Appetitively motivated instrumental learning in SynGAP heterozygous knockout mice.

Abstract

The synaptic Ras/Rap-GTPase-activating protein (SynGAP) regulates specific intracellular events following N-methyl-d-aspartate receptor (NMDAR) activation. Here, the impact of SynGAP heterozygous knockout (SG ϩ/Ϫ ) on NMDAR-dependent functions was assessed using different positive reinforcement schedules in instrumental conditioning. The knockout did not affect the temporal control of operant responding under a fixed interval (FI) schedule, but led to a putative enhancement in response vigor and/or disinhibition. When examined on differential reinforcement of low rates of response (DRL) schedules, SG ϩ/Ϫ mice showed increased responding under DRL-4s and DRL-8s, without impairing the response efficiency (total rewards/total lever presses) because both rewarded and nonrewarded presses were elevated. Motivation was unaffected as evaluated using a progressive ratio (PR) schedule. Yet, SG ϩ/Ϫ mice persisted in responding during extinction at the end of PR training, although an equivalent phenotype was not evident in extinction learning following FI-20s training. This extinction phenotype is therefore schedule-specific and cannot be generalized to Pavlovian conditioning. In conclusion, constitutive SynGAP reduction increases vigor in the execution of learned operant behavior without compromising its temporal control, yielding effects readily distinguishable from NMDAR blockade.

Molecular and behavioral changes associated with adult hippocampus-specific SynGAP1 knockout

“…Collectively, the anomalous changes indicate that hippocampus-specific SynGAP1 loss is sufficient to alter distinct functions known to depend on NMDAR and hippocampal integrity. We have also shown that changes associated with SynGAP1 deficiency cannot be wholly attributed to its malfunction during development by demonstrating similar features with adult hippocampus SynGAP1 knockout (Komiyama et al 2002;Guo et al 2009;Muhia et al 2009Muhia et al , 2010. SynGAP1 therefore continues to play a critical role in adulthood by possibly mediating similar biochemical cascades following NMDAR activation.…”

“…The loss of Syn-GAP1 is associated with alterations in complex behavior and cognitive processes including learning and memory. We and others have recently shown that constitutive heterozygous SynGAP1 deficiency produces multiple behavioral phenotypes ranging from hyperactivity, anxiolysis, cognitive deficits, to altered sensitivity to psychomimetics (Guo et al 2009;Muhia et al 2009Muhia et al , 2010.…”

Decrease of SYNGAP1 in GABAergic cells impairs inhibitory synapse connectivity, synaptic inhibition and cognitive function

“…While its expression in glutamatergic cell is well documented114151629303132, few studies have also reported SYNGAP1 expression in GABAergic neurons173334. To confirm that SYNGAP1 is present in GABAergic neurons, we prepared dissociated neuronal cultures from E18 wild-type embryos and immunostained them for GAD67, which is the main GABA synthesizing enzyme35, and SYNGAP1 at DIV21, after the peak of synapse formation.…”

Modulation of behavior by scaffolding proteins of the post-synaptic density

“…Additional phenotypes associated with reduced SynGAP1 levels include marked hyperactivity, impairments of sensory gating, aversive conditioning, social interactions, and working memory (Guo, Hamilton, Reish, Sweatt, Miller et al, 2009), whereas anxiety is reduced (Muhia, Yee, Feldon, Markopoulos, & Knuesel, 2010). Impaired extinction of appetitive conditioning (Muhia, Feldon, Knuesel, & Yee, 2009) and increased sensitivity to thermal pain (Duarte, Duan, Nicol, Vasko, & Hingtgen, 2011) are also observed.…”

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