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Papers by sophie hulo

Research paper thumbnail of Enhanced Hippocampal Long-Term Potentiation and Fear Memory in Btbd9 Mutant Mice

PLoS ONE, 2012

Polymorphisms in BTBD9 have recently been associated with higher risk of restless legs syndrome (... more Polymorphisms in BTBD9 have recently been associated with higher risk of restless legs syndrome (RLS), a neurological disorder characterized by uncomfortable sensations in the legs at rest that are relieved by movement. The BTBD9 protein contains a BTB/POZ domain and a BACK domain, but its function is unknown. To elucidate its function and potential role in the pathophysiology of RLS, we generated a line of mutant Btbd9 mice derived from a commercial gene-trap embryonic stem cell clone. Btbd9 is the mouse homolog of the human BTBD9. Proteins that contain a BTB/POZ domain have been reported to be associated with synaptic transmission and plasticity. We found that Btbd9 is naturally expressed in the hippocampus of our mutant mice, a region critical for learning and memory. As electrophysiological characteristics of CA3-CA1 synapses of the hippocampus are well characterized, we performed electrophysiological recordings in this region. The mutant mice showed normal input-output relationship, a significant impairment in pre-synaptic activity, and an enhanced long-term potentiation. We further performed an analysis of fear memory and found the mutant mice had an enhanced cued and contextual fear memory. To elucidate a possible molecular basis for these enhancements, we analyzed proteins that have been associated with synaptic plasticity. We found an elevated level of dynamin 1, an enzyme associated with endocytosis, in the mutant mice. These results suggest the first identified function of Btbd9 as being involved in regulating synaptic plasticity and memory. Recent studies have suggested that enhanced synaptic plasticity, analogous to what we have observed, in other regions of the brain could enhance sensory perception similar to what is seen in RLS patients. Further analyses of the mutant mice will help shine light on the function of BTBD9 and its role in RLS.

Research paper thumbnail of Tetrodotoxin-sensitive enhancement of inhibition in CA1 pyramidal neurones by nicotine

Neuroreport, 2001

Nicotine modulates excitatory and inhibitory transmission in the hippocampus by acting on recepto... more Nicotine modulates excitatory and inhibitory transmission in the hippocampus by acting on receptors located on various cellular compartments. We report that nicotine, applied for 5± 10 min at concentrations similar to those found during smoking (0.5±5 ìM), resulted in all CA1 pyramidal neurones in a marked, phasic and tonic increase in the frequency and amplitude of spontaneous inhibitory currents. This effect was fully prevented by pre-incubation with the sodium channel blocker tetrodotoxin and was partially inhibited by the two nicotinic receptor antagonists methyllicaconitine (MLA) and dihydro-â-erythroidine (DHâE). We conclude that, under conditions found during smoking, nicotine enhances inhibitory transmission, an effect exclusively mediated through an enhancement of the ®ring rate of interneurones, without changes in spontaneous quantal release of GABA. NeuroReport 12:1351± 1354 & 2001 Lippincott Williams & Wilkins.

Research paper thumbnail of Synaptic transmission at nicotinic acetylcholine receptors in rat hippocampal organotypic cultures and slices

The Journal of Physiology, 1999

Despite its predominant role in the peripheral nervous system and particularly at the motor endpl... more Despite its predominant role in the peripheral nervous system and particularly at the motor endplate where it was first discovered, fast nicotinic cholinergic transmission has been found up to now only exceptionally in the central nervous system. One classic example is the synaptic activation of the Renshaw cell in the spinal cord, which receives a cholinergic nicotinic input from motoneurones (Eccles et al. 1954). Similarly, synaptic nicotinic potentials have been reported in brainstem vagal motoneurones (Zhang et al. 1993) and neuronal nicotinic acetylcholine receptor (nAChR) mediated responses could at least in part mediate dopamine release in the striatum (Clarke et al. 1987; Futami et al. 1995). So far, however, there has been no report of fast cholinergic transmission in mammalian cortical regions. Contrasting with this, nicotine has been shown to play a major role in modulating brain functions (Wonnacott, 1997). Recent developments in gene technology have revealed the presence in many brain areas of mRNA coding for different nicotinic receptor subtypes (Goldman et al. 1987; Sargent, 1993). Furthermore, the presence of these mRNAs correlates well with reports of the existence of specific binding sites for both ACh analogues and the selective nicotinic receptor antagonist á_bungarotoxin (á-BgTX; Clarke et al. 1985). In addition, electrophysiological studies made on dissociated hippocampal neurones have demonstrated the existence of functional nicotinic receptors and identified several types of nicotinic currents (Alkondon & Albuquerque, 1993; Albuquerque et al. 1997). Finally, strong evidence implicates nicotinic acetylcholine receptors in behaviour, learning and memory as well as in the reinforcing actions of nicotine (Role & Berg, 1996; Picciotto et al. 1998). A major issue, therefore, has been to understand whether neuronal nAChRs have purely a modulatory role, representing mainly targets for the low concentrations of nicotine that reach the brain during smoking, or whether, as found in the peripheral nervous system, they also mediate fast synaptic transmission. This is not unlikely considering the evidence showing the existence in the hippocampus of a

Research paper thumbnail of A point mutant of GAP-43 induces enhanced short-term and long-term hippocampal plasticity

European Journal of Neuroscience, 2002

The growth-associated protein GAP-43 (or neuromodulin or B-50) plays a critical role during devel... more The growth-associated protein GAP-43 (or neuromodulin or B-50) plays a critical role during development in mechanisms of axonal growth and formation of synaptic networks. At later times, GAP-43 has also been implicated in the regulation of synaptic transmission and properties of plasticity such as long-term potentiation. In a molecular approach, we have analyzed transgenic mice overexpressing different mutated forms of GAP-43 or de®cient in GAP-43 to investigate the role of the molecule in shortterm and long-term plasticity. We report that overexpression of a mutated form of GAP-43 that mimics constitutively phosphorylated GAP-43 results in an enhancement of long-term potentiation in CA1 hippocampal slices. This effect is speci®c, because LTP was affected neither in transgenic mice overexpressing mutated forms of non-phosphorylatable GAP-43 nor in GAP-43 de®cient mice. The increased LTP observed in transgenic mice expressing a constitutively phosphorylated GAP-43 was associated with an increased paired-pulse facilitation as well as an increased summation of responses during high frequency bursts. These results indicate that, while GAP-43 is not necessary for LTP induction, its phosphorylation may regulate presynaptic properties, thereby affecting synaptic plasticity and the induction of LTP.

Research paper thumbnail of Modulation of synaptic transmission by nicotine and nicotinic antagonists in hippocampus

Modulation of synaptic transmission by nicotine and nicotinic antagonists in hippocampus

Brain Research Bulletin, 1999

Using rat hippocampal slices, we studied the effects of nicotine and three antagonists of neurona... more Using rat hippocampal slices, we studied the effects of nicotine and three antagonists of neuronal nicotinic receptors on excitatory and inhibitory transmission. We report that nicotine at concentrations between 0.5 and 100 microM enhanced excitatory synaptic responses and increased the size of the presynaptic fiber volley. This effect was reproduced by three neuronal nicotinic receptor antagonists: dihydro-beta-erythroidine, methyllycaconitine and mecamylamine. In contrast, nicotine, but not nicotinic antagonists, produced a dual effect on inhibition: nicotine enhanced gamma-aminobutyric-acid A (GABA(A)) receptor-mediated synaptic responses at low concentration (0.5 microM) and blocked them at high concentration (100 microM). We conclude that the excitatory effects of nicotine are reproduced by nicotinic receptor antagonists, thereby suggesting that these effects might be mediated through receptor desensitization. These results also indicate that nicotine differentially affects GABAergic inhibition at low and high concentrations-effects that are not reproduced by antagonists.

Research paper thumbnail of Enhanced Hippocampal Long-Term Potentiation and Fear Memory in Btbd9 Mutant Mice

PLoS ONE, 2012

Polymorphisms in BTBD9 have recently been associated with higher risk of restless legs syndrome (... more Polymorphisms in BTBD9 have recently been associated with higher risk of restless legs syndrome (RLS), a neurological disorder characterized by uncomfortable sensations in the legs at rest that are relieved by movement. The BTBD9 protein contains a BTB/POZ domain and a BACK domain, but its function is unknown. To elucidate its function and potential role in the pathophysiology of RLS, we generated a line of mutant Btbd9 mice derived from a commercial gene-trap embryonic stem cell clone. Btbd9 is the mouse homolog of the human BTBD9. Proteins that contain a BTB/POZ domain have been reported to be associated with synaptic transmission and plasticity. We found that Btbd9 is naturally expressed in the hippocampus of our mutant mice, a region critical for learning and memory. As electrophysiological characteristics of CA3-CA1 synapses of the hippocampus are well characterized, we performed electrophysiological recordings in this region. The mutant mice showed normal input-output relationship, a significant impairment in pre-synaptic activity, and an enhanced long-term potentiation. We further performed an analysis of fear memory and found the mutant mice had an enhanced cued and contextual fear memory. To elucidate a possible molecular basis for these enhancements, we analyzed proteins that have been associated with synaptic plasticity. We found an elevated level of dynamin 1, an enzyme associated with endocytosis, in the mutant mice. These results suggest the first identified function of Btbd9 as being involved in regulating synaptic plasticity and memory. Recent studies have suggested that enhanced synaptic plasticity, analogous to what we have observed, in other regions of the brain could enhance sensory perception similar to what is seen in RLS patients. Further analyses of the mutant mice will help shine light on the function of BTBD9 and its role in RLS.

Research paper thumbnail of Tetrodotoxin-sensitive enhancement of inhibition in CA1 pyramidal neurones by nicotine

Neuroreport, 2001

Nicotine modulates excitatory and inhibitory transmission in the hippocampus by acting on recepto... more Nicotine modulates excitatory and inhibitory transmission in the hippocampus by acting on receptors located on various cellular compartments. We report that nicotine, applied for 5± 10 min at concentrations similar to those found during smoking (0.5±5 ìM), resulted in all CA1 pyramidal neurones in a marked, phasic and tonic increase in the frequency and amplitude of spontaneous inhibitory currents. This effect was fully prevented by pre-incubation with the sodium channel blocker tetrodotoxin and was partially inhibited by the two nicotinic receptor antagonists methyllicaconitine (MLA) and dihydro-â-erythroidine (DHâE). We conclude that, under conditions found during smoking, nicotine enhances inhibitory transmission, an effect exclusively mediated through an enhancement of the ®ring rate of interneurones, without changes in spontaneous quantal release of GABA. NeuroReport 12:1351± 1354 & 2001 Lippincott Williams & Wilkins.

Research paper thumbnail of Synaptic transmission at nicotinic acetylcholine receptors in rat hippocampal organotypic cultures and slices

The Journal of Physiology, 1999

Despite its predominant role in the peripheral nervous system and particularly at the motor endpl... more Despite its predominant role in the peripheral nervous system and particularly at the motor endplate where it was first discovered, fast nicotinic cholinergic transmission has been found up to now only exceptionally in the central nervous system. One classic example is the synaptic activation of the Renshaw cell in the spinal cord, which receives a cholinergic nicotinic input from motoneurones (Eccles et al. 1954). Similarly, synaptic nicotinic potentials have been reported in brainstem vagal motoneurones (Zhang et al. 1993) and neuronal nicotinic acetylcholine receptor (nAChR) mediated responses could at least in part mediate dopamine release in the striatum (Clarke et al. 1987; Futami et al. 1995). So far, however, there has been no report of fast cholinergic transmission in mammalian cortical regions. Contrasting with this, nicotine has been shown to play a major role in modulating brain functions (Wonnacott, 1997). Recent developments in gene technology have revealed the presence in many brain areas of mRNA coding for different nicotinic receptor subtypes (Goldman et al. 1987; Sargent, 1993). Furthermore, the presence of these mRNAs correlates well with reports of the existence of specific binding sites for both ACh analogues and the selective nicotinic receptor antagonist á_bungarotoxin (á-BgTX; Clarke et al. 1985). In addition, electrophysiological studies made on dissociated hippocampal neurones have demonstrated the existence of functional nicotinic receptors and identified several types of nicotinic currents (Alkondon & Albuquerque, 1993; Albuquerque et al. 1997). Finally, strong evidence implicates nicotinic acetylcholine receptors in behaviour, learning and memory as well as in the reinforcing actions of nicotine (Role & Berg, 1996; Picciotto et al. 1998). A major issue, therefore, has been to understand whether neuronal nAChRs have purely a modulatory role, representing mainly targets for the low concentrations of nicotine that reach the brain during smoking, or whether, as found in the peripheral nervous system, they also mediate fast synaptic transmission. This is not unlikely considering the evidence showing the existence in the hippocampus of a

Research paper thumbnail of A point mutant of GAP-43 induces enhanced short-term and long-term hippocampal plasticity

European Journal of Neuroscience, 2002

The growth-associated protein GAP-43 (or neuromodulin or B-50) plays a critical role during devel... more The growth-associated protein GAP-43 (or neuromodulin or B-50) plays a critical role during development in mechanisms of axonal growth and formation of synaptic networks. At later times, GAP-43 has also been implicated in the regulation of synaptic transmission and properties of plasticity such as long-term potentiation. In a molecular approach, we have analyzed transgenic mice overexpressing different mutated forms of GAP-43 or de®cient in GAP-43 to investigate the role of the molecule in shortterm and long-term plasticity. We report that overexpression of a mutated form of GAP-43 that mimics constitutively phosphorylated GAP-43 results in an enhancement of long-term potentiation in CA1 hippocampal slices. This effect is speci®c, because LTP was affected neither in transgenic mice overexpressing mutated forms of non-phosphorylatable GAP-43 nor in GAP-43 de®cient mice. The increased LTP observed in transgenic mice expressing a constitutively phosphorylated GAP-43 was associated with an increased paired-pulse facilitation as well as an increased summation of responses during high frequency bursts. These results indicate that, while GAP-43 is not necessary for LTP induction, its phosphorylation may regulate presynaptic properties, thereby affecting synaptic plasticity and the induction of LTP.

Research paper thumbnail of Modulation of synaptic transmission by nicotine and nicotinic antagonists in hippocampus

Modulation of synaptic transmission by nicotine and nicotinic antagonists in hippocampus

Brain Research Bulletin, 1999

Using rat hippocampal slices, we studied the effects of nicotine and three antagonists of neurona... more Using rat hippocampal slices, we studied the effects of nicotine and three antagonists of neuronal nicotinic receptors on excitatory and inhibitory transmission. We report that nicotine at concentrations between 0.5 and 100 microM enhanced excitatory synaptic responses and increased the size of the presynaptic fiber volley. This effect was reproduced by three neuronal nicotinic receptor antagonists: dihydro-beta-erythroidine, methyllycaconitine and mecamylamine. In contrast, nicotine, but not nicotinic antagonists, produced a dual effect on inhibition: nicotine enhanced gamma-aminobutyric-acid A (GABA(A)) receptor-mediated synaptic responses at low concentration (0.5 microM) and blocked them at high concentration (100 microM). We conclude that the excitatory effects of nicotine are reproduced by nicotinic receptor antagonists, thereby suggesting that these effects might be mediated through receptor desensitization. These results also indicate that nicotine differentially affects GABAergic inhibition at low and high concentrations-effects that are not reproduced by antagonists.