The function of the amyloid precursor protein (APP) is not fully understood, but its cleavage product amyloid beta (Aβ) together with neurofibrillary tangles constitute the hallmarks of Alzheimer's ...disease (AD). Yet, imbalance of excitatory and inhibitory neurotransmission accompanied by loss of synaptic functions, has been reported much earlier and independent of any detectable pathological markers. Recently, soluble APP fragments have been shown to bind to presynaptic GABA
receptors (GABA
Rs), subsequently decreasing the probability of neurotransmitter release. In this body of work, we were able to show that overexpression of wild-type human APP in mice (hAPP
) causes early cognitive impairment, neuronal loss, and electrophysiological abnormalities in the absence of amyloid plaques and at very low levels of Aβ. hAPP
mice exhibited neuronal overexcitation that was evident in EEG and increased long-term potentiation (LTP). Overexpression of hAPP
did not alter GABAergic/glutamatergic receptor components or GABA production ability. Nonetheless, we detected a decrease of GABA but not glutamate that could be linked to soluble APP fragments, acting on presynaptic GABA
Rs and subsequently reducing GABA release. By using a specific presynaptic GABA
R antagonist, we were able to rescue hyperexcitation in hAPP
animals. Our results provide evidence that APP plays a crucial role in regulating inhibitory neurotransmission.
Trigeminal neuralgia (TN) is a unique pain disorder characterized by intense paroxysmal facial pain within areas innervated by the trigeminal nerve. Although most cases of TN are sporadic, familial ...clusters of TN suggest that genetic factors may contribute to this disorder. Whole-exome sequencing in patients with TN reporting positive family history demonstrated a spectrum of variants of ion channels including TRP channels. Here, we used patch-clamp analysis and Ca
and Na
imaging to assess a rare variant in the TRPM7 channel, p.Ala931Thr, within transmembrane domain 3, identified in a man suffering from unilateral TN. We showed that A931T produced an abnormal inward current carried by Na
and insensitive to the pore blocker Gd
. Hypothesizing that replacement of the hydrophobic alanine at position 931 with the more polar threonine destabilizes a hydrophobic ring, near the voltage sensor domain, we performed alanine substitutions of F971 and W972 and obtained results suggesting a role of A931-W972 hydrophobic interaction in S3-S4 hydrophobic cleft stability. Finally, we transfected trigeminal ganglion neurons with A931T channels and observed that expression of this TRPM7 variant lowers current threshold and resting membrane potential, and increases evoked firing activity in TG neurons. Our results support the notion that the TRPM7-A931T mutation located in the S3 segment at the interface with the transmembrane region S4, generates an omega current that carries Na
influx in physiological conditions. A931T produces hyperexcitability and a sustained Na
influx in trigeminal ganglion neurons that may underlie pain in this kindred with trigeminal neuralgia.
Group I metabotropic glutamate receptors, in particular mGluR5, have been implicated in various forms of synaptic plasticity that are believed to underlie declarative memory. We observed that mGluR5 ...specifically activated a channel containing TRPC1, an isoform of the canonical family of transient receptor potential (TRPC) channels highly expressed in CA1-3 regions of the hippocampus. TRPC1 is able to form tetrameric complexes with TRPC4 and/or TRPC5 isoforms. TRPC1/4/5 complexes have recently been involved in the efficiency of synaptic transmission in the hippocampus. We therefore used a mouse model devoid of TRPC1 expression to investigate the involvement of mGluR5-TRPC1 pathway in synaptic plasticity and memory formation.
mice showed alterations in spatial working memory and fear conditioning. Activation of mGluR increased synaptic excitability in neurons from WT but not from
mice. LTP triggered by a theta burst could not maintain over time in brain slices from
mice. mGluR-induced LTD was also impaired in these mice. Finally, acute inhibition of TRPC1 by Pico145 on isolated neurons or on brain slices mimicked the genetic depletion of
and inhibited mGluR-induced entry of cations and subsequent effects on synaptic plasticity, excluding developmental or compensatory mechanisms in
mice. In summary, our results indicate that TRPC1 plays a role in synaptic plasticity and spatial working memory processes.
Group I metabotropic glutamate receptors (mGluR) are involved in various forms of synaptic plasticity that are believed to underlie declarative memory. We previously showed that mGluR5 specifically ...activates channels containing TRPC1, an isoform of the canonical family of Transient Receptor Potential channels highly expressed in the CA1-3 regions of the hippocampus. Using a tamoxifen-inducible conditional knockout model, we show here that the acute deletion of the
gene alters the extinction of spatial reference memory. mGluR-induced long-term depression, which is partially responsible for memory extinction, was impaired in these mice. Similar results were obtained in vitro and in vivo by inhibiting the channel by its most specific inhibitor, Pico145. Among the numerous known postsynaptic pathways activated by type I mGluR, we observed that the deletion of
impaired the activation of ERK1/2 and the subsequent expression of Arc, an immediate early gene that plays a key role in AMPA receptors endocytosis and subsequent long-term depression.
Key points
Increase in blood pressure in the renal afferent arteriole is known to induce an increase in cytosolic calcium concentration (Ca2+i) of juxtaglomerular (JG) cells and to result in a ...decreased secretion of renin.
Mechanical stimulation of As4.1 JG cells induces an increase in Ca2+i that is inhibited by HC067047 and RN1734, two inhibitors of TRPV4, or by siRNA‐mediated repression of TRPV4.
Inhibition of TRPV4 impairs pressure‐induced decrease in renin secretion.
Compared to wild‐type mice, Trpv4−/− mice present increased resting plasma levels of renin and aldosterone and present a significantly altered pressure–renin relationship.
We suggest that TRPV4 channel participates in mechanosensation at the juxtaglomerular apparatus.
The renin–angiotensin system is a crucial blood pressure regulation system. It consists of a hormonal cascade where the rate‐limiting enzyme is renin, which is secreted into the blood flow by renal juxtaglomerular (JG) cells in response to low pressure in the renal afferent arteriole. In contrast, an increase in blood pressure results in a decreased renin secretion. This is accompanied by a transitory increase in Ca2+i of JG cells. The inverse relationship between Ca2+i and renin secretion has been called the ‘calcium paradox’ of renin release. How increased pressure induces a Ca2+i transient in JG cells, is however, unknown. We observed that Ca2+i transients induced by mechanical stimuli in JG As4.1 cells were completely abolished by HC067047 and RN1734, two inhibitors of TRPV4. They were also reduced by half by siRNA‐mediated repression of TRPV4 but not after repression or inhibition of TRPV2 or Piezo1 ion channels. Interestingly, the stimulation of renin secretion by the adenylate cyclase activator forskolin was totally inhibited by cyclic stretching of the cells. This effect was mimicked by stimulation with GSK1016790A and 4αPDD, two activators of TRPV4 and inhibited in the presence of HC067047. Moreover, in isolated perfused kidneys from Trpv4−/− mice, the pressure–renin relationship was significantly altered. In vivo, Trpv4−/− mice presented increased plasma levels of renin and aldosterone compared to wild‐type mice. Altogether, our results suggest that TRPV4 is involved in the pressure‐induced entry of Ca2+ in JG cells, which inhibits renin release and allows the negative feedback regulation on blood pressure.
Key points
Increase in blood pressure in the renal afferent arteriole is known to induce an increase in cytosolic calcium concentration (Ca2+i) of juxtaglomerular (JG) cells and to result in a decreased secretion of renin.
Mechanical stimulation of As4.1 JG cells induces an increase in Ca2+i that is inhibited by HC067047 and RN1734, two inhibitors of TRPV4, or by siRNA‐mediated repression of TRPV4.
Inhibition of TRPV4 impairs pressure‐induced decrease in renin secretion.
Compared to wild‐type mice, Trpv4−/− mice present increased resting plasma levels of renin and aldosterone and present a significantly altered pressure–renin relationship.
We suggest that TRPV4 channel participates in mechanosensation at the juxtaglomerular apparatus.
The postsynaptic inhibition through GABA
receptors (GABA
R) relies on two mechanisms, a shunting effect due to an increase in the postsynaptic membrane conductance and, in mature neurons, a ...hyperpolarization effect due to an entry of chloride into postsynaptic neurons. The second effect requires the action of the K
-Cl
cotransporter KCC2 which extrudes Cl
from the cell and maintains its cytosolic concentration very low. Neuronal chloride equilibrium seems to be dysregulated in several neurological and psychiatric conditions such as epilepsy, anxiety, schizophrenia, Down syndrome, or Alzheimer's disease. In the present study, we used the KCC2 Cre-lox knockdown system to investigate the role of KCC2 in synaptic plasticity and memory formation in adult mice. Tamoxifen-induced conditional deletion of KCC2 in glutamatergic neurons of the forebrain was performed at 3 months of age and resulted in spatial and nonspatial learning impairment. On brain slices, the stimulation of Schaffer collaterals by a theta burst induced long-term potentiation (LTP). The lack of KCC2 did not affect potentiation of field excitatory postsynaptic potentials (fEPSP) measured in the stratum radiatum (dendrites) but increased population spike (PS) amplitudes measured in the CA1 somatic layer, suggesting a reinforcement of the EPSP-PS potentiation, i.e., an increased ability of EPSPs to generate action potentials. At the cellular level, KCC2 deletion induced a positive shift in the reversal potential of GABA
R-driven Cl
currents (E
), suggesting an intracellular accumulation of chloride subsequent to the downregulation of KCC2. After treatment with bumetanide, an antagonist of the Na
-K
-Cl
cotransporter NKCC1, spatial memory impairment, chloride accumulation, and EPSP-PS potentiation were rescued in mice lacking KCC2. The presented results emphasize the importance of chloride equilibrium and GABA-inhibiting ability in synaptic plasticity and memory formation.
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