- Persistence of Long-Term Memory Storage Requires a Late Protein Synthesis- and BDNF- Dependent Phase in the Hippocampus
Pedro Bekinschtein, Martín Cammarota1, Lionel Müller Igaz1, Lia R.M. Bevilaqua, Iván Izquierdo, and Jorge H. Medina
- Neuron, Volume 53, Issue 2, 261-277, 18 January 2007
Behavioral Test Used to Measure Long Term Memory (LTM)
- Inhibitory Avoidance (IA) task was used to measure LTM formation and persistence
- Inhibitory Avoidance
- Subject is placed on a platform in testing apparatus for pretraining
- Subject explores platform then steps onto and external grid
- External grid delivers a 3 second mild foot shock
- Subject given an opportunity to explore apparatus again at a later date (test trial)
- LTM associated with time spent on platform before stepping onto grid in 2nd test
Experiment
- Substance Infused
- Ani is a protein synthesis inhibitor known to block LTM formation by interfering with peptidyl transferase (S80 ribosomal system)
Ani time of infusion into dorsal hippocampus CA1 region (units: hours after IA pretraining) and +/- result for amnesia during test trial measured 2 days later and 7 days later
Ani administration time
(hours after IA pretraining) | induced amnesia
2 days later | induced amnesia
7 days later
|
| 24 h | no | no
|
| 12 h | no | yes
|
| 9 h | no | no
|
| 3 h | yes | yes
|
| 0 h | yes | yes
|
- anti-BDNF antibodies: knocks out BDNF function in a rapid and transiet manner. Using anti-BDNF antibodies with the same parameters as above yielded the same results as above
- antisense oligonucleotide (ASO): binds mRNA and blocks BDNF expression. Using ASO with the same parameters as above yielded the same results as above. Human recombinant BDNF restored normal LTM.
- c-Fos immediate early gene (IEG): a transcription factor associated with recent synapitc activity, placticity , and memory formation. IEG was present during LTM formation.
- Dopamine Controls Persistence of Long-Term Memory Storage
Janine I. Rossato, Lia R. M. Bevilaqua, Iván Izquierdo, Jorge H. Medina, Martín Cammarota
- Science 21 August 2009: Vol. 325. no. 5943, pp. 1017 - 1020
- SCH23390 (SCH#): is a dopamine D1 receptor antagonist. SCH# induces amnesia at 7 and 14 days but not 2 days later when given 12 hours after IA training. SCH# does not induce amnesia when given between 0 - 9 hours post IA training.
- SKF38393 (SKF#): is a dopamine D1 receptor agonist. SKF# enhanced LTM formation when given 12 hours post IA training and was most evident at 7 and 14 days.
- SCH# did not interrupt immediate encoding of IA behavioral memory (as shown by 0 h administration); rats remembered the shock at 2, 7, and 14 days just as wel as controls.
- SCH# and SKF# coinfusion had the same effects as SCH# (antagonist) infusion alone. This indicates that the antagonist trumped the agonist.
- Hippocampal D1 receptors are coupled to cAMP-PKA. Subjects given 8Br-cAMP at 0 hours, increased LTM persistance at 2, 7, and 14 days post IA training. Subjects given 8Br-cAMP at 12 hours post IA benefited at 7 and 14 days and had no difference from controls at 2 days post IA.
- PKA inhibitor reversed the efects of 8Br-cAMP. SKF# did not re-reverse this effect
- Hippocampal DBNF is downstream of D1 dopamine receptor activation
- The Ventral Tegmenta Area (VTA) gates relevant information into the LTM through a D1/D5 mechanism. VTA is run by NMDA receptors that establish persistant behaviors by inducing burst discharge of dopamine receptors
- NMDAR antagonists administered to the VTA at 12 hours post IA hindered LTM at 14 days but not 2 days later.