serotonin in learning and plasticity pt.1 immediate action
L P H N NRX N N R X N CDH RhoA/ROCK RAC1 DAG [Ca2+] camp GIRK2 P11 Gq CASK PICK1 VELI MINT-1 CaMK Ca2+ channel AC Gi mglur7 mglur5 Glutamate NMDAR L R R T M AMPAR Serotonin /2C 5-HTT SHANK GKAP SAP-97 NCAM FGFR HOMER Lesch & Waider 2012 NOS1 ( e.g. glutamate, GABA, dopamine, acetylcholine ) [Ca2+] DAG PTEN MPP3 PSD size NMDAR/AMPAR ratio LTP LTD Spine volume
serotonin or 5-hydroxytryptamine (5-HT) derived from tryptophan
serotoninergic centers in the brain stem raphe nuclei: B1 raphe pallidus B2 raphe obscurus B3 raphe magnus B5 raphe pontis B6/B8 Nu. centralis sup. B7 dorsal nu. raphe Duvernoy 2009
receptors 5HT3 is an ionotropic receptor all other 5HT receptors are G-protein linked 5HTT or SERT presynaptic transporter (reuptake) intracellular: Vesicular MonoAmine Transporters both ionpump coupled Stahl 2008
receptors Prefrontal cortex 5-HT projections Basket axon system (M fibers) Thin, varicose axon system (D fibers) hippocampus striatum CA1 TAN $ CA3 DG MSN LA Midbrain DR 5-HT2C 5-HT3 5-HT4 Amygdala BLA Pyramidal neuron GABAergic neurons PV Non-PV MR Lesch & Waider 2012
receptors presynaptic 5HT1A in raphe nuclei activation induces hyperpolarization firing rate of the 5HT neuron synthesis, turnover and release at projection area Prefrontal cortex 5-HT projections Basket axon system (M fibers) Thin, varicose axon system (D fibers) hippocampus striatum CA1 TAN $ CA3 DG MSN LA Midbrain DR 5-HT2C 5-HT3 5-HT4 Amygdala BLA Pyramidal neuron GABAergic neurons PV Non-PV MR
receptors postsynaptic 5HT1A in hippocampus mediates neuronal inhibition by binding to specific ion channels downregulated by chronic stress variation in genes associated with negative emotionality, Prefrontal anxio-depressive cortex desease spectrum striatum 5-HT projections hippocampus Basket axon system (M fibers) Thin, varicose axon system (D fibers) CA1 TAN $ CA3 DG MSN LA Midbrain DR 5-HT2C 5-HT3 5-HT4 Amygdala BLA Pyramidal neuron GABAergic neurons PV Non-PV MR
receptors postsynaptic 5HT1A in hippocampus mediates neuronal inhibition by binding to specific ion channels downregulated by chronic stress 5HT2A/C can bind to a variety of GPRCs impact on many different pathways mainly activating variation in genes associated with negative emotionality, Prefrontal anxio-depressive cortex desease spectrum striatum 5-HT projections hippocampus Basket axon system (M fibers) Thin, varicose axon system (D fibers) CA1 TAN $ CA3 DG MSN LA Midbrain DR 5-HT2C 5-HT3 5-HT4 Amygdala BLA Pyramidal neuron GABAergic neurons PV Non-PV MR
L P H N NRX N N R X N 5HT2C a) pathway b) Ca2+ release c) PSD DAG [Ca2+] camp GIRK2 CDH P11 RhoA/ROCK RAC1 Gq CASK PICK1 VELI MINT-1 CaMK Ca2+ channel AC Gi mglur7 mglur5 Glutamate NMDAR L R R T M AMPAR Serotonin /2C 5-HTT SHANK GKAP SAP-97 NCAM FGFR HOMER NOS1 ( e.g. glutamate, GABA, dopamine, acetylcholine ) [Ca2+] DAG PTEN MPP3 PSD size NMDAR/AMPAR ratio LTD LTP Spine volume
receptors 5HT1A and 5HT2A/C expressed in excitatory principal & inhibitory interneurons! different local concentrations for variation in functionality (e.g. glutamatergic pyramidal vs. GABAergic interneuron) Prefrontal cortex 5-HT projections Basket axon system (M fibers) Thin, varicose axon system (D fibers) hippocampus striatum CA1 TAN $ CA3 DG MSN LA Midbrain DR 5-HT2C 5-HT3 5-HT4 Amygdala BLA Pyramidal neuron GABAergic neurons PV Non-PV MR
receptors 5HT1A activation in pyramidal neurons of PFC: MAP2 phosphorilation MAP2-microtubule interaction microtubule stability (specifically involved with NMDA 2B subunit) Prefrontal cortex striatum 5HT2A/C counteracts these exact effects via a different pathway activating 5-HT projections hippocampus Basket axon system (M fibers) Thin, varicose axon system (D fibers) CA1 NMDAR mediated currents. MSN TAN $ LA Midbrain DR CA3 DG 5-HT2C 5-HT3 5-HT4 Amygdala BLA Pyramidal neuron GABAergic neurons PV Non-PV MR
receptors Hippocampal excitatory transmission in the Cornu Ammonis based on 3 different glutamatergic pathways. 5HT fine tuning examples: -5HT1B at axon terminals inhibit GLU release in CA1 inhibitory interneurons: -5HT2/3 stimulate GABA release -5HT1A inhibits Prefrontal cortex 5-HT projections Basket axon system (M fibers) Thin, varicose axon system (D fibers) hippocampus striatum CA1 TAN $ CA3 DG MSN LA Midbrain DR 5-HT2C 5-HT3 5-HT4 Amygdala BLA Pyramidal neuron GABAergic neurons PV Non-PV \ MR
A B C SSC GLU AMPA NMDA GLU AMPA NMDA GLU AMPA LTP AMPA 5-HTT 5-HT Raphe 5-HT 5-HT Raphe 5-HT 5-HT Raphe 5-HT GLU 5-HTT GLU GLU TCA Neonatal development TCA 5-HT transporter inactivation TCA Adult cross-modal synaptic plasticity 1 2 3 4 S1 cortex 1 2 3 4 1 2 3 4 Layer 4 barrel 5 6 5 6 5 6 5-HT neuron terminals Ventrobasal thalamus Barrel cortex Ganglion Gasseri th V sensory nerve Lesch & Waider 2012 for details see references therein
L P H N NRX N N R X N 5HT and synaptic adhesion molecules (modulating synapse formation) intracellular signaling cascades involving 5HT, GLU, neurotrophin receptors NCAMS interact with the fibroblast growth factor receptor signaling the pathway SHANKs connect neurotransmitter receptors, ion channels and other membrane to the actin cytosceleton Gq mglur7 mglur5 DAG SHANK CASK PICK1 HOMER [Ca2+] VELI GKAP MINT-1 NOS1 CaMK Ca2+ channel Glutamate NMDAR L R R T M all these path ways are connected and ultimately converge on the gene transcription ( e.g. glutamate, GABA, dopamine, machinery acetylcholine ) synthesis of structural and functional synaptic SAP-97 camp AC [Ca2+] AMPAR GIRK2 DAG CDH Gi Serotonin /2C PTEN MPP3 P11 RhoA/ROCK RAC1 5-HTT NCAM PSD size NMDAR/AMPAR ratio FGFR LTD LTP Spine volume
L P H N NRX N N R X N why did we look at all that? Lont Term Facilitation in conditioned fear response and autism-linked mutation experiments evidence supporting 5HT induced recruitment of NRXN and is implicated in long term memory formation (structural remodeling expanding synaptic connections and increasing signaling efficiency) DAG [Ca2+] CASK VELI Gq PICK1 mglur7 mglur5 MINT-1 CaMK Ca2+ channel Glutamate NMDAR L R R T M CDH camp AC P11 GIRK2 AMPAR Gi Serotonin /2C RhoA/ROCK RAC1 5-HTT SHANK GKAP SAP-97 NCAM FGFR Choi & al. 2011 Miniaci & al. 2008 HOMER NOS1 ( e.g. glutamate, GABA, dopamine, acetylcholine ) [Ca2+] DAG PTEN MPP3 PSD size NMDAR/AMPAR ratio LTP LTD Spine volume
L P H N NRX N N R X N remember where the pathways end... 5HT modulates synaptic plasticity by influencing epigenetic modification (DNA methylation, histone mod.) through microrna-facilitated transcriptional repression via 5HT receptor mediated activation of pathways converging on gene transcription Gq DAG CASK PICK1 [Ca2+] VELI MINT-1 CaMK Ca2+ channel camp AC GIRK2 CDH Gi P11 RhoA/ROCK RAC1 mglur7 mglur5 Glutamate NMDAR L R R T M AMPAR Serotonin /2C 5-HTT SHANK HOMER GKAP NOS1 SAP-97 ( e.g. glutamate, GABA, dopamine, acetylcholine ) [Ca2+] DAG PTEN MPP3 NCAM PSD size NMDAR/AMPAR ratio FGFR LTD LTP Spine volume
take home serotonin is implicated in all sorts of stuff, notably: synaptic plasticity and long term potentiation coming up serotonin and reward (Rike) serotonin pathology and role in punishment (Quentin) downstream regulation of dopamine (including serotonin glutamate interaction implicated in neurodevelopmental disorders particularly ASD - next semester) thanks