How Nicotinic Signaling Shapes Neural Networks

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1 How Nicotinic Signaling Shapes Neural Networks Darwin K. Berg Division of Biological Sciences University of California, San Diego

2 Nicotinic Cholinergic Signaling Uses the transmitter ACh to activate cation-selective nicotinic receptors (ligand-gated ion channels). First understood at the neuromuscular junction. Stephen Kuffler & Bernard Katz Mediates excitatory transmission through autonomic ganglia.

3 Nicotinic Cholinergic Signaling in the CNS Heteromeric 2*-nAChRs Homomeric 7-nAChRs Two major nicotinic receptor species: block w DH E block w Bgt, MLA In the Adult: Nicotinic receptors both pre- and postsynaptically at many kinds of synapses. Thought to modulate synaptic transmission. During Development: High levels of nicotinic receptors when glutamatergic synapses are first forming and GABA is initially depolarizing (reversed Cl - gradient). Spontaneous waves of nicotinic excitation.

4 Flight Plan Nicotinic activity and the conversion of GABAergic signaling from excitation to inhibition Role of 7-nAChRs in glutamatergic synapse formation Role of β2*-nachrs in spine formation and synapse location Lasting effects of early nicotine exposure on the construction of neural networks

5 KCC2 NKCC1 7-nAChR knockout mice have an extended GABAergic excitatory phase in the hippocampus A * * Control 7 KO P6 P9 P13 B Wildtype 7 KOs P13 P13 P13 P13 NKCC1 -Tubulin P13 WT * P13 7KO C KCC2 -Tubulin Wildtype 7 KOs P6 P6 P6 P9 P9 P9 P9 P9 P P6 P9 P9 WT WT 7KO *

6 Peak of GABAergic currents (pa) Potential (mv) Adult-born 7KO neurons have delayed maturation of chloride gradients and conversion of GABA PSPs V hold WT 7KO (mv) Resting membrane potential (V rest ) and reversal potential (E GABA ) for GABA PSPs in 3-wk-old adult-born WT and 7KO neurons: ms 25 pa 25 pa WT 7KO WT 7KO 25 ms 1 WT KO * -5-8 V rest E GABA -1 Holding potential (mv)

7 spscs Frequency (Hz) spscs Amplitude (pa) Spontaneous PSCs in 3-wk-old adult-born neurons labeled by MMLV-GFP injection WT KO 1.5 * ms 25 pa WT 7KO WT 7KO PSPs in adult-born 7KO neurons are less frequent and smaller than in WT.

8 Summary 1: Nicotinic Effects on GABAergic Maturation GABAergic excitation promotes neuronal development and innervation. Endogenous activity through α7-nachrs determines when GABAergic signaling converts from excitation to inhibition. Nicotinic activity does this by increasing KCC2 and decreasing NKCC1 to make a mature chloride gradient. (Liu, Neff, & Berg, Science 26) Nicotinic activity plays a similar role in adult-born neurons. Extended period of GABAergic depolarization in 7KOs reflects inadequate development, rather than opportunity for excess innervation to occur. (Campbell, Fernandes, Halff, & Berg, J Neurosci 21)

9 Flight Plan Nicotinic activity and the conversion of GABAergic signaling from excitation to inhibition Role of 7-nAChRs in glutamatergic synapse formation Role of β2*-nachrs in spine formation and synapse location Lasting effects of early nicotine exposure on the construction of neural networks

10 EM quantification of synapses in vivo in the hippocampal CA1 at P8 Synapses per m WT 2KO 7KO 7/ 2 -dko Removal of the 7-nAChR gene causes fewer synapses to be present in P8 CA1. Endogenous nicotinic cholinergic activity apparently helps promote synapse formation during development.

11 Immunostaining of hippocampal CA1 slices for markers of glutamatergic synapses WT 7KO 5 μm 2 μm Arrows indicate examples of co-localized VGluT and PSD-95 puncta, taken to represent synaptic contacts.

12 Puncta (per 4 m 2 ) Puncta (per 4 m 2 ) Quantification of glutamatergic synapses by immunostaining 12 VGluT PSD-95 Co-local P12 Hippocampal CA1 8 * ** ** ** ** 4 12 VGluT PSD-95 Co-local P12 Visual Cortex Layer 5/6 8 4 Fewer total glutamatergic synapses in 7KOs than in WTs at P12.

13 mepsc Freq (Hz) mepsc Amp (pa) mepsc Freq (Hz) mepsc Amp (pa) Reduced mepsc frequency in 7KOs A WT 7KO 1 pa 2 pa 1 s.1 s B P C P ** * 8.4 * ** Fewer spontaneous mepscs in CA1 pyramidal neurons of 7KOs vs WTs at P12 and at P25, recorded in TTX & gabazine. Results are consistent with fewer functional glutamatergic synapses in 7KOs.

14 No decrements are seen in GABAergic synapses. WT α7ko Both 7KOs and 2KOs had WT levels of GABAergic synapses. The decrement in glutamatergic synapses found in 7KOs is not offset by an equivalent reduction in GABAergic synapses.

15 2 pa PPR 2 pa Glut/GABA PSC Decreased ratio of glutamatergic/gabaergic input in 7KO neurons C WT 7KO 2. P12 P12 P25 P25 Acute Block Acute Block mv mv -7 mv -7 mv * ** 2 ms No change in Paired-Pulse Ratio: P12 P ms Lack of 7-nAChRs during development causes neurons to receive fewer functional glutamatergic synapses, thereby changing the E/I ratio that they can receive.

16 Summary 2: α7-nachr effects on glutamatergic synapse formation Endogenous cholinergic signaling through α7-nachrs promotes glutamatergic synapse formation during early postnatal development EM, immunostaining, patch-clamping The deficits are seen both in the hippocampal CA1 and cortex layer 5/6 indicating the scope of the effect. No deficit is seen in GABAergic synapses. Neurons lacking α7-nachrs during development have a reduced ratio of glutamatergic-gabaergic input. This remains throughout development and is likely to produce substantial behavioral deficits, accounting for those reported for α7kos. (Lozada et al, J Neurosci, 212a)

17 Flight Plan Nicotinic activity and the conversion of GABAergic signaling from excitation to inhibition Role of 7-nAChRs in glutamatergic synapse formation Role of β2*-nachrs in spine formation and synapse location Lasting effects of early nicotine exposure on the construction of neural networks

18 Spines per 2 m Spine numbers depend on 2*-nAChRs (Labeled with viral-gfp construct in vivo) ----Hippocampus Cortex---- WT 2 2 2KO m WT 2KO 7KO 7/ 2 -dko WT 2KO 7KO 7/ 2 -dko Constitutive knockout of the 2-nAChR gene reduces spine numbers both in hippocampus and in cortex. Knockout of 7-nAChR has no effect on spine number.

19 Spine vs shaft synapses in CA1 at P25 WT 7KO 2KO VGluT PSD-95 Merged Thresholded 1 m Constitutive 2KOs at P25 have fewer glutamatergic synapses on spines and more on dendritic shafts in the hippocampus than do WTs.

20 Spines per 2 m Cell-autonomous effects of 2*-nAChRs on spine number (Injected lenti-rnai in vivo at P1; analyzed at P12.) 2-Scr 2 2-RNAi 1 1 m Local knockdown of 2-nAChRs reduces spine numbers in early postnates. No effect of 7-nAChR knockdown.

21 Puncta/2 m dendrite RNAi in vivo shows cell-autonomous actions of 7-nAChRs to promote glutamatergic synapse formation 7-Scr 7-RNAi 1 m 3 VGluT PSD-95 Co-Local 2 1 RNAi knockdown of 7-nAChRs in vivo shows that the receptor acts cell-autonomously to enhance glutamate synapse formation.

22 Nicotine rapidly induces spines in vivo CA1 dendrites in P7 Thy-1M-GFP mouse pups stereotaxically injected with 1 μm nicotine 1 hr earlier. Con Nic 1 m Nicotine induction of dendritic spines is rapid, requires β2*-nachrs, and is most prominent early in postnatal life.

23 Summary 3: β2*-nachrs and dendritic spines Endogenous cholinergic signaling via β2*-nachrs acts in a cell-autonomous manner to induce dendritic spines. Nicotine can induce spines quickly in vivo via β2*-nachrs; in culture the induction is mediated by calcium and CaMKII. Spine deficits on neurons lacking β2*-nachrs result in more glutamatergic synapses being located on dendritic shafts. This shift is likely to alter information processing. (Lozada et al., J Neurosci, 212b)

24 Flight Plan Nicotinic activity and the conversion of GABAergic signaling from excitation to inhibition Role of 7-nAChRs in glutamatergic synapse formation Role of β2*-nachrs in spine formation and synapse location Lasting effects of early nicotine exposure on the construction of neural networks

25 Strategy Methods: Give nicotine to pups for 2 weeks (P2-P16) via nursing on moms with nicotine from an implanted osmotic mini-pump. Analysis: Immunostain for synaptic number; patch-clamp for synaptic function. Timing: Analyze after nicotine cessation (P16) and after 2 weeks of abstinence (P3). c-fos-gfp mice: Determine if early nicotine exposure (P2- P16) commits a subpopulation of adult neurons to excessive activity.

26 Spines/2 m Spines/2 m Long-term nicotine exposure in early postnates --- P16 Hippocampus P16 Visual Cortex --- Puncta/4 m VGluT PSD-95 Co-Local Nicotine for 2 weeks in early postnatal life (P2-P16) via mother s milk increases the number of glutamatergic synapses and dendritic spines.

27 Early Nicotine Exposure Increases the Ratio of Excitatory-to-Inhibitory Input to Neurons A Control Nicotine IPSCs EPSCs Early nicotine exposure (P2-P16) increases EPSC frequency and E/I, consistent with more excitatory synapses.

28 Spines/2 m Long-term persistence of nicotine-induced changes P3 Hippocampus (Nicotine P2-P16 followed by 2 wks abstention) VGluT PSD-95 Co-Local Synaptic Input Puncta/4 m * ** * 4 2 * E to I ratio * con Nic Part of the nicotine-induced increases in synapses, spines, and E/I remain 2 weeks after stopping the nicotine (P3).

29 Use c-fos-gfp mice to identify highly active neurons High activity can induce immediate early genes, e.g. c-fos. c-fos-gfp mice display sparse populations of GFP+ neurons with high activity levels. Expose c-fos-gfp mouse pups to nicotine P2-P16. Quantify GFP+ cells: - few at P16 following the nicotine exposure. - few at P3 after 2 weeks of abstention. Try re-challenging with a shot of nicotine (IP) at P45?

30 Long-term re-programming of hyperactive cells in c-fos-gfp mice by early nicotine exposure Methods: P2 P16 P45 Nicotine or Saline Inject nicotine IP Saline Postnatal (control) Nicotine Postnatal 1 µm Early exposure to nicotine commits a large subpopulation of neurons to respond aberrantly to nicotine in the adult.

31 Summary 4: Lasting Effects of Early Nicotine Exposure Early nicotine exposure at levels found in smokers elevates the number of glutamate synapses, dendritic spines, and excitatory-to-inhibitory input during development. Some of the changes are long-lasting and produce a subset of neurons that over-react to later challenges with nicotine. Current medical practices encouraging nicotinereplacement therapy for pregnant women who smoke and e-cigarette usage need to be re-assessed. Adrian Lozada Danielle John

32 Overall Summary 1) Endogenous nicotinic activity through 7-nAChRs determines when GABA switches from excitation to inhibition both in early postnatal and in adult-born neurons. 2) Activity through 7-nAChRs increases glutamate synapses on developing neurons in a cell-autonomous manner. 3) Activity through 2-nAChRs increases dendritic spine number in a cell-autonomous manner. 4) Changing the ratio of 2- and 7-nAChR activation changes the location/type of glutamate synapses formed. 5) These changes in synapse number and location persist and likely to account for behavioral deficits in nachr KOs. 6) Early exposure to nicotine increases the number of glutamatergic synapses in a persistent manner. 7) Long-lasting effects to early nicotine exposure include retaining a propensity for excessive firing in a distributed neuronal subpopulation.

33 The People! Zhaoping Liu Rob Neff Nolan Campbell Catarina Fernandes Adrian Lozada Xulong Wang Natalia Gunko Kerri Massey Jingjing Duan Grant Support: NIH/NINDS & TRDRP Andrew Halff David Gomez-Varela Danielle John

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