells has important implications for nervous system development and may contribute to our understanding of neurodegenerative disorders and their treatment. We have characterized the process of olfactory neurogenesis in adult mice lacking inhibitor of DNA binding 2(-/-) (Id2(-/-)). We found a diminished olfactory bulb containing reduced numbers of granular and periglomerular neurons with a distinct paucity of dopaminergic periglomerular neurons. While no deficiency of the stem cell compartment was detectable, migrating neuroblasts in Id2(-/-) mutant mice prematurely undergo astroglial differentiation within a disorganized rostral migratory stream. Further, when evaluated in vitro loss of Id2 results in decreased proliferation of neural progenitors and decreased expression of the Hes1 and Ascl1 (Mash1) transcription factors, known mediators of neuronal differentiation. These data support a novel role for sustained Id2 expression in migrating neural progenitors mediating olfactory dopaminergic neuronal differentiation in adult animals.

Synaptic function for the Nogo-66 receptor NgR1: regulation of dendritic spine morphology and activity-dependent synaptic strength.

In the mature nervous system, changes in synaptic strength correlate with changes in neuronal structure. Members of the Nogo-66 receptor family have been implicated in regulating neuronal morphology. Nogo-66 receptor 1 (NgR1) supports binding of the myelin inhibitors Nogo-A, MAG (myelin-associated glycoprotein), and OMgp (oligodendrocyte myelin glycoprotein), and is important for growth cone collapse in response to acutely presented inhibitors in vitro. After injury to the corticospinal tract, NgR1 limits axon collateral sprouting but is not important for blocking long-distance regenerative growth in vivo. Here, we report on a novel interaction between NgR1 and select members of the fibroblast growth factor (FGF) family. FGF1 and FGF2 bind directly and with high affinity to NgR1 but not to NgR2 or NgR3. In primary cortical neurons, ectopic NgR1 inhibits FGF2-elicited axonal branching. Loss of NgR1 results in altered spine morphologies along apical dendrites of hippocampal CA1 neurons in vivo. Analysis of synaptosomal fractions revealed that NgR1 is enriched synaptically in the hippocampus. Physiological studies at Schaffer collateral-CA1 synapses uncovered a synaptic function for NgR1. Loss of NgR1 leads to FGF2-dependent enhancement of long-term potentiation (LTP) without altering basal synaptic transmission or short-term plasticity. NgR1 and FGF receptor 1 (FGFR1) are colocalized to synapses, and mechanistic studies revealed that FGFR kinase activity is necessary for FGF2-elicited enhancement of hippocampal LTP in NgR1 mutants. In addition, loss of NgR1 attenuates long-term depression of synaptic transmission at Schaffer collateral-CA1 synapses. Together, our findings establish that physiological NgR1 signaling regulates activity-dependent synaptic strength and uncover neuronal NgR1 as a regulator of synaptic plasticity.

Ethanol consumption during early pregnancy alters the disposition of tangentially migrating GABAergic interneurons in the fetal cortex.

Consumption of alcohol (ethanol) during pregnancy can lead to developmental defects in the offspring, the most devastating being the constellation of symptoms collectively referred to as fetal alcohol syndrome (FAS). In the brain, a hallmark of FAS is abnormal cerebral cortical morphology consistent with insult during corticogenesis. Here, we report that exposure to a relatively low level of ethanol in utero (average maternal and fetal blood alcohol level of 25 mg/dl) promotes premature tangential migration into the cortical anlage of primordial GABAergic interneurons, including those originating in the medial ganglionic eminence (MGE). This ethanol-induced effect was evident in vivo at embryonic day 14.5 (E14.5) in GAD67 knock-in and BAC-Lhx6 embryos, as well as in vitro in isotypic telencephalic slice cocultures obtained from E14.5 embryos exposed to ethanol in utero. Analysis of heterotypic cocultures indicated that both cell-intrinsic and -extrinsic factors contribute to the aberrant migratory profile of MGE-derived cells. In this light, we provide evidence for an interaction between ethanol exposure in utero and the embryonic GABAergic system. Exposure to ethanol in utero elevated the ambient level of GABA and increased the sensitivity to GABA of MGE-derived cells. Our results uncovered for the first time an effect of ethanol consumption during pregnancy on the embryonic development of GABAergic cortical interneurons. We propose that ethanol exerts its effect on the tangential migration of GABAergic interneurons extrinsically by modulating extracellular levels of GABA and intrinsically by altering GABA(A) receptor function.

TrkB is necessary for pruning at the climbing fibre-Purkinje cell synapse in the developing murine cerebellum.

TrkB, the cognate receptor for brain-derived neurotrophic factor and neurotrophin-4, has been implicated in regulating synapse formation in the central nervous system. Here we asked whether TrkB plays a role in the maturation of the climbing fibre-Purkinje cell (CF-PC) synapse. In rodent cerebellum, Purkinje cells are initially innervated by multiple climbing fibres that are subsequently culled to assume the mature mono-innervated state, and whose contacts translocate from the soma to the dendrites. By employing transgenic mice hypomorphic or null for TrkB expression, our results indicated that perturbation of TrkB in the immature cerebellum resulted in ataxia, that Purkinje cells remained multiply innervated by climbing fibres beyond the normal developmental time frame, and that synaptic transmission at the parallel fibre-Purkinje cell synapse remained functionally unaltered. Mechanistically, we present evidence that attributes the persistence of multiple climbing fibre innervation to an obscured discrimination of relative strengths among competing climbing fibres. Soma-to-dendrite translocation of climbing fibre terminals was unaffected. Thus, TrkB regulates pruning but not translocation of nascent CF-PC synaptic contacts.

Cajal-Retzius cells switch from expressing gamma-less to gamma-containing GABA receptors during corticogenesis.

Cajal-Retzius cells are implicated in regulating neuronal migration and lamination during corticogenesis. In rodents, Cajal-Retzius cells are transient, being prevalent in the marginal zone of the embryonic neocortex and declining over the first two postnatal weeks. While studies have examined in postnatal neocortex the properties of GABA(A) receptors in Cajal-Retzius cells, less is known about their disposition at embryonic stages. Here, we combined patch-clamp electrophysiology and single-cell mRNA profiling to probe the expression of GABA(A) receptors in Cajal-Retzius cells. In embryonic neocortical slices, GABA elicited GABA(A) receptor-mediated current responses that were diazepam-insensitive and inhibited by Zn(2+), a pharmacological profile consistent with expression of gamma-less GABA(A) receptor isoforms. Non-Cajal-Retzius cells in the same embryonic slices, on the other hand, were robustly potentiated by diazepam and were insensitive to Zn(2+), typical of gamma-containing GABA(A) receptor isoforms, as were Cajal-Retzius cells in the postnatal neocortex. Single-cell mRNA profiling and immunohistochemistry confirmed expression of GABA(A) receptor gamma subunit transcript and protein, respectively, in individual reelin-expressing cells in the postnatal cortex but not in their embryonic counterparts. We conclude that Cajal-Retzius cells express gamma-less GABA(A) receptors at embryonic stages and switch to expressing gamma-containing GABA(A) receptor isoforms during postnatal neocortical development.