TARGETING PRE-DEMENTIA SYNAPTIC MECHANISMS DURING AGING AND COGNITIVE IMPAIRMENT

Few therapeutics are available to reverse or halt cognitive impairment that leads to dementia. Synaptic dysfunction has been recognized as one of the earliest hallmarks of Alzheimer's disease (AD) and in many animal models it is not only the best correlate but also detected prior to cognitive impairment. We hypothesize that disruption of excitatory/inhibitory synaptic ratio in the basal forebrain (BF) during aging is associated with cognitive dysfunction in a pre-dementia aging model, and that therapeutic intervention should focus on resurrecting the synapses. We are using young (2–6 mon), middle aged (10–16 mon) and aged (18–24 mon) ChR2(H134)-EYFP BAC transgenic mice specific for the gamma-aminobutyric acid (GABA) transporter (VGAT) to study selective GABAergic inhibitory synaptic currents. Cognitive status is assessed in a 5 week-long modified Barnes maze protocol for spatial learning and memory, reversal learning and sensory/motor abilities. Whole cell patch electrophysiology is used in a reduced synaptic preparation from mechanically dissociated BF neurons and light (470 nm) is used to depolarize neurons and terminals. Minimum stimulation is used to study drug effects on light evoked synaptic currents. Preliminary behavioral data show mice from all age groups learned the initial position of the escape location comparably. However, when the escape location was moved to the opposite side of the maze, aged mice were significantly impaired in readjusting their learning to the new position. A subpopulation of the aged performed outside the range of young in the reversal probe trial (cognitively impaired aged group). Further, we recorded both spontaneous and light-evoked inhibitory postsynaptic potentials (IPSCs). Under conditions of reduced neurotransmitter release (with varying calcium concentrations), we were able to show that light-evoked responses can be used for estimation differences between pre- post-synaptic mechanism in the neuron. We were able to use the scores from the probe trial to define a portion of the age group that performed outside the age of the young (cognitively impaired cohort). Spontaneous and light-evoked IPSC's from these characterized animals will allows us to identify age- and sex-related mechanisms of synaptic dysfunction relative to cognitive function in a pre-dementia mouse model.