Protracted Postnatal Development of Inhibitory Synaptic Transmission in Rat Hippocampal Area CA1 Neurons

2000 ◽  
Vol 84 (5) ◽  
pp. 2465-2476 ◽  
Author(s):  
Akiva S. Cohen ◽  
Dean D. Lin ◽  
Douglas A. Coulter
Keyword(s):  
Synaptic Transmission ◽  
Postnatal Development ◽  
Pyramidal Neurons ◽  
Synaptic Function ◽  
Ca1 Neurons ◽  
Inhibitory Synaptic Transmission ◽  
The Third ◽  
Ca1 Pyramidal Neurons ◽  
Decay Times ◽  
And Function

In the CNS, inhibitory synaptic function undergoes profound transformation during early postnatal development. This is due to variations in the subunit composition of subsynaptic GABAA receptors (GABAARs) at differing developmental stages as well as other factors. These include changes in the driving force for chloride-mediated conductances as well as the quantity and/or cleft lifetime of released neurotransmitter. The present study was undertaken to investigate the nature and time course of developmental maturation of GABAergic synaptic function in hippocampal CA1 pyramidal neurons. In neonatal [postnatal day (P) 1–7] and immature (P8–14) CA1 neurons, miniature inhibitory postsynaptic currents (mIPSCs) were significantly larger, were less frequent, and had slower kinetics compared with mIPSCs recorded in more mature neurons. Adult mIPSC kinetics were achieved by the third postnatal week in CA1 neurons. However, despite this apparent maturation of mIPSC kinetics, significant differences in modulation of mIPSCs by allosteric agonists in adolescent (P15–21) neurons were still evident. Diazepam (1–300 nM) and zolpidem (200 nM) increased the amplitude of mIPSCs in adolescent but not adult neurons. Both drugs increased mIPSC decay times equally at both ages. These differential agonist effects on mIPSC amplitude suggest that in adolescent CA1 neurons, inhibitory synapses operate differently than adult synapses and function as if subsynaptic receptors are not fully occupied by quantal release of GABA. Rapid agonist application experiments on perisomatic patches pulled from adolescent neurons provided additional support for this hypothesis. In GABAAR currents recorded in these patches, benzodiazepine amplitude augmentation effects were evident only when nonsaturating GABA concentrations were applied. Furthermore nonstationary noise analysis of mIPSCs in P15–21 neurons revealed that zolpidem-induced mIPSC augmentation was not due to an increase in single-channel conductance of subsynaptic GABAARs but rather to an increase in the number of open channels responding to a single GABA quantum, further supporting the hypothesis that synaptic receptors may not be saturated during synaptic function in adolescent neurons. These data demonstrate that inhibitory synaptic transmission undergoes a markedly protracted postnatal maturation in rat CA1 pyramidal neurons. In the first two postnatal weeks, mIPSCs are large in amplitude, are slow, and occur infrequently. By the third postnatal week, mIPSCs have matured kinetically but retain distinct responses to modulatory drugs, possibly reflecting continued immaturity in synaptic structure and function persisting through adolescence.

scholarly journals Neuroligin3 splice isoforms shape inhibitory synaptic function in the mouse hippocampus

2020 ◽  
Vol 295 (25) ◽  
pp. 8589-8595 ◽  
Author(s):  
Motokazu Uchigashima ◽  
Ming Leung ◽  
Takuya Watanabe ◽  
Amy Cheung ◽  
Timmy Le ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Single Cell ◽  
Pyramidal Neurons ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Synaptic Activity ◽  
Dependent Manner ◽  
Splice Isoforms ◽  
Inhibitory Synaptic Transmission ◽  
Ca1 Pyramidal Neurons

Synapse formation is a dynamic process essential for the development and maturation of the neuronal circuitry in the brain. At the synaptic cleft, trans-synaptic protein–protein interactions are major biological determinants of proper synapse efficacy. The balance of excitatory and inhibitory synaptic transmission (E-I balance) stabilizes synaptic activity, and dysregulation of the E-I balance has been implicated in neurodevelopmental disorders, including autism spectrum disorders. However, the molecular mechanisms underlying the E-I balance remain to be elucidated. Here, using single-cell transcriptomics, immunohistochemistry, and electrophysiology approaches to murine CA1 pyramidal neurons obtained from organotypic hippocampal slice cultures, we investigate neuroligin (Nlgn) genes that encode a family of postsynaptic adhesion molecules known to shape excitatory and inhibitory synaptic function. We demonstrate that the NLGN3 protein differentially regulates inhibitory synaptic transmission in a splice isoform–dependent manner at hippocampal CA1 synapses. We also found that distinct subcellular localizations of the NLGN3 isoforms contribute to the functional differences observed among these isoforms. Finally, results from single-cell RNA-Seq analyses revealed that Nlgn1 and Nlgn3 are the major murine Nlgn genes and that the expression levels of the Nlgn splice isoforms are highly diverse in CA1 pyramidal neurons. Our results delineate isoform-specific effects of Nlgn genes on the E-I balance in the murine hippocampus.

scholarly journals Latrophilin-2 and latrophilin-3 are redundantly essential for parallel-fiber synapse function in cerebellum

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Roger Shen Zhang ◽  
Kif Liakath-Ali ◽  
Thomas C Südhof
Keyword(s):  
Synaptic Transmission ◽  
Purkinje Cells ◽  
Cerebellar Cortex ◽  
Pyramidal Neurons ◽  
Bergmann Glia ◽  
Parallel Fiber ◽  
Excitatory Synapses ◽  
Inhibitory Synaptic Transmission ◽  
Ca1 Pyramidal Neurons ◽  
Double Deletion

Latrophilin-2 (Lphn2) and latrophilin-3 (Lphn3) are adhesion GPCRs that serve as postsynaptic recognition molecules in CA1 pyramidal neurons of the hippocampus, where they are localized to distinct dendritic domains and are essential for different sets of excitatory synapses. Here, we studied Lphn2 and Lphn3 in the cerebellum. We show that latrophilins are abundantly and differentially expressed in the cerebellar cortex. Using conditional KO mice, we demonstrate that the Lphn2/3 double-deletion but not the deletion of Lphn2 or Lphn3 alone suppresses parallel-fiber synapses and reduces parallel-fiber synaptic transmission by ~50% without altering release probability. Climbing-fiber synapses, conversely, were unaffected. Even though ~50% of total cerebellar Lphn3 protein is expressed in Bergmann glia, Lphn3 deletion from Bergmann glia did not detectably impair excitatory or inhibitory synaptic transmission. Our studies demonstrate that Lphn2 and Lphn3 are selectively but redundantly required in Purkinje cells for parallel-fiber synapses.

scholarly journals Therapeutic Hypothermia Influences Cell Genesis and Survival in the Rat Hippocampus following Global Ischemia

2011 ◽  
Vol 31 (8) ◽  
pp. 1725-1735 ◽  
Author(s):  
Gergely Silasi ◽  
Frederick Colbourne
Keyword(s):  
Pyramidal Neurons ◽  
Granule Cells ◽  
Brdu Incorporation ◽  
Ca1 Neurons ◽  
Neuronal Nuclei ◽  
The Third ◽  
Ca1 Pyramidal Neurons ◽  
Brdu Label ◽  
Repair Mechanisms ◽  
Cell Genesis

Delayed hypothermia salvages CA1 neurons from global ischemic injury. However, the effects of this potent neuroprotectant on endogenous repair mechanisms, such as neurogenesis, have not been clearly examined. In this study, we quantified and phenotyped newly generated cells within the hippocampus following untreated and hypothermia-treated ischemia. We first show that CA1 pyramidal neurons did not spontaneously regenerate after ischemia. We then compared the level of neuroprotection when hypothermia was initiated either during or after ischemia. Treatment efficacy decreased with longer delays, but hypothermia delayed for up to 12 hours was neuroprotective. Although bromodeoxyuridine (BrdU) incorporation was elevated in ischemic groups, CA1 neurogenesis did not occur as the BrdU label did not colocalize with neuronal nuclei (NeuN) in any of the groups. Instead, the majority of BrdU-labeled cells were Iba-positive microglia, and neuroprotective hypothermia decreased the delayed generation of microglia during the third postischemic week. Conversely, hypothermia delayed for 12 hours significantly increased the survival of newly generated dentate granule cells at 4 weeks after ischemia. Thus, our findings show that CA1 neurogenesis does not contribute to hypothermic neuroprotection. Importantly, we also show that prolonged hypothermia positively interacts with postischemic repair processes, such as neurogenesis, resulting in improved functional outcome.

scholarly journals Altered synaptic transmission and maturation of hippocampal CA1 neurons in a mouse model of human chr16p11.2 microdeletion

2018 ◽  
Vol 119 (3) ◽  
pp. 1005-1018 ◽  
Author(s):  
Hung-Chi Lu ◽  
Alea A. Mills ◽  
Di Tian
Keyword(s):  
Mouse Model ◽  
Synaptic Transmission ◽  
Neurodevelopmental Disorders ◽  
Synaptic Function ◽  
Glutamatergic Synapses ◽  
Ca1 Neurons ◽  
Hippocampal Ca1 Neurons ◽  
Hippocampal Ca1 ◽  
And Function ◽  
Circuit Function

The pathophysiology of neurodevelopmental disorders is often observed early in infancy and toddlerhood. Mouse models of syndromic disorders have provided insight regarding mechanisms of action, but most studies have focused on characterization in juveniles and adults. Insight into developmental trajectories, particularly those related to circuit and synaptic function, will likely yield important information regarding disorder pathogenesis that leads to symptom progression. Chromosome 16p11.2 microdeletion is one of the most common copy number variations associated with a spectrum of neurodevelopmental disorders. Yet, how haploinsufficiency of chr16p11.2 affects early synaptic maturation and function is unknown. To address this knowledge gap, the present study focused on three key components of circuit formation and function, basal synaptic transmission, local circuit function, and maturation of glutamatergic synapses, in developing hippocampal CA1 neurons in a chr16p11.2 microdeletion mouse model. The data demonstrate increased excitability, imbalance in excitation and inhibition, and accelerated maturation of glutamatergic synapses in heterozygous deletion mutant CA1 neurons. Given the critical role of early synaptic development in shaping neuronal connectivity and circuitry formation, these newly identified synaptic abnormalities in chr16p11.2 microdeletion mice may contribute to altered developmental trajectory and function of the developing brain. NEW & NOTEWORTHY The synaptic pathophysiology underlying neurodevelopmental disorders often emerges during infancy and toddlerhood. Therefore, identifying initial changes in synaptic function is crucial for gaining a mechanistic understanding of the pathophysiology, which ultimately will facilitate the design of early interventions. Here, we investigated synaptic and local circuit properties of hippocampal CA1 neurons in a human chr16p11.2 microdeletion mouse model during early postnatal development (preweaning). The data demonstrate increased neuronal excitability, excitatory/inhibitory imbalance, and accelerated maturation of glutamatergic synapses. These perturbations in early hippocampal circuit function may underlie the early pathogenesis of the heterozygous chr16p11.2 microdeletion, which is often associated with epilepsy and intellectual disability.

scholarly journals Hypoxia Results in GABAergic Channelopathy

2005 ◽  
Vol 5 (6) ◽  
pp. 234-235 ◽  
Author(s):  
Nicholas P. Poolos
Keyword(s):  
Synaptic Transmission ◽  
Ampa Receptors ◽  
Pyramidal Neurons ◽  
Immature Brain ◽  
Fk 506 ◽  
Inhibitory Synaptic Transmission ◽  
Ca1 Pyramidal Neurons ◽  
Developing Rat ◽  
In Vivo Administration

AMPA/Kainate Receptor–mediated Downregulation of GABAergic Synaptic Transmission by Calcineurin after Seizures in the Developing Rat Brain Sanchez RM, Dai W, Levada RE, Lippman JJ, Jensen FE J Neurosci 2005;25:3442–3451 Hypoxia is the most common cause of perinatal seizures and can be refractory to conventional anticonvulsant drugs, suggesting an age-specific form of epileptogenesis. A model of hypoxia-induced seizures in immature rats reveals that seizures result in immediate activation of the phosphatase calcineurin (CaN) in area CA1 of hippocampus. After seizures, CA1 pyramidal neurons exhibit a downregulation of GABAA receptor (GABAAR)-mediated inhibition that was reversed by CaN inhibitors. CaN activation appears to be dependent on seizure-induced activation of Ca2+-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs), because the upregulation of CaN activation and GABAAR inhibition were attenuated by GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride] or Joro spider toxin. GABAAR β2/3 subunit protein was dephosphorylated at 1 h after seizures, suggesting this subunit as a possible substrate of CaN in this model. Finally, in vivo administration of the CaN inhibitor FK-506 significantly suppressed hypoxic seizures, and posttreatment with NBQX (2,3-dihydroxy-6-nitro-7-sulfonylbenzo[ f]quinoxaline) or FK-506 blocked the hypoxic seizure-induced increase in CaN expression. These data suggest that Ca2+-permeable AMPARs and CaN regulate inhibitory synaptic transmission in a novel plasticity pathway that may play a role in epileptogenesis in the immature brain.

scholarly journals Deletion of LRRTM1 and LRRTM2 in adult mice impairs basal AMPA receptor transmission and LTP in hippocampal CA1 pyramidal neurons

2018 ◽  
Vol 115 (23) ◽  
pp. E5382-E5389 ◽  
Author(s):  
Mehdi Bhouri ◽  
Wade Morishita ◽  
Paul Temkin ◽  
Debanjan Goswami ◽  
Hiroshi Kawabe ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Ampa Receptor ◽  
Pyramidal Neurons ◽  
Conditional Knockout ◽  
Synaptic Proteins ◽  
Mammalian Brain ◽  
Ca1 Pyramidal Neurons ◽  
Hippocampal Ca1 ◽  
Genetic Deletion ◽  
And Function

Leucine-rich repeat transmembrane (LRRTM) proteins are synaptic cell adhesion molecules that influence synapse formation and function. They are genetically associated with neuropsychiatric disorders, and via their synaptic actions likely regulate the establishment and function of neural circuits in the mammalian brain. Here, we take advantage of the generation of a LRRTM1 and LRRTM2 double conditional knockout mouse (LRRTM1,2 cKO) to examine the role of LRRTM1,2 at mature excitatory synapses in hippocampal CA1 pyramidal neurons. Genetic deletion of LRRTM1,2 in vivo in CA1 neurons using Cre recombinase-expressing lentiviruses dramatically impaired long-term potentiation (LTP), an impairment that was rescued by simultaneous expression of LRRTM2, but not LRRTM4. Mutation or deletion of the intracellular tail of LRRTM2 did not affect its ability to rescue LTP, while point mutations designed to impair its binding to presynaptic neurexins prevented rescue of LTP. In contrast to previous work using shRNA-mediated knockdown of LRRTM1,2, KO of these proteins at mature synapses also caused a decrease in AMPA receptor-mediated, but not NMDA receptor-mediated, synaptic transmission and had no detectable effect on presynaptic function. Imaging of recombinant photoactivatable AMPA receptor subunit GluA1 in the dendritic spines of cultured neurons revealed that it was less stable in the absence of LRRTM1,2. These results illustrate the advantages of conditional genetic deletion experiments for elucidating the function of endogenous synaptic proteins and suggest that LRRTM1,2 proteins help stabilize synaptic AMPA receptors at mature spines during basal synaptic transmission and LTP.

Age-dependent enhancement of inhibitory synaptic transmission in CA1 pyramidal neurons via GluR5 kainate receptors

Hippocampus ◽  
2009 ◽  
Vol 19 (8) ◽  
pp. 706-717 ◽  
Author(s):  
Changqing Xu ◽  
Changhai Cui ◽  
Daniel L. Alkon
Keyword(s):  
Synaptic Transmission ◽  
Pyramidal Neurons ◽  
Kainate Receptors ◽  
Inhibitory Synaptic Transmission ◽  
Ca1 Pyramidal Neurons ◽  
Age Dependent

Differential Ethanol Sensitivity of Subpopulations of GABAA Synapses Onto Rat Hippocampal CA1 Pyramidal Neurons

1997 ◽  
Vol 77 (3) ◽  
pp. 1306-1312 ◽  
Author(s):  
J. L. Weiner ◽  
C. Gu ◽  
T. V. Dunwiddie
Keyword(s):  
Synaptic Transmission ◽  
Pyramidal Neurons ◽  
Decay Rates ◽  
Receptor Subunit ◽  
Ethanol Sensitivity ◽  
Ca1 Neurons ◽  
Ca1 Pyramidal Neurons ◽  
Hippocampal Ca1 Neurons ◽  
Hippocampal Ca1 ◽  
Synaptic Responses

Weiner, J. L., C. Gu, and T. V. Dunwiddie. Differential ethanol sensitivity of subpopulations of GABAA synapses onto rat hippocampal CA1 pyramidal neurons. J. Neurophysiol. 77: 1306–1312, 1997. The actions of ethanol on γ-aminobutyric acid-A (GABAA) receptor-mediated synaptic transmission in rat hippocampal CA1 neurons remain controversial. Recent studies have reported that intoxicating concentrations of ethanol (10–100 mM) can potentiate, inhibit, or have no effect on GABAA receptor-mediated synaptic responses in this brain region. The essential determinants of ethanol sensitivity have not been defined; however, GABAA receptor subunit composition, as well as posttranslational modifications of these receptors, have been suggested as important factors in conferring ethanol sensitivity to the GABAA receptor complex. Multiple types of GABAA receptor-mediated synaptic responses have been described within individual hippocampal CA1 neurons. These responses have been shown to differ in some of their physiological and pharmacological properties. In the present study we tested the hypothesis that some of the disparate findings concerning the effects of ethanol may have resulted from differences in the ethanol sensitivity of GABAA receptor-mediated synapses on single CA1 pyramidal cells. Electrical stimulation adjacent to the stratum pyramidale (proximal) and within the stratum lacunosum-moleculare (distal) activated nonoverlapping populations of GABAA receptors on rat hippocampal CA1 neurons. Proximal inhibitory postsynaptic currents (IPSCs) decayed with a single time constant and were significantly potentiated by ethanol at all concentrations tested (40, 80, and 160 mM). Distal IPSCs had slower decay rates that were often described better by the sum of two exponentials and were significantly less sensitive to ethanol at all concentrations tested. Three other allosteric modulators of GABAA receptor function with well-defined GABAA receptor subunit requirements, pentobarbital, flunitrazepam, and zolpidem, potentiated proximal and distal GABAA IPSCs to the same extent. These results demonstrate that the ethanol sensitivity of GABAA receptors can differ, not only between brain regions but within single neurons. These findings offer a possible explanation for the conflicting results of previous studies on ethanol modulation of GABAA receptor-mediated synaptic transmission in rat hippocampal CA1 neurons.

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